Publications by authors named "Emmanuel Sevin"

46 Publications

Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound.

Toxicol In Vitro 2021 Feb 22:105112. Epub 2021 Feb 22.

University of Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Faculté des sciences Jean Perrin, Rue Jean Souvraz SP18, F-62300 Lens, France. Electronic address:

The blood-brain barrier (BBB) is a highly restrictive barrier that preserves central nervous system homeostasis and ensures optimal brain functioning. Using BBB cell assays makes it possible to investigate whether a compound is likely to compromise BBBs functionality, thereby probably resulting in neurotoxicity. Recently, several protocols to obtain human brain-like endothelial cells (BLECs) from induced pluripotent stem cells (iPSCs) have been reported. Within the framework of the European MSCA-ITN in3 project, we explored the possibility to use an iPSC-derived BBB model to assess the effects of repeated dose treatment with chemicals, using Cyclosporine A (CsA) as a model compound. The BLECs were found to exhibit important BBB characteristics up to 15 days after the end of the differentiation and could be used to assess the effects of repeated dose treatment. Although BLECs were still undergoing transcriptional changes over time, a targeted transcriptome analysis (TempO-Seq) indicated a time and concentration dependent activation of ATF4, XBP1, Nrf2 and p53 stress response pathways under CsA treatment. Taken together, these results demonstrate that this iPSC-derived BBB model and iPSC-derived models in general hold great potential to study the effects of repeated dose exposure with chemicals, allowing personalized and patient-specific studies in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tiv.2021.105112DOI Listing
February 2021

Time-Dependent Internalization of Polymer-Coated Silica Nanoparticles in Brain Endothelial Cells and Morphological and Functional Effects on the Blood-Brain Barrier.

Int J Mol Sci 2021 Feb 6;22(4). Epub 2021 Feb 6.

Division of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Bern, Länggassstrasse 124, 3012 Bern, Switzerland.

Nanoparticle (NP)-assisted procedures including laser tissue soldering (LTS) offer advantages compared to conventional microsuturing, especially in the brain. In this study, effects of polymer-coated silica NPs used in LTS were investigated in human brain endothelial cells (ECs) and blood-brain barrier models. In the co-culture setting with ECs and pericytes, only the cell type directly exposed to NPs displayed a time-dependent internalization. No transfer of NPs between the two cell types was observed. Cell viability was decreased relatively to NP exposure duration and concentration. Protein expression of the nuclear factor ĸ-light-chain-enhancer of activated B cells and various endothelial adhesion molecules indicated no initiation of inflammation or activation of ECs after NP exposure. Differentiation of CD34+ ECs into brain-like ECs co-cultured with pericytes, blood-brain barrier (BBB) characteristics were obtained. The established endothelial layer reduced the passage of integrity tracer molecules. NP exposure did not result in alterations of junctional proteins, BBB formation or its integrity. In a 3-dimensional setup with an endothelial tube formation and tight junctions, barrier formation was not disrupted by the NPs and NPs do not seem to cross the blood-brain barrier. Our findings suggest that these polymer-coated silica NPs do not damage the BBB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915594PMC
February 2021

Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure-Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.

J Med Chem 2021 Feb 20;64(3):1593-1610. Epub 2021 Jan 20.

Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000 Lille, France.

PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates. We describe herein an extensive structure-properties relationships study allowing us to finely describe the non-linear effects of the PEG length on the physicochemical as well as the and pharmacokinetic properties of these compounds. When appending a PEG of suitable length to the TGR5 pharmacophore, we were able to identify either systemic or gut lumen-restricted TGR5 agonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01774DOI Listing
February 2021

First step to the improvement of the blood brain barrier passage of atazanavir encapsulated in sustainable bioorganic vesicles.

Int J Pharm 2020 Sep 12;587:119604. Epub 2020 Jul 12.

