Despite the utility of tumour characterisation using quantitative parameter maps from multi-b-value diffusion-weighted MRI (DWI), clinicians often prefer the use of the image with highest ...diffusion-weighting (b-value), for instance for defining regions of interest (ROIs). However, these images are typically degraded by noise, as they do not utilize the information from the full acquisition. We present a principal component analysis (PCA) approach for model-free denoising of DWI data. PCA-denoising was compared to synthetic MRI, where a diffusion model is fitted for each voxel and a denoised image at a given b-value is generated from the model fit. A quantitative comparison of systematic and random errors was performed on data simulated using several diffusion models (mono-exponential, bi-exponential, stretched-exponential and kurtosis). A qualitative visual comparison was also performed for in vivo images in six healthy volunteers and three pancreatic cancer patients. In simulations, the reduction in random errors from PCA-denoising was substantial (up to 55%) and similar to synthetic MRI (up to 53%). Model-based synthetic MRI denoising resulted in substantial (up to 29% of signal) systematic errors, whereas PCA-denoising was able to denoise without introducing systematic errors (less than 2%). In vivo, the signal-to-noise ratio (SNR) and sharpness of PCA-denoised images were superior to synthetic MRI, resulting in clearer tumour boundaries. In the presence of motion, PCA-denoising did not cause image blurring, unlike image averaging or synthetic MRI. Multi-b-value MRI can be denoised model-free with our PCA-denoising strategy that reduces noise to a level similar to synthetic MRI, but without introducing systematic errors associated with the synthetic MRI method.
Purpose To assess the repeatability of apparent diffusion coefficient (ADC) estimates in extracranial soft-tissue diffusion-weighted magnetic resonance imaging across a wide range of imaging ...protocols and patient populations. Materials and Methods Nine prospective patient studies and one prospective volunteer study, performed between 2006 and 2016 with research ethics committee approval and written informed consent from each subject, were included in this single-institution study. A total of 141 tumors and healthy organs were imaged twice (interval between repeated examinations, 45 minutes to 10 days, depending the on study) to assess the repeatability of median and mean ADC estimates. The Levene test was used to determine whether ADC repeatability differed between studies. The Pearson linear correlation coefficient was used to assess correlation between coefficient of variation (CoV) and the year the study started, study size, and volumes of tumors and healthy organs. The repeatability of ADC estimates from small, medium, and large tumors and healthy organs was assessed irrespective of study, and the Levene test was used to determine whether ADC repeatability differed between these groups. Results CoV aggregated across all studies was 4.1% (range for each study, 1.7%-6.5%). No correlation was observed between CoV and the year the study started or study size. CoV was weakly correlated with volume (r = -0.5, P = .1). Repeatability was significantly different between small, medium, and large tumors (P < .05), with the lowest CoV (2.6%) for large tumors. There was a significant difference in repeatability between studies-a difference that did not persist after the study with the largest tumors was excluded. Conclusion ADC is a robust imaging metric with excellent repeatability in extracranial soft tissues across a wide range of tumor sites, sizes, patient populations, and imaging protocol variations. Online supplemental material is available for this article.
A new approach to prepare polymeric capsules was developed to obtain an efficient controlled release system for pain treatment. Capsules with a mean diameter between 400 and 1000 nm were prepared ...using an interfacial condensation method between a natural polymer, chitosan, and a synthetic one, poly(maleic anhydride-alt-vinyl acetate). The influence of different reaction parameters on capsule diameter and properties was investigated. Zeta-potential determinations indicated a good stability of the capsules in aqueous solution containing KCl. Scanning electron microscopy confirmed the submicron dimensions and the spherical shape of the capsules. The thermal properties of the capsules were determined by differential scanning calorimetry and thermogravimetric analysis. In addition, these particles presented a good swelling capacity, which was influenced by the reaction parameters used in this study (molar ratio between the two polymers, the volume ratio between aqueous and organic phase, the amount of surfactant and the reaction time). The ibuprofen loading and release capacity were influenced by the swelling degree. In vivo, the ibuprofen-loaded capsules presented a delayed effect in peripheral pain inhibition and a sustained effect in central pain inhibition.
