Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial.
Ontology highlight
ABSTRACT:
SUBMITTER: Kotb S
PROVIDER: S-EPMC4737727 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial.
Kotb Shady S Detappe Alexandre A Lux François F Appaix Florence F Barbier Emmanuel L EL Tran Vu-Long VL Plissonneau Marie M Gehan Hélène H Lefranc Florence F Rodriguez-Lafrasse Claire C Verry Camille C Berbeco Ross R Tillement Olivier O Sancey Lucie L
Theranostics 20160120 3
Nanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours ...[more]
Similar Datasets
Project description:INTRODUCTION:Occurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study. METHODS AND ANALYSIS:The NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100?mg/kg. A total of 15-18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits. ETHICS AND DISSEMINATION:Approval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences. TRIAL REGISTRATION NUMBER:NCT02820454; Pre-results.
| S-EPMC6377538 | biostudies-literature
Project description:PurposeChondrosarcomas (CHSs), which represent 20% of primary bone tumors in adults, are mostly resistant to radio- and chemotherapy. It is therefore essential that new therapeutic approaches, targeted to the tumour, be developed to improve the prognosis of patients. The effectiveness, as a radiosensitizing agent, of gadolinium oxide nanoparticles (GdoNP, AGuIX®) nanoparticles in CHS was evaluated in vitro, in spheroid CHS models allowing to reproduce cell-cell extracellular matrix interactions, and, in vivo, in a nude mouse model with heterotopic tumour xenograft.MethodsSpheroids from SW1353 and HEMC-SS cells were characterized by confocal microscopy with or without GdoNP treatment. Real-time microscopy enabled quantification of cell viability, cell migration and invasion. In vivo, the efficacy of the association of GdoNP combined with a single (4Gy) or fractionated (4x1Gy) irradiation was evaluated in HEMC-SS tumor-bearing mice by monitoring tumor growth, mouse survival and gene expression profile.ResultsThe expression of proteoglycans in the extra-cellular matrix (ECM) of spheroids demonstrated the relevance of the 3-D model. The combination of GdoNP with single or fractionated irradiation increased the lethal effects of irradiation on 2-D- and 3-D-cultured cells. In vivo, a single or a fractionated dose of 4 Gy associated with IT or IV injection of GdoNP decreased tumor growth significantly. Only IT injection increased mice survival. Unexpectedly, the radiosensitizing effect of GdoNP was associated, in vitro, with a significant decrease in invasion-migration capacities and, in vivo, with the decreased expression of PTX3, a protein involved in the epithelial-to-mesenchymal transition process, suggesting a potential impact of GdoNP on metastasis formation.ConclusionThese results provide the first proof of concept of the radiosensitizing effect of GdoNP in CHSs and opened the way for a multicentre, randomized Phase 2 trial evaluating the association of GdoNP with radiotherapy for the therapeutic management of patients with symptomatic inoperable musculoskeletal tumor lesions.
| S-EPMC9793741 | biostudies-literature
Project description:BACKGROUND:The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. METHODS:This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. RESULTS:Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16?+?CD56?+?cells (natural killer cells; P?=?0.0124) and a marginally significant decrease in CD4?+?CD25?+?cells (regulatory T cells; P?=?0.0546) were observed three weeks after the first cycle of treatment in the combined stage. CONCLUSIONS:The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.
| S-EPMC7413875 | biostudies-literature
Project description:This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
| S-EPMC4591941 | biostudies-literature
Project description:The purpose of this study is to determine whether AGuIX (Activation and Guidance of Irradiation by X-ray) gadolinium-based nanoparticles make radiation work more effectively in the treatment of patients with brain metastases that are more difficult to control with stereotactic radiation alone.
| 2378535 | ecrin-mdr-crc
Project description:This paper concerns the feasibility of x-ray differential phase contrast (DPC) tomosynthesis imaging using a grating-based DPC benchtop experimental system, which is equipped with a commercial digital flat-panel detector and a medical-grade rotating-anode x-ray tube. An extensive system characterization was performed to quantify its imaging performance.The major components of the benchtop system include a diagnostic x-ray tube with a 1.0 mm nominal focal spot size, a flat-panel detector with 96 μm pixel pitch, a sample stage that rotates within a limited angular span of ± 30°, and a Talbot-Lau interferometer with three x-ray gratings. A total of 21 projection views acquired with 3° increments were used to reconstruct three sets of tomosynthetic image volumes, including the conventional absorption contrast tomosynthesis image volume (AC-tomo) reconstructed using the filtered-backprojection (FBP) algorithm with the ramp kernel, the phase contrast tomosynthesis image volume (PC-tomo) reconstructed using FBP with a Hilbert kernel, and the differential phase contrast tomosynthesis image volume (DPC-tomo) reconstructed using the shift-and-add algorithm. Three inhouse physical phantoms containing tissue-surrogate materials were used to characterize the signal linearity, the signal difference-to-noise ratio (SDNR), the three-dimensional noise power spectrum (3D NPS), and the through-plane artifact spread function (ASF).While DPC-tomo highlights edges and interfaces in the image object, PC-tomo removes the differential nature of the DPC projection data and its pixel values are linearly related to the decrement of the real part of the x-ray refractive index. The SDNR values of polyoxymethylene in water and polystyrene in oil are 1.5 and 1.0, respectively, in AC-tomo, and the values were improved to 3.0 and 2.0, respectively, in PC-tomo. PC-tomo and AC-tomo demonstrate equivalent ASF, but their noise characteristics quantified by the 3D NPS were found to be different due to the difference in the tomosynthesis image reconstruction algorithms.It is feasible to simultaneously generate x-ray differential phase contrast, phase contrast, and absorption contrast tomosynthesis images using a grating-based data acquisition setup. The method shows promise in improving the visibility of several low-density materials and therefore merits further investigation.
