Purpose To determine the usefulness of whole-body diffusion-weighted imaging (DWI) to assess the response of bone metastases to treatment in patients with metastatic castration-resistant prostate ...cancer (mCRPC). Materials and Methods A phase II prospective clinical trial of the poly-(adenosine diphosphate-ribose) polymerase inhibitor olaparib in mCRPC included a prospective magnetic resonance (MR) imaging substudy; the study was approved by the institutional research board, and written informed consent was obtained. Whole-body DWI was performed at baseline and after 12 weeks of olaparib administration by using 1.5-T MR imaging. Areas of abnormal signal intensity on DWI images in keeping with bone metastases were delineated to derive total diffusion volume (tDV); five target lesions were also evaluated. Associations of changes in volume of bone metastases and median apparent diffusion coefficient (ADC) with response to treatment were assessed by using the Mann-Whitney test and logistic regression; correlation with prostate-specific antigen level and circulating tumor cell count were assessed by using Spearman correlation (r). Results Twenty-one patients were included. All six responders to olaparib showed a decrease in tDV, while no decrease was observed in all nonresponders; this difference between responders and nonresponders was significant (P = .001). Increases in median ADC were associated with increased odds of response (odds ratio, 1.08; 95% confidence interval CI: 1.00, 1.15; P = .04). A positive association was detected between changes in tDV and best percentage change in prostate-specific antigen level and circulating tumor cell count (r = 0.63 95% CI: 0.27, 0.83 and r = 0.77 95% CI: 0.51, 0.90, respectively). When assessing five target lesions, decreases in volume were associated with response (odds ratio for volume increase, 0.89; 95% CI: 0.80, 0.99; P = .037). Conclusion This pilot study showed that decreases in volume and increases in median ADC of bone metastases assessed with whole-body DWI can potentially be used as indicators of response to olaparib in mCRPC. Online supplemental material is available for this article.
Drug delivery is an important field of nanomedicine, and its aim is to deliver specific active substances to a precise site of action in order to produce a desired pharmacological effect. In the ...present study nanocapsules were obtained by a process of interfacial condensation between chitosan (dissolved in the aqueous phase) and poly(
-vinyl pyrrolidone-
-itaconic anhydride), a highly reactive copolymer capable of easily opening the anhydride ring under the action of amine groups of chitosan. The formed amide bonds led to the formation of a hydrogel membrane. The morphology of the obtained nanocapsules, their behavior in aqueous solution of physiological pH, and their ability to encapsulate and release a model drug can be modulated by the parameters of the synthesis process, such as the molar ratio between functional groups of polymers and the ratio of the phases in which the polymers are solubilized. Although a priori both polymers are biocompatible, this paper reports the results of a very detailed in vivo study conducted on experimental animals which have received the obtained nanocapsules by three administration routes-intraperitoneal, subcutaneous, and oral. The organs taken from the animals' kidney, liver, spleen, and lung and analyzed histologically demonstrated the ability of nanocapsules to stimulate the monocytic macrophage system without producing inflammatory changes. Moreover, their in vivo behavior has been shown to depend not only on the route of administration but also on the interaction with the cells of the organs with which they come into contact. The results clearly argue the biocompatibility of nanocapsules and hence the possibility of their safe use in biomedical applications.
Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need ...for better patient selection.
Patients with
mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (K
), enhancing fraction (EF) and their product KEF (summarised median values of K
× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal
mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.
Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04).
mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06).
Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
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.
BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.
...This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).
Seventy-three patients received BAL101553 at doses of 15-80 mg/m
(phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m
; DLTs observed at doses ≥60 mg/m
were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m
. The RP2D for 2-h intravenous infusion was 30 mg/m
. The overall disease control rate was 26.3% in the efficacy population.
The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties.
EudraCT: 2010-024237-23.