LG2A UMR CNRS 7378 Institut de Chimie de Picardie FR CNRS 3085, SFR Condorcet, Université de Picardie Jules Verne, 33 Rue St Leu, 80039 Amiens, France. Electronic address:

The blood - brain barrier (BBB) prevents the majority of therapeutic drugs from reaching the brain following intravenous or oral administration. In this context, polymer nanoparticles are a promising alternative to bypass the BBB and carry drugs to brain cells. Amphiphilic cyclodextrins can form self-assemblies whose nanoparticles have a 100-nm-diameter range and are thus able to encapsulate drugs for controlled release. Our goal is to propose an optimized chemical synthesis of amphiphilic cyclodextrin, which remains a challenging task which commonly leads to only a low-milligram level of the high purity compound. Such cyclodextrin derivatives were used to prepare vesicles and to study their ability to vectorize a drug through the BBB. As a result, we introduced a convergent synthesis for a family of lipophosphoramidyl permethylated β-CDs (Lip-β-CDs) with various chain lengths. It was demonstrated that mixed vesicles comprised of phosphatidylcholine (POPC) and LipCDs were able to encapsulate atazanavir (ATV), a well-known protease inhibitor used as an antiretroviral drug against HIV. We highlighted that neo-vesicles promote the penetration of ATV in endothelial cells of the BBB, presumably due to the low fusogenicity of Lip-β-CDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2020.119604DOI Listing
September 2020

GM1 Oligosaccharide Crosses the Human Blood-Brain Barrier In Vitro by a Paracellular Route.

Int J Mol Sci 2020 Apr 19;21(8). Epub 2020 Apr 19.

Department of Medical Biotechnology and Translational Medicine, University of Milano, 20122 Milano, Italy.

Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1's potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1's pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 °C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1's pharmacological potential, offering a tangible therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21082858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215935PMC
April 2020

New Lipidyl-Cyclodextrins Obtained by Ring Opening of Methyl Oleate Epoxide Using Ball Milling.

Biomolecules 2020 02 20;10(2). Epub 2020 Feb 20.

LG2A UMR CNRS 7378, Université de Picardie Jules Verne, 80039 Amiens CEDEX, France.

Bearing grafts based on fatty esters derivatives, lipidyl-cyclodextrins (L-CDs) are compounds able to form water-soluble nano-objects. In this context, bicatenary biobased lipidic-cyclodextrins of low DS were easily synthesized from a fatty ester epoxide by means of alternative methods (ball-milling conditions, use of enzymes). The ring opening reaction of methyl oleate epoxide needs ball-milling and is highly specific of cyclodextrins in solventless conditions. L-CDs are thus composed of complex mixtures that were deciphered by an extensive structural analysis using mainly mass spectrometry and NMR spectroscopy. In addition, as part of their potential use as vectors of active drugs, these products were submitted to an integrity study on in vitro model of the blood-brain-barrier (BBB) and the intestinal epithelium. No toxicity has been observed, suggesting that applications for the vectorization of active ingredients can be expected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10020339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072689PMC
February 2020

Ketone Bodies Promote Amyloid-β Clearance in a Human in Vitro Blood-Brain Barrier Model.

Int J Mol Sci 2020 Jan 31;21(3). Epub 2020 Jan 31.

Laboratoire de la Barrière Hémato-Encéphalique (LBHE), UR 2465, Université d'Artois, F-62300 Lens, France.

Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood-brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21030934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037612PMC
January 2020

Nonionotropic Action of Endothelial NMDA Receptors on Blood-Brain Barrier Permeability via Rho/ROCK-Mediated Phosphorylation of Myosin.

J Neurosci 2020 02 17;40(8):1778-1787. Epub 2020 Jan 17.

Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale U1237, PhIND, Centre Cyceron, Caen 14000, France,

