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The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the predicted cancer cell death to the actual cell death measured from corresponding resected tumors treated with neoadjuvant chemoradiation in a calibration cohort (n = 80) and prospective cohort (n = 25). After calibration, we applied the model to 2 separate cohorts for pathologic and clinical associations: targeted therapy cohort (n = 101), cetuximab/bevacizumab + radiosensitizing chemotherapy, and standard chemoradiation cohort (n = 81), radiosensitizing chemotherapy to 50.4 Gy in 28 fractions.We established the relationship between pretreatment computed v nAUC to pathologically verified blood volume fraction of the tumor (r = 0.65; P = .009) and fractional tumor cell death (r = 0.97-0.99; P.0001) in the calibration and prospective cohorts. On multivariate analyses, accounting for traditional covariates, nAUC independently associated with overall survival in all cohorts (mean hazard ratios, 0.14-0.31). Receiver operator characteristic analyses revealed discrimination of good and bad prognostic groups in the cohorts with area under the curve values of 0.64 to 0.71.This work presents a new mathematical modeling approach to predict clinical response from chemotherapy and radiation for PDAC. Our findings indicate that oxygen/drug diffusion strongly influences clinical responses and that nAUC is a potential tool to select patients with PDAC for radiation therapy.

ObjectivesTumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.Materials and methodsRetrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.ResultsAs a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P&nbsp

International audience; This work aims at better understanding the interactions existing between the liquid electrolyte and the solid composite electrode in a Li-ion battery. We substituted the common active material (e.g. LiNi1/3Mn1/3Co1/3O2 or LiFePO4) by an insulating (inactive) gamma-Al2O3 compound in order to detect and evidence the interaction between the carbon black electronic additive and the liquid electrolyte. Our study presents the characterization of charge (electrons and ions) transport at different scales by combining a high-frequency analysis performed by broadband dielectric spectroscopy (BDS, up to 10(10) Hz), along with a low-frequency analysis performed by electrochemical impedance spectroscopy (EIS, down to 10(-3) Hz). Two carbon black materials with two different specific surface areas (80 m(2).g(-1) and 65 m(2).g(-1), respectively) were studied. The electronic percolation threshold and the kinetics of impregnation of the hierarchical composite electrode by the liquid electrolyte have been determined with respect to the carbon black content. The significant influence of the adsorbtion of ions at the carbon black surface on the electrons transport is particularly highlighted and explained.

International audience; The permittivity and conductivity of a porous composite consisting of a mixture of a lithium-ion battery electrode material, LiNi0.5Mn0.3Co0.2O2 (NMC532), and a polymeric binder, poly(vinylidene fluoride-co-hexafluoropropylene) (PVdF-HFP), were simultaneously measured by broadband dielectric spectroscopy (BDS). The composite was either dry or wetted with a conventional battery electrolyte [LP30, LiPF6 in ethylene carbonate/dimethylcarbonate (EC/DMC)] or a mixture of electrolytic solvents (EC/DMC). The experimental results show that the electronic conductivity of NMC532 was much higher than that obtained with LiNi0.33Mn0.33Co0.33O2 (NMC333). In addition, a strong influence of liquids was evidenced. Dipolar species (in particular, EC dipoles) and ions (in particular, PF6– in LP30) considerably increased the surface conductivity of NMC532 clusters, leading to a facilitated electronic transfer from one cluster to another. The effective ionic conductivity was measured and compared to the ionic conductivity of the electrolyte to express the tortuosity factor of this composite electrode.