Lung infections, such as: pneumonia, chronic obstructive cystic fibrosis, tuberculosis are generally caused by viruses, bacteria and fungi. As these infections are very difficult to treat, new ...therapeutic approaches are investigated in order to maximize the efficiency of the treatment and to reduce the major complications that can occur. The main objective of this study was focused on the preparation of drug-loaded peptides-functionalized microcapsules, obtained by a double emulsion, based on carboxylated chitosan (CMCS), poly(vinyl alcohol) (PVA) and an activator 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), for the dual active targeting and treatment of pulmonary infections. The microcapsules were functionalized on the surface with both CGSPGWVRC and indolicidin (IN) peptides, as effective ligands for the active targeting of both alveolar capillary endothelial cells and bacterial cells. FTIR spectroscopy confirmed the formation of ester and amide bonds into the structure of prepared microcapsules. Microcapsules diameter varied between 893 and 965 nm. The swelling degree in PBS, at pH 7.4, ranged between 1760 %- 2100 %. All the analyzed samples showed hemolysis degrees lower than 2 %, which demonstrated their non-hemolytic character. Evaluation of the impact of microcapsules on WI-38 normal human lung cells and RAW 264.7 mouse macrophages revealed a non-toxic or slightly cytotoxic effect. Internalization assay proved that microcapsules were localized at intracellular level.
Multicomponent composites based on natural biopolymers: chitosan, starch and gelatin in two different ratios (0.5:1:1 and 1:1:1) were in situ crosslinked by intermolecular interactions and used as ...matrices for zinc oxide and magnetite fillers. The bionanocomposite films have been evaluated by spectral and microscopy methods: Fourier-Transform Infrared spectrometry (FT-IR), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) confirming the electrostatic and hydrogen bonding interactions between the components of the polymeric matrices and the inorganic fillers and the crosslinking process. AFM and SEM images showed a compact, non-porous and homogenous morphology of the hybrid films, proving a good miscibility of the blends. At lower concentrations of embedded filler, the composites were less hardened and more ductile due to the interaction with the polymeric matrix. Increased amounts of inorganic NPs led to the reduced mechanical properties of the prepared materials and increased thermal stability. The bionanocomposites revealed a similar behavior of the dielectric constant with frequency and increased values at higher temperatures. The wettability of the films' surface and the values of the water sorption capacity revealed a slight hydrophilicity of the bionanocomposites as compared with the initial matrices. The biocompatibility, evaluated by means of the surface free energy components and the interfacial tension with blood, and the hemolysis analysis demonstrated that the bionanocomposites possess a low risk of thrombosis, being promising materials for in vivo biomedical applications.
•Bionanocomposites based on chitosan, starch and gelating have been prepared.•ZnO and Fe3O4 nanoparticles were used as fillers.•Structure, morphology, wettability, mechanical, thermal, dielectrical, magnetic properties were evaluated.•All the studied bionanocomposite samples are non-hemolytic.
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Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. ...Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (K
trans
)
derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and K
trans
were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour K
trans
was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median K
trans
change (-36 to + 17%). Overall, the cohort average K
trans
decreased from 0.17 to 0.07 min
-1
(58%). No significant ADC changes were observed at day 15. Of the 4 pts with K
trans
reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no K
trans
change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with K
trans
reduction were classified as responders.
Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings.
Clinical trial information: EUDRACT No: 2014- 003579-51.
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Background: REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for ...better patient selection. Methods: RAS mutant mCRC pts with biopsiable metastases were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (K
trans
) and enhancing fraction (EF) K-trans*EF/100 were generated. Circulating tumour (ct)DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI. Results: mCRC pts (n = 27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median K-trans*EF/100 product decrease was 58.2%. In the 23 analysable pts (4 received < 1 cycle of treatment due to toxicities), > 70% drop in K-trans*EF/100 (8/23) was associated with higher disease control rate (6/6 vs. 0/6, p = 0.048) measured by RECIST 1.1 at 2 months, improved progression free survival (PFS) HR = 0.24 (0.07-0.86), p = 0.03, and 4-month PFS (58.3% VS 21.2%). Sequential tissue biopsies analysis confirmed reduction in CD31 in pts with K-trans*EF/100 drop. RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS HR = 0.25 (0.08 - 0.83), p = 0.02 independently of K-trans*EF/100 drop. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p = 0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p = 0.02). Conclusions: Combining DCE MRI and ctDNA predicts depth and duration of anti-angiogenic response to REG monotherapy and may improve pt selection with potential health/economic implications. Clinical trial information: 201400357951.
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