Increase in blood-brain barrier (BBB) permeability is a crucial step in neuroinflammatory processes. We previously showed that N Methyl D Aspartate Receptor (NMDARs), expressed on cerebral endothelial cells forming the BBB, regulate immune cell infiltration across this barrier in the mouse. Here, we describe the mechanism responsible for the action of NMDARs on BBB permeabilization. We report that mouse CNS endothelial NMDARs display the regulatory GluN3A subunit. This composition confers to NMDARs' unconventional properties: these receptors do not induce Ca influx but rather show nonionotropic properties. In inflammatory conditions, costimulation of human brain endothelial cells by NMDA agonists (NMDA or glycine) and the serine protease tissue plasminogen activator, previously shown to potentiate NMDAR activity, induces metabotropic signaling via the Rho/ROCK pathway. This pathway leads to an increase in permeability via phosphorylation of myosin light chain and subsequent shrinkage of human brain endothelial cells. Together, these data draw a link between NMDARs and the cytoskeleton in brain endothelial cells that regulates BBB permeability in inflammatory conditions. The authors describe how NMDARs expressed on endothelial cells regulate blood-brain barrier function via myosin light chain phosphorylation and increase in permeability. They report that these non-neuronal NMDARs display distinct structural, functional, and pharmacological features than their neuronal counterparts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0969-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046331PMC
February 2020

A Miniaturized Pump Out Method for Characterizing Molecule Interaction with ABC Transporters.

Int J Mol Sci 2019 Nov 6;20(22). Epub 2019 Nov 6.

Laboratoire de la Barrière Hémato-Encéphalique (LBHE), University Artois, EA 2465, F-62300 Lens, France.

Characterizing interaction of newly synthetized molecules with efflux pumps remains essential to improve their efficacy and safety. Caco-2 cell line cultivated on inserts is widely used for measuring apparent permeability of drugs across biological barriers, and for estimating their interaction with efflux pumps such as P-gp, BCRP and MRPs. However, this method remains time consuming and expensive. In addition, detection method is required for measuring molecule passage across cell monolayer and false results can be generated if drugs concentrations used are too high as demonstrated with quinidine. For this reason, we developed a new protocol based on the use of Caco-2 cell directly seeded on 96- or 384-well plates and the use of fluorescent substrates for efflux pumps. We clearly observed that the new method reduces costs for molecule screening and leads to higher throughput compared to traditional use of Caco-2 cell model. This accelerated model could provide quick feedback regarding the molecule design during the early stage of drug discovery and therefore reduce the number of compounds to be further evaluated using the traditional Caco-2 insert method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20225529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888615PMC
November 2019

Derivation of Brain Capillary-like Endothelial Cells from Human Pluripotent Stem Cell-Derived Endothelial Progenitor Cells.

Stem Cell Reports 2019 10 5;13(4):599-611. Epub 2019 Sep 5.

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

The derivation of human brain capillary endothelial cells is of utmost importance for drug discovery programs focusing on diseases of the central nervous system. Here, we describe a two-step differentiation protocol to derive brain capillary-like endothelial cells from human pluripotent stem cells. The cells were initially differentiated into endothelial progenitor cells followed by specification into a brain capillary-like endothelial cell phenotype using a protocol that combined the induction, in a time-dependent manner, of VEGF, Wnt3a, and retinoic acid signaling pathways and the use of fibronectin as the extracellular matrix. The brain capillary-like endothelial cells displayed a permeability to lucifer yellow of 1 × 10 cm/min, a transendothelial electrical resistance value of 60 Ω cm and were able to generate a continuous monolayer of cells expressing ZO-1 and CLAUDIN-5 but moderate expression of P-glycoprotein. Further maturation of these cells required coculture with pericytes. The study presented here opens a new approach for the study of soluble and non-soluble factors in the specification of endothelial progenitor cells into brain capillary-like endothelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829749PMC
October 2019

Long survival of patients with metastatic clear cell renal cell carcinoma. Results of real life study of 344 patients.

Int J Cancer 2020 03 1;146(6):1643-1651. Epub 2019 Aug 1.

Institut de Cancérologie de l'Ouest, Angers, Nantes, France.

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32578DOI Listing
March 2020

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial.

JAMA Oncol 2019 May;5(5):623-632

Association pour la Recherche sur les Thérapeutiques Innovantes en Cancérologie, Paris, France.

Importance: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting.

Objective: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease.

Design, Setting, And Participants: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used.

Interventions: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year).

Main Outcomes And Measures: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life.

Results: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life.

Conclusions And Relevance: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease.