Background and purpose Customized mouth-opening-tongue-depressing-stents (MOTDs) may reduce toxicity in patients with head and neck cancers (HNC) receiving radiotherapy (RT). However, making MOTDs requires substantial resources, which limits their utilization. Previously, we described a workflow for fabricating customized 3D-printed MOTDs. This study reports the results of a prospective trial testing the non-inferiority of 3D-printed to standard and commercially-available (TruGuard) MOTDs as measured by patient reported outcomes (PROs). Materials and methods PROs were collected at 3 time points: (t1) simulation, (t2) prior to RT, (t3) between fractions 15–25 of RT. Study participants received a 3D-printed MOTDs (t1, t2, t3), a wax-pattern (t1), an acrylic-MOTDs (t2, t3) and an optional TruGuard (t1, t2, t3). Patients inserted the stents for 5–10 min and completed a PRO-questionnaire covering ease-of-insertion and removal, gagging, jaw-pain, roughness and stability. Inter-incisal opening and tongue-displacement were recorded. With 39 patients, we estimated 90% power to detect a non-inferiority margin of 2 at a significance level of 0.025. Matched pairs and t-test were used for statistics. Results 41 patients were evaluable. The 3D-printed MOTDs achieved a significantly better overall PRO score compared to the wax-stent (p = 0.0007) and standard-stent (p = 0.0002), but was not significantly different from the TruGuard (p = 0.41). There was no difference between 3D-printed and standard MOTDs in terms of inter-incisal opening (p = 0.4) and position reproducibility (p = 0.98). The average 3D-printed MOTDs turn-around time was 8 vs 48 h for the standard-stent. Conclusions 3D-printed stents demonstrated non-inferior PROs compared to TruGuard and standard-stents. Our 3D-printing process may expand utilization of MOTDs.

Determine electron and ion transfers in composite porous electrodes is essential to improve their electrochemical performance. When mounting the battery, the composite electrode is soaked with a liquid electrolyte (EL) that completely fills its pores. An electrode has a double hierarchical structure: the first consists of agglomerates (secondary particles) of AM (primary) particles and the second of agglomerates of carbon black/binder (CB-B) mixture. From the nanometric level to the macroscopic level, this double structure leads to numerous interfaces: AM / AM, CB / CB, CB / AM, EL / AM, EL / CB, electrode / current collector. The charge transport in composite electrodes of lithium batteries is generally explained by the percolation and tortuosity of the carbon black particle network for the electrons on the one hand, and the pore network for the ions on the other hand. In return, the contributions of the various interfaces within the composite electrodes have been little studied. Indeed, this requires the simultaneous measurement of ionic and electronic conductivities. The development of an instrumentation taking into account both the constraints imposed by the nature of the samples and the dynamics of mobile species (ions, electrons) is necessary. In-situ and ex-situ dielectric spectroscopy achieves this goal over a wide frequency range from 40 Hz to 10 GHz. Many factors and parameters affect the electrical properties [1-5]. The nature and quality of the interfaces, which depend on morphologies of the different agglomerates and their distribution can strongly limit electronic and ionic transfers within composite electrodes. Contact resistance at interface between current collector and the electrode can partially hamper charge transfers. Moreover, strong interactions occur between the liquid electrolyte (i.e. dipoles and ions) and the active material, as well as between the electrolyte and the carbon black. Space charges, created on the surface of electronically conductive materials (active material and carbon black), generate electrical polarizations whose frequency responses are in the range of radio frequencies and microwaves. The presence of an electrolyte influences the intensities and dynamics of space charge polarizations due to ion-electron and dipole-electron interactions [3,4]. In this presentation, recent discoveries are reported on influences of different interfaces on electronic and ionic conductions in composite electrodes composed of LiNi0.5Mn0.3Co0.2O2, Poly(vinylidene) fluoride and carbon black with an aluminium current collector. Acknowledgments Financial funding from the ANR program no. ANR-15-CE05-0001-01 is acknowledged. References [1] K.A. Seid, J.C. Badot, O. Dubrunfaut, S. Levasseur, D. Guyomard, B. Lestriez, Multiscale electronic transport mechanism and true conductivities in amorphous carbon-LiFePO4 composites. J. Mater. Chem., 22, 2641-2649 (2012). [2] K.A. Seid, J.C. Badot, O. Dubrunfaut, M.T. Caldes, N. Stephant, L. Gautier, D. Guyomard, B. Lestriez, Multiscale electronic transport in Li1+xNi1/3-uCo1/3-vMn1/3-wO2: a broadband dielectric study from 40 Hz to 10 GHz. Phys. Chem. Chem. Phys., 15, 19790-19798 (2013). [3] K.A. Seid, J.C. Badot, C. Perca, O. Dubrunfaut , P. Soudan , D. Guyomard, B. Lestriez, An In Situ Multiscale Study of Ion and Electron Motion in a Lithium-Ion Battery Composite Electrode. Adv. Energy Mater., 5, 1400903 (2015). [4] E. Panabière, J.C. Badot, O. Dubrunfaut, A. Etiemble, B. Lestriez. Electronic and Ionic Dynamics Coupled at Solid-Liquid Electrolyte Interfaces in Porous Nanocomposites of Carbon Black, Poly(vinylidene fluoride), and g-Alumina. J. Phys. Chem. C, 121, 8364-8377 (2017). [5] P.E. Cabelguen, D. Peralta, M. Cugnet, J.C. Badot, O. Dubrunfaut, P. Mailley. Rational Analysis of Layered Oxide Power Performance Limitations in a Lithium Battery Application. Adv. Sustainable Syst., DOI: 10.1002/adsu.201700078 (2017).