| S-EPMC3874057 | biostudies-other
Project description:Lipid nanoparticles are a successful carrier system for dermal drug delivery. They possess various beneficial properties, i.e., increased chemical stability for chemically labile compounds, increased dermal penetration of active compounds, or skin carrying properties after dermal application due to the formation of a so-called "invisible patch." Despite manifold studies showing these properties individually, a study that investigates if one lipid nanoparticle formulation can really combine all the above-mentioned benefits at once is not yet available. In the present study, lipid nanoparticles (NLC) were produced and characterized regarding their physico-chemical properties. The chemical stability of the incorporated active ingredient (AI) was determined, as well as the dermal penetration efficacy of the AI, and the skin carrying properties of the NLC after dermal penetration. The properties of the NLC were compared to classical formulations, i.e., AI dissolved in pure oil, an o/w cream base and a nanoemulsion. All formulations contained similar lipids and emulsifiers, which allowed for a direct comparison of the different properties. NLC were shown to provide most efficient chemical stabilization and most efficient dermal penetration for the AI. The formation of the invisible patch was shown for the NLC but not for the other formulations. Skin hydration and skin carrying properties were also most pronounced for the NLC. Results provide evidence that NLC can combine all beneficial effects that were previously described in one formulation. Thus, providing evidence that NLC are a holistically superior formulation principle when compared to other formulation principles.
| S-EPMC9061673 | biostudies-literature
Project description:PurposeTo propose a nonisocentric treatment strategy as a special form of station parameter optimized radiation therapy, to improve sparing of critical structures while preserving target coverage in breast radiation therapy.Methods and materialsTo minimize the volume of exposed lung and heart in breast irradiation, we propose a novel nonisocentric treatment scheme by strategically placing nonconverging beams with multiple isocenters. As its name suggests, the central axes of these beams do not intersect at a single isocenter as in conventional breast treatment planning. Rather, the isocenter locations and beam directions are carefully selected, in that each beam is only responsible for a certain subvolume of the target, so as to minimize the volume of irradiated normal tissue. When put together, the beams will provide an adequate coverage of the target and expose only a minimal amount of normal tissue to radiation. We apply the nonisocentric planning technique to 2 previously treated clinical cases (breast and chest wall).ResultsThe proposed nonisocentric technique substantially improved sparing of the ipsilateral lung. Compared with conventional isocentric plans using 2 tangential beams, the mean lung dose was reduced by 38% and 50% using the proposed technique, and the volume of the ipsilateral lung receiving ≥ 20 Gy was reduced by a factor of approximately 2 and 3 for the breast and chest wall cases, respectively. The improvement in lung sparing is even greater compared with volumetric modulated arc therapy.ConclusionsA nonisocentric implementation of station parameter optimized radiation therapy has been proposed for breast radiation therapy. The new treatment scheme overcomes the limitations of existing approaches and affords a useful tool for conformal breast radiation therapy, especially in cases with extreme chest wall curvature.
| S-EPMC4010385 | biostudies-literature
Project description:Transcranial near-infrared radiation (NIR) is an innovative treatment for major depressive disorder (MDD), but clinical evidence for its efficacy is limited. Our objective was to investigate the tolerability and efficacy of NIR in patients with MDD. We conducted a proof of concept, prospective, double-blind, randomized study of 6 sessions of NIR versus sham treatment for patients with MDD, using a crossover design. Four patients with MDD with mean age 47 ± 14 (SD) years (1 woman and 3 men) were exposed to irradiance of 700 mW/cm(2) and a fluence of 84 J/cm(2) for a total NIR energy of 2.40 kJ delivered per session for 6 sessions. Baseline mean HAM-D17 scores decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) after treatment (t = 7.905; df = 3; P = 0.004). Patients tolerated the treatment well without any serious adverse events. These findings confirm and extend the preliminary data on NIR as a novel intervention for patients with MDD, but further clinical trials are needed to better understand the efficacy of this new treatment. This trial is registered with ClinicalTrials.gov NCT01538199.
| S-EPMC4556873 | biostudies-literature
Project description:BackgroundLonger patient intervals can lead to more late-stage cancer diagnoses and higher mortality rates. Individuals may delay presenting to primary care with red flag symptoms and instead turn to the internet to seek information, purchase over-the-counter medication, and change their diet or exercise habits. With advancements in machine learning, there is the potential to explore this complex relationship between a patient's symptom appraisal and their first consultation at primary care through linkage of existing datasets (eg, health, commercial, and online).ObjectiveHere, we aimed to explore feasibility and acceptability of symptom appraisal using commercial- and health-data linkages for cancer symptom surveillance.MethodsA proof-of-concept study was developed to assess the general public's acceptability of commercial- and health-data linkages for cancer symptom surveillance using a qualitative focus group study. We also investigated self-care behaviors of ovarian cancer patients using high-street retailer data, pre- and postdiagnosis.ResultsUsing a high-street retailer's data, 1118 purchases-from April 2013 to July 2017-by 11 ovarian cancer patients and one healthy individual were analyzed. There was a unique presence of purchases for pain and indigestion medication prior to cancer diagnosis, which could signal disease in a larger sample. Qualitative findings suggest that the public are willing to consent to commercial- and health-data linkages as long as their data are safeguarded and users of this data are transparent about their purposes.ConclusionsCancer symptom surveillance using commercial data is feasible and was found to be acceptable. To test efficacy of cancer surveillance using commercial data, larger studies are needed with links to individual electronic health records.
| S-EPMC6354198 | biostudies-literature