Trial Registration: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2018.6607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512307PMC
May 2019

Corrigendum to "Mimicking brain tissue binding in an in vitro model of the blood-brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration" [Eur. J. Pharm. Biopharm. 127 (2018) 453-461].

Eur J Pharm Biopharm 2018 12 27;133:200-202. Epub 2018 Oct 27.

Univ. Artois, EA 2465 - Blood-Brain Barrier Laboratory (LBHE), F-62300 Lens, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.10.012DOI Listing
December 2018

Sexual Disorders of Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Antiangiogenic Therapies.

Clin Genitourin Cancer 2018 10 21;16(5):369-375.e1. Epub 2018 May 21.

U1086 INSERM-UCBN "Cancers & Préventions", Normandie Université, Caen, France; Departments of Clinical Research Unit, Centre François Baclesse, Caen, France; Department of Medical Oncology, Centre François Baclesse, Caen, France. Electronic address:

Background: Targeted therapies, in particular antiangiogenic therapies (AATs), have become the standard of treatment for metastatic renal cell carcinoma (mRCC). Although common adverse effects like fatigue have been well-established, sexual disorders induced by these treatments, although often reported, have been poorly evaluated. The aim of this study was to evaluate the impact of AATs on the sexual life of patients with mRCC and the relationships with quality of life (QoL), fatigue, and biologic parameters.

Patients And Methods: This longitudinal study included patients with mRCC on first- or second-line AATs. Sexuality was evaluated by the French version of Changes in Sexual Functioning Questionnaire short-Form (CSFQ); QoL and fatigue were measured by the Functional Assessment of Cancer Therapy General (FACT-G) and the Multidimensional Fatigue Inventory (MFI-20), respectively. Biologic parameters were also assessed.

Results: Among 75 patients included in the study, 39 agreed to respond to the sexual functioning questionnaire (CSFQ). At baseline, all patients had at least 1 sexual dysfunction. No relationship with QoL, fatigue, and biologic parameters was shown. After 3 months of treatment, a decrease in at least 1 sexual dimension was observed in 69% of patients. The most affected sexual dimensions were pleasure (34%) and desire/interest (38%). No significant relationship between sexual dysfunctions and biologic parameters was found. The percentage of non-participants (50%) and the absence of a control arm are the main limitations.

Discussion: Patients with mRCC exhibit sexual dysfunction that could be increased by AATs independently of the impact on fatigue and QoL. Further studies aiming to define the role of biologic parameters like inflammatory markers and thyroid parameters are warranted.

Conclusion: Sexual disorders induced or degraded by AAT are an independent side effect that should be taken into account in oncology supportive care departments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2018.05.013DOI Listing
October 2018

Mimicking brain tissue binding in an in vitro model of the blood-brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration.

Eur J Pharm Biopharm 2018 Jun 28;127:453-461. Epub 2018 Mar 28.

Univ. Artois, EA 2465 - Blood-Brain Barrier Laboratory (LBHE), F-62300 Lens, France. Electronic address:

Assessing the rate of drug delivery to the central nervous system (CNS) in vitro has been used for decades to predict whether CNS drug candidates are likely to attain their pharmacological targets, located within the brain parenchyma, at an effective dose. The predictive value of in vitro blood-brain barrier (BBB) models is therefore frequently assessed by comparing in vitro BBB permeability, usually quoted as the endothelial permeability coefficient (P) or apparent permeability (P), to their rate of BBB permeation measured in vivo, the latter being commonly assessed in rodents. In collaboration with AstraZeneca (DMPK department, Södertälje, Sweden), the in vitro BBB permeability (P and P) of 27 marketed CNS drugs has been determined using a bovine in vitro BBB model and compared to their in vivo permeability (P), obtained by rat in-situ brain perfusion. The latter was taken from published data from Summerfield et al. (2007). This comparison confirmed previous reports, showing a strong in vitro/in vivo correlation for hydrophilic compounds, characterized by low brain tissue binding and a weak correlation for lipophilic compounds, characterized by high brain tissue binding. This observation can be explained by the influence of brain tissue binding on the uptake of drugs into the CNS in vivo and the absence of possible brain tissue binding in vitro. The use of glial cells (GC) in the in vitro BBB model to mimic brain tissue binding and the introduction of a new calculation method for in vitro BBB permeability (P) resulted in a strong correlation between the in vitro and in vivo rate of BBB permeation for the whole set of compounds. These findings might facilitate further in vitro to in vivo extrapolation for CNS drug candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.03.007DOI Listing
June 2018

Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer.