The electrochemical performance of composite electrode materials suffers strong kinetic limitations due to non-optimized electronic and ionic transport properties. Electrode materials consist of complex hierarchical architectures in which interfaces create junction resistances and capacitance causing electronic transfer limitations. Moreover, the tortuosity of the pore network within the electrodes gives rise to ionic transfer limitations. Ionic and electronic dynamics occur at widely different time scales: long times (i.e. low frequencies) for slow ionic motions and short times (i.e. high frequencies) for fast electronic motions. Electrochemical Impedance Spectroscopy technique, which is appropriated to determine ionic diffusion, cannot characterize electronic transfers within electrode materials. This requires thus the simultaneous measurement of ionic and electronic conductivities. The broadband dielectric spectroscopy (BDS) over a frequency range from 40 Hz to 10 GHz is a powerful technique to discriminate ionic and electronic motions at different scales of the materials. Previous BDS studies have distinguished different types of interfaces inducing electric polarizations and disturbing charge transport at all scales of the materials [1-5]. Strong interactions between ions (Li+, PF6 - ) of the electrolyte (LP30) and electrons were evidenced in active material (LiNi1/3Mn1/3Co1/3O2) and carbon black (CB) by conductivity measurements. Comprehensive characterization of the multiscale electronic transport in LiNi0.5Mn0.3Co0.2O2 (hereafter called NMC532) by BDS is here detailed. This study is assumed without carbon-black addition to only understand the interactions of the electrolyte with mixtures based on NMC532 and PVdF. A systematic approach is followed, which consists of studying the materials at different temperatures, starting by a study of NMC532 with polyvinylidene fluoride (i.e. PVdF) first in the dry state, then filled with the solvent EC-DMC alone and finally the LP30 electrolyte (containing ions). The PVdF content impacts the quality of the interfaces within the samples hampering the electronic transfer in NMC. When EC: DMC fills the pores of the mixture, it is shown that the dipoles of ethylene carbonate adsorbed on the NMC532 modify its electronic properties. Moreover, strong interactions occur between the liquid electrolyte LP30 (i.e. dipoles and ions) and the active material, as well as between the electrolyte and the carbon black. Space charges, created on the surface of electronically conductive NMC532 generate electrical polarizations whose frequency responses are in the range of radio frequencies and microwaves. The presence of the electrolyte changes the intensities and dynamics of space charge polarizations due to ion-electron and dipole-electron interactions [3,4]. Acknowledgments Financial funding from the ANR program no. ANR-15-CE05-0001-01 is acknowledged References [1] K.A. Seid, J.C. Badot, O. Dubrunfaut, S. Levasseur, D. Guyomard, B. Lestriez, Multiscale electronic transport mechanism and true conductivities in amorphous carbon-LiFePO4 composites. J. Mater. Chem., 22, 2641-2649 (2012). [2] K.A. Seid, J.C. Badot, O. Dubrunfaut, M.T. Caldes, N. Stephant, L. Gautier, D. Guyomard, B. Lestriez, Multiscale electronic transport in Li1+xNi1/3-uCo1/3-vMn1/3-wO2: a broadband dielectric study from 40 Hz to 10 GHz. Phys. Chem. Chem. Phys., 15, 19790-19798 (2013). [3] K.A. Seid, J.C. Badot, C. Perca, O. Dubrunfaut , P. Soudan , D. Guyomard, B. Lestriez, An In Situ Multiscale Study of Ion and Electron Motion in a Lithium-Ion Battery Composite Electrode. Adv. Energy Mater., 5, 1400903 (2015). [4] E. Panabière, J.C. Badot, O. Dubrunfaut, A. Etiemble, B. Lestriez. Electronic and Ionic Dynamics Coupled at Solid-Liquid Electrolyte Interfaces in Porous Nanocomposites of Carbon Black, Poly(vinylidene fluoride), and g-Alumina. J. Phys. Chem. C, 121, 8364-8377 (2017). [5] P.E. Cabelguen, D. Peralta, M. Cugnet, J.C. Badot, O. Dubrunfaut, P. Mailley. Rational Analysis of Layered Oxide Power Performance Limitations in a Lithium Battery Application. Adv. Sustainable Syst., DOI: 10.1002/adsu.201700078 (2017).