Eur Urol Focus 2016 Dec 17;2(6):642-649. Epub 2016 May 17.

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Background: Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue.

Objective: To evaluate the impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC.

Design, Setting, And Participants: This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo (n=58) and 6 mo (n=50).

Outcome Measurements And Statistical Analysis: We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient.

Results And Limitations: A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed (p<0.05) but not with objective cognitive decline. Cognitive complaints and fatigue had a significant impact on most of the domains of QoL (p<0.01). A positive correlation was found between fatigue and inflammatory markers but not with cognition. The main limitation of this study is the absence of a control group.

Conclusions: AAT induced cognitive decline in patients with mRCC independently of fatigue. These side effects affecting QoL should be better assessed in clinical trials and taken into account in routine practice.

Patient Summary: Fatigue is a well-known effect of antiangiogenic therapies (AATs) of cancer. The study performed in patients with treated metastatic renal cancer shows a decline of cognitive functions induced by AATs, such as information-processing speed or working memory, in a third of patients, independently of fatigue. Patients on AATs should be informed of these possible adverse effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2016.04.009DOI Listing
December 2016

Topical Intestinal Aminoimidazole Agonists of G-Protein-Coupled Bile Acid Receptor 1 Promote Glucagon Like Peptide-1 Secretion and Improve Glucose Tolerance.

J Med Chem 2017 05 5;60(10):4185-4211. Epub 2017 May 5.

Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.

The role of the G-protein-coupled bile acid receptor TGR5 in various organs, tissues, and cell types, specifically in intestinal endocrine L-cells and brown adipose tissue, has made it a promising therapeutical target in several diseases, especially type-2 diabetes and metabolic syndrome. However, recent studies have shown deleterious on-target effects of systemic TGR5 agonists. To avoid these systemic effects while stimulating glucagon-like peptide-1 (GLP-1) secreting enteroendocrine L-cells, we have designed TGR5 agonists with low intestinal permeability. In this article, we describe their synthesis, characterization, and biological evaluation. Among them, compound 24 is a potent GLP-1 secretagogue, has low effect on gallbladder volume, and improves glucose homeostasis in a preclinical murine model of diet-induced obesity and insulin resistance, making the proof of concept of the potential of topical intestinal TGR5 agonists as therapeutic agents in type-2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b01873DOI Listing
May 2017

Resveratrol and Grape Extract-loaded Solid Lipid Nanoparticles for the Treatment of Alzheimer's Disease.

Molecules 2017 Feb 13;22(2). Epub 2017 Feb 13.

LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, Porto 4500-465, Portugal.

The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules22020277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155722PMC
February 2017

Adjuvant Chemotherapy After Radical Cystectomy for Urothelial Bladder Cancer: Outcome and Prognostic Factors for Survival in a French Multicenter, Contemporary Cohort.

Clin Genitourin Cancer 2017 02 21;15(1):e45-e52. Epub 2016 Jul 21.

Department of Medical Oncology, Hôpital Saint-Louis, AP-HP, Paris, France; Paris Diderot University, Paris, France.

Background: In the past decade, adjuvant chemotherapy (AC) after radical cystectomy (RC) was preferred worldwide for patients with muscle-invasive urothelial bladder cancer. In this study we aimed to determine the outcome of patients who received AC and evaluated prognostic factors associated with survival.

Patients And Methods: We retrospectively analyzed 226 consecutive patients treated in 6 academic hospitals between 2000 and 2009. Multivariate Cox proportional hazards regression adjusted for center to estimate adjusted hazard ratios (HRs) with 95% confidence intervals were used.

Results: The median age was 62.4 (range, 35-82) years. Patients had pT3/pT4 and/or pN+ in 180 (79.6%) and 168 patients (74.3%), respectively. Median lymph node (LN) density was 25% (range, 3.1-100). Median time between RC and AC was 61.5 (range, 18-162) days. Gemcitabine with cisplatin, gemcitabine with carboplatin, and MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimens were delivered in 161 (71.2%), 49 (21.7%), and 12 patients (5.3%) of patients, respectively. The median number of cycles was 4 (range, 1-6). Thirteen patients (5.7%) with LN metastases also received adjuvant pelvic radiotherapy (ART). After a median follow-up of 4.2 years, 5-year overall survival (OS) was 40.7%. In multivariate analysis, pT ≥3 stage (HR, 1.73; P = .05), LN density >50% (HR, 1.94; P = .03), and number of AC cycles <4 (HR, 4.26; P = .001) were adverse prognostic factors for OS. ART (HR, 0.30; P = .05) tended to provide survival benefit.

Conclusion: Classical prognostic features associated with survival are not modified by the use of AC. Patients who derived benefit from AC had a low LN density and received at least 4 cycles of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2016.07.012DOI Listing
February 2017

Adapting coculture in vitro models of the blood-brain barrier for use in cancer research: maintaining an appropriate endothelial monolayer for the assessment of transendothelial migration.

Lab Invest 2016 05 22;96(5):588-98. Epub 2016 Feb 22.

Laboratoire de la Barrière Hémato-Encéphalique-EA 2465, Faculté des Sciences Jean Perrin, Université d'Artois, LBHE, Lens, France.

Although brain metastases are the most common brain tumors in adults, there are few treatment options in this setting. To colonize the brain, circulating tumor cells must cross the blood-brain barrier (BBB), which is situated within specialized, restrictive microvascular endothelium. Understanding how cancer cells manage to transmigrate through the BBB might enable this process to be prevented. In vitro models are dedicated tools for characterizing the cellular and molecular mechanisms that underlie transendothelial migration process, as long as they accurately mimic the brain endothelium's in vivo characteristics. The objective of the present study was to adapt an existing in vitro model of the human BBB for use in studying cancer cell transmigration. The model is based on the coculture of endothelial cells (ECs, derived from cord blood hematopoietic stem cells) and brain pericytes. To allow the migration of cancer cells into the lower compartment, our model had to be transposed onto inserts with a larger pore size. However, we encountered a problem when culturing ECs on large (3-μm)-pore inserts: the cells crossed the membrane and formed a non-physiological second layer on the lower face of the insert. Using 3-μm-pore inserts (in a 12-well plate format), we report here on a method that enables the maintenance of a single monolayer of ECs on the insert's upper face only. Under these chosen conditions, the ECs exhibited typical BBB properties found in the original model (including restricted paracellular permeability and the expression of continuous tight junctions). This modified in vitro model of the human BBB enabled us to investigate the migratory potential of the MDA-MB-231 cell line (derived from highly metastatic human breast cancer cells). Last, the results obtained were compared with the rate of transmigration through endothelia with no BBB features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/labinvest.2016.35DOI Listing
May 2016

Pairwise comparison of 18F-FDG and 18F-FCH PET/CT in prostate cancer patients with rising PSA and known or suspected second malignancy.

Nucl Med Commun 2016 Apr;37(4):348-55

aNuclear Medicine Department bBiostatistics and Clinical Research Unit Departments of cMedical Oncology dRadiation Oncology eUro-Oncology Multidisciplinary Staff Meeting, François Baclesse Cancer Centre fNormandie University gNuclear Medicine Department, University Hospital, Caen, France.

Objective: This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific antigen and known or suspected second malignancy.

Materials And Methods: F-FCH and F-FDG PET/CT were performed 15±9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean±SD: 15±9 months).

Results: Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P<0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively).

Conclusion: We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MNM.0000000000000457DOI Listing
April 2016

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.

Lancet Oncol 2016 Jan 16;17(1):78-89. Epub 2015 Nov 16.

Kliniken Essen Mitte, Essen, Germany.

Background: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.

Methods: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.

Findings: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).