Good ionic and electronic conductivities are required in battery electrodes to facilitate redox reactions and thus efficient charge and discharge of the battery. However, limitations of charge transport properties in state of the art lithium-ion positive composite electrodes greatly restrain the electrode thickness. This is largely attributed to: (i) the multitude of interfaces/contacts that arise with the different materials, and at different scales inside the composite electrode; and (ii) to the degree of percolation and tortuosity of the different phases. The active material studied, LiNi0.5Mn0.3Co0.2 O2 (NMC532), consists of 1µm size grains (or particles) that agglomerate to form 4µm clusters. The binding polymer PVDF is used with Carbon Black (CB) to impart higher electronic conductivity. The aim of this project is to study the effect of the electrode morphology and the various interfaces on electronic and ionic limitations. By changing the morphology of the electrode (i.e. composition and porosity) the aim is to minimize the transport limitations in the electrode [1]. In doing so it is hoped to be possible to increase electrode thickness and thus minimize the non-electroactive part in the battery electrodes, reducing cost and increasing efficiency. This research may also help in developing a faster method to optimize new active materials and thus reduce its time to market. Broadband Dielectric Spectroscopy (BDS) apply AC perturbations, between 20Hz to 18GHz in our case, across a metal coated sample at the end of a coaxial waveguide. Complex permittivity and conductivity (resistivity) are then calculated from admittance (low-frequency) and the coefficient of reflection (high-frequency). The inferred electric polarisations (or susceptibilities) at each interface are additive in nature. It provides information about multiscale charge transfer phenomenon across interfaces. This allows for a multi-hierarchical study of the composite. The interfacial characterisation of resistive and capacitive responses is carried out using Nyquist plots. Measurements are undertaken using dry nitrogen, from room temperature to -100°C. The conductivity of NMC532 is thermally activated and activation energies are derived using Arrhenius plots. To characterise the NMC532 active material alone, samples with no carbon black were referenced. Electrode metal contact, clusters and particles of NMC532 were characterised for dry samples. Samples were then impregnated with solvent and electrolyte to study their effect on the active material. Both conductivity and interfacial capacitance were seen to increase for the impregnated electrodes. Industrially fabricated NMC532 composite electrodes with varying CB content and porosity, coated on aluminium, were also characterised. It was seen that the electrochemical performance was better for electrodes with a non-percolated CB-polymer network The results obtained bring to question the necessity to have percolated electrodes when using an active material with relatively high conductivity. This is investigated with the help of electrochemical impedance spectroscopy (1mHz-50kHz) characterising the charge-transfer resistance as well as operando BDS, allowing for interfacial characterisation of electrodes at different levels of charge/discharge. The research is part of the project ANR Pepite comprising researchers conducting further characterisations such as FIB-SEM X-Ray tomography and PF-NMR to allow for a complete characterisation of the composite electrode and a better understanding on the effect of the electrode architecture on its performance. Acknowledgement We are grateful to the ANR for the funding of the Pepite project (ANR-15-CE05-0001). References [1] Besnard N., Tran-Van P., Etiemble A., Maire E., Douillard T., Dubrunfaut O., Gautier L., Franger S., Badot J.-C. and Lestriez B.. “Multiscale Morphological and Electrical Characterization of Charge Transport and Charge Transfer Limitations to Power Performance of - Positive Electrode for Li-Ion Batteries.” Jounral of the Electrochemical Society, Charge Transfer Electrons 2 (2018) [2] Kalid-Ahmed Seid , Jean-Claude Badot ,Cristian Perca , Olivier Dubrunfaut, Patrick Soudan , Dominique Guyomard , and Bernard Lestriez " An In Situ Multiscale Study of Ion and Electron Motion in a Lithium-Ion Battery Composite Electrode." Advanced Energy Materials 5.2 (2015). [3] Badot, J.-C., Ligneel, É., Dubrunfaut, O., Guyomard, D. and Lestriez, B., “A Multiscale Description of the Electronic Transport within the Hierarchical Architecture of a Composite Electrode for Lithium Batteries.” Adv. Funct. Mater., 19 (2009): 2749–2758.