Interpretation: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(15)00366-6DOI Listing
January 2016

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier.

J Alzheimers Dis 2015 ;48(3):849-62

One of the prime features of Alzheimer's disease (AD) is the excessive accumulation of amyloid-β (Aβ) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional Aβ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug's therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene's effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug's effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of Aβ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of Aβ peptides, bexarotene increases the expression of ABCB1, which in turn decreases Aβ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of Aβ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-150469DOI Listing
July 2016

Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.

Nat Commun 2015 Sep 23;6:8250. Epub 2015 Sep 23.

Institut Pasteur de Lille, Lille F-59000, France.

Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms9250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580987PMC
September 2015

How to improve the prevention of chemotherapy-induced nausea and vomiting? The French NAVI study.

Support Care Cancer 2016 Mar 14;24(3):1131-8. Epub 2015 Aug 14.

Centre François Baclesse, Clinical Research Department, av général Harris, Caen, 14000, France.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) still remain frequent. The procedure for announcing the diagnosis (PAD) was an emblematic measure of the first French Plan Cancer aiming at providing patients with time to listen, information after cancer diagnosis, and discussion on treatments and their side effects. We aimed at assessing the risk factors of CINV, focusing on patients' satisfaction with the PAD.

Methods: This prospective multicentre study assessed the frequency and intensity of CINV among chemonaïve patients during the first cycle of treatment. CINV was defined by ≥1 emetic episode or reported nausea intensity ≥3 on a 0-10 scale. Multivariate analysis was used to identify factors related to global CINV onset including satisfaction with the PAD (satisfaction score ≥the median on a 0-10 scale).

Results: Data from 291 patients (women, 85.2%; mean age, 57 years) were analyzed. Most patients (69.4%) received highly emetogenic chemotherapy regimens and 77.7% received antiemetic drugs consistent with international guidelines. Acute, delayed and overall CINV were experienced by 40.4, 34.8 and 52.4% of patients, respectively. Sixty-seven per cent of patients were satisfied with the PAD. No relation was noted between PAD satisfaction and CINV onset. The nausea and vomiting dimension of the QLQ-C30 questionnaire before chemotherapy (OR 3.62), motion sickness history (OR 2.73), highly emetogenic CT (OR 2.73), anxiety (OR 1.99) and younger age (OR 1.96) were independent predictive factors.

Conclusions: Although patients were mostly satisfied with the PAD, half of them experienced CINV. A state of anxiety could be identified during the PAD to be managed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-015-2882-7DOI Listing
March 2016

Newborn hearing screening: analysis and outcomes after 100,000 births in Upper-Normandy French region.

Int J Pediatr Otorhinolaryngol 2015 Jun 23;79(6):829-833. Epub 2015 Mar 23.

Department of Pediatric Ear Nose and Throat and Head and Neck Surgery, Rouen University Hospital (CHU), 1 rue de Germont, 76031 Rouen Cedex, France; Department of Ear Nose and Throat and Head and Neck Surgery, Evreux General Hospital, rue Léon Schwartzenberg, 27015 Evreux Cedex, France.

Objectives: Neonatal hearing impairment is a common disorder with a prevalence of 1 to 2‰ worldwide, with significant consequences on overall development when rehabilitated too late. New-born hearing screening has been implemented in the 1990s in most European countries and the USA. The Upper-Normandy region of France has been conducting a pilot program since 1999. The aim of this prospective study was to evaluate and critically analyse it.

Methods: The Upper-Normandy universal new-born hearing screening program is performed in two steps. Between 1999 and 2004, first, we administered a Transient Evoked Oto Acoustic Emission (TEOAE) test was administered a few days after birth for healthy newborns without risk factors. For newborns admitted to a neonatal intensive care unit (NICU) or presenting risk factors, was administered an automated auditory brainstem response (AABR) test prior to discharge. Second, newborns who failed the initial hearing screening were retested as outpatients using TEOAE. Since 2004, infants who failed the initial screen were tested with AABR 3 to 4 weeks later as outpatients, providing an opportunity to compare the two protocols.

Results: Overall screening coverage in the Upper-Normandy region is 99.8%. First step coverage is 99.58% in well-infant nurseries and 97.09% in the NICU. The test-retest procedure during the first step and the use of AABR for the second resulted in higher follow-up rates and lower false positive rates.

Conclusions: The Upper-Normandy region universal newborn hearing screening program facilitated diagnosis and rehabilitation of infants before age of 9 months, most notably when severe to profound hearing impairment was found.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2015.03.012DOI Listing
June 2015

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients.

Clin Cancer Res 2015 Jun 27;21(11):2530-7. Epub 2015 Feb 27.

Institut Curie, Paris, France.

Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.

Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.

Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).

Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-14-2368DOI Listing
June 2015

A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

PLoS One 2014 17;9(6):e99733. Epub 2014 Jun 17.

CNC - Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal; Biomaterials and Stem Cell-based Therapeutics Laboratory, Biocant - Center of Innovation in Biotechnology, Cantanhede, Portugal.

The human blood brain barrier (BBB) is a selective barrier formed by human brain endothelial cells (hBECs), which is important to ensure adequate neuronal function and protect the central nervous system (CNS) from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs) express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061029PMC
February 2015

Cognitive dysfunctions in elderly cancer patients: a new challenge for oncologists.

Cancer Treat Rev 2014 Jul 20;40(6):810-7. Epub 2014 Mar 20.

INSERM, U1086, Caen, France; Unité de Recherche Clinique, Centre François Baclesse, Caen, France; CHU de Caen, Service de médecine, Caen, France. Electronic address:

While chemotherapy is more commonly proposed to the elderly population with cancer, little is known about the impact of therapy on cognitive functions and the way of managing such dysfunctions in clinical practice among this population. Aging by itself is associated with cognitive modifications, comorbidities and functional decline, which may have a significant impact on the autonomy. In elderly patients with cancer, several factors like the biologic processes underlying the disease and therapies will contribute to favor the cognitive decline. The chemobrain phenomenon, referring to the chemotherapy-induced impairment of memory, executive function or information processing speed has been extensively described in patients with breast cancer, and the few studies available in older patients suggest that the impact could be more pronounced in patients with pre-existing troubles. Because cognitive dysfunction may impact the quality of life as well as compliance to treatment, assessing cognitive dysfunctions in the elderly cancer population is a challenge in clinical practice as it should influence the choice of the most appropriate therapy, including oral drugs. In that respect, geriatric assessment in oncology should include more sensitive screening tests than Mini Mental State Examination (MMSE) and if needed they have to be completed with a more detailed assessment of subtle disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctrv.2014.03.003DOI Listing
July 2014

Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study.

J Clin Oncol 2014 May 31;32(14):1412-8. Epub 2014 Mar 31.

Bernard Escudier, Institut Gustave Roussy, Villejuif; Emmanuel Sevin, Centre François Baclesse, Caen; Sylvie Négrier, Leon Berard Cancer Center, Lyon, France; Camillo Porta, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia; Cora N. Sternberg, San Camillo Forlanini Hospital, Rome; Ugo De Giorgi, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Petri Bono, Helsinki University Central Hospital, Helsinki, Finland; Thomas Powles, Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London; Tim Eisen, Cambridge University Health Partners, Cambridge; Omi Parikh, Royal Preston Hospital, Lancashire; Robert Hawkins, Christie Cancer Research UK, Manchester; Sadya Khan, Jose Diaz, and Faisal Mehmud, GlaxoSmithKline, Uxbridge, United Kingdom; Jürgen E. Gschwend, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany; Suman Redhu, GlaxoSmithKline, Collegeville, PA; and David Cella, Northwestern University Feinberg School of Medicine, Chicago, IL.

Purpose: Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind cross-over study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference.

Patients And Methods: Patients with metastatic RCC were randomly assigned to pazopanib 800 mg per day for 10 weeks, a 2-week washout, and then sunitinib 50 mg per day (4 weeks on, 2 weeks off, 4 weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL.

Results: Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P < .001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug's known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness.

Conclusion: This innovative cross-over trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2013.50.8267DOI Listing
May 2014