The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

The present investigation deals with the development and statistical optimization of solid lipid nanoparticles (SLNs) of ondansetron HCl (OND) for intranasal (i.n.) delivery. SLNs were prepared using the solvent diffusion technique and a 2(3) factorial design. The concentrations of lipid, surfactant and cosurfactant were independent variables in this design, whereas, particle size and entrapment efficiency (EE) were dependent variables. The particle size of the SLNs was found to be 320-498 nm, and the EE was between 32.89 and 56.56 %. The influence of the lipid, surfactant and cosurfactant on the particle size and EE was studied. A histological study revealed no adverse response of SLNs on sheep nasal mucosa. Transmission electron microscopic analysis showed spherical shape particles. Differential scanning calorimetry and X-ray diffraction studies indicated that the drug was completely encapsulated in a lipid matrix. In vitro drug release studies carried out in phosphate buffer (pH 6.6) indicated that the drug transport was of Fickian type. Gamma scintigraphic imaging in rabbits after i.n. administration showed rapid localization of the drug in the brain. Hence, OND SLNs is a promising nasal delivery system for rapid and direct nose-to-brain delivery.

In the present study, tramadol HCl microspheres were designed in order to accomplish rapid delivery of drug to the brain. For this purpose, lower viscosity grade HPMC (E15) was chosen as mucoadhesive polymer and used at different drug/polymer ratios in the microspheres formulations. The spray-dried microspheres were evaluated with respect to the production yield, incorporation efficiency, particle size, mucoadhesive property, in vitro drug release, histopathological study, and radio imaging study in rabbits. DSC and XRD study showed molecular dispersion and conversion of the drug into amorphous form. Size and surface morphology of microspheres was analyzed by SEM and found to be spherical in shape with smooth surface. It was found that the particle size, swelling ability, and incorporation efficiency of microspheres increase with increasing drug-to-polymer ratio. Microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. In vitro drug release of optimized formulation was found to be 94% after 90 min. The radio imaging study indicated localization of drug in the brain. Hence, tramadol HCl microspheres based on a HPMC E15 may be a promising nasal delivery system for CNS targeting.