Overuse of antimicrobials by the population has contributed to genetic modifications in bacteria and development of antimicrobial resistance, which is very difficult to combat nowadays. To solve this ...problem, it is necessary to develop new systems for the administration of antimicrobial active principles. Biocomposite systems containing silver nanoparticles can be a good medical alternative. In this context, the main objective of this study was to obtain a complex system in the form of a biocomposite film with antimicrobial properties based on chitosan, poly (vinyl alcohol) and silver nanoparticles. This new system was characterized from a structural and morphological point of view. The swelling degree, the mechanical properties and the efficiency of loading and release of an anti-inflammatory drug were also evaluated. The obtained biocomposite films are biocompatibles, this having been demonstrated by in vitro tests on HDFa cell lines, and have antimicrobial activity against S. aureus. The in vivo tests, carried out on rabbit subjects, highlighted the fact that signs of reduced fibrosis were specific to the C2P4.10.Ag1-IBF film sample, demonstrated by: intense expression of TNFAIP8 factors; as an anti-apoptotic marker, MHCII that favors immune cooperation among local cells; αSMA, which marks the presence of myofibroblasts involved in approaching the interepithelial spaces for epithelialization; and reduced expression of the Cox2 indicator of inflammation, Col I.
(1) Background: We assessed the test-re-test repeatability of radiomics in metastatic castration-resistant prostate cancer (mCPRC) bone disease on whole-body diffusion-weighted (DWI) and T1-weighted ...Dixon MRI. (2) Methods: In 10 mCRPC patients, 1.5 T MRI, including DWI and T1-weighted gradient-echo Dixon sequences, was performed twice on the same day. Apparent diffusion coefficient (ADC) and relative fat-fraction-percentage (rFF%) maps were calculated. Per study, up to 10 target bone metastases were manually delineated on DWI and Dixon images. All 106 radiomic features included in the Pyradiomics toolbox were derived for each target volume from the ADC and rFF% maps. To account for inter- and intra-patient measurement repeatability, the log-transformed individual target measurements were fitted to a hierarchical model, represented as a Bayesian network. Repeatability measurements, including the intraclass correlation coefficient (ICC), were derived. Feature ICCs were compared with mean ADC and rFF ICCs. (3) Results: A total of 65 DWI and 47 rFF% targets were analysed. There was no significant bias for any features. Pairwise correlation revealed fifteen ADC and fourteen rFF% feature sub-groups, without specific patterns between feature classes. The median intra-patient ICC was generally higher than the inter-patient ICC. Features that describe extremes in voxel values (minimum, maximum, range, skewness, and kurtosis) showed generally lower ICCs. Several mostly shape-based texture features were identified, which showed high inter- and intra-patient ICCs when compared with the mean ADC or mean rFF%, respectively. (4) Conclusions: Pyradiomics texture features of mCRPC bone metastases varied greatly in inter- and intra-patient repeatability. Several features demonstrated good repeatability, allowing for further exploration as diagnostic parameters in mCRPC bone disease.
Non-aqueous dispersions (NAD) with two types of polymeric nanoparticles (NPs), such as hydrophobic poly(
-caprolactone) (PCL) and hydrophilic cross-linked poly(vinylpyrrolidone) (PNVP), were ...synthesized in the present study starting from monomer-in-silicone oil (PDMS) polymerizable non-aqueous emulsions stabilized with the same tailor-made PDMS-based block copolymer. These NPs were loaded with CCisplatin, an antitumoral model drug, directly from the emulsion polymerization step, and it was observed that the presence of the drug leads only to a slight increase of the NPs size, from 120 to 150 nm. The drug release kinetics was evaluated at 37 °C in phosphate buffer at pH = 7.4 and it appeared that the drug release rate from the hydrophilic cross-linked PNVP-based NPs is higher than that from the hydrophobic PCL-based NPs. Moreover, haemolysis tests revealed the fact that these two types of NPs have a good compatibility with the blood. Furthermore, for both the free and drug-loaded NPs, the
cytotoxicity and apoptosis was studied on two types of cancer cell lines, such as MCF-7 (breast cancer cell line) and A-375 (skin cancer cell line). Both types of NPs had no cytotoxic effect but, at a concentration of 500 μg/mL, presented an apoptotic effect similar to that of the free drug.
Glaucoma is the second leading cause of blindness in the world. Despite the fact that many treatments are currently available for eye diseases, the key issue that arises is the administration of ...drugs for long periods of time and the increased risk of inflammation, but also the high cost of eye surgery. Consequently, numerous daily administrations are required, which reduce patient compliance, and even in these conditions, the treatment of eye disease is too ineffective. Micellar polymers are core-shell nanoparticles formed by the self-assembly of block or graft copolymers in selective solvents. In the present study, polymeric micelles (PMs) were obtained by dialysis from smart biocompatible poly(ε-caprolactone)-poly(N-vinylcaprolactam-co-N-vinylpyrrolidone) PCL-g-P(NVCL-co-NVP) graft copolymers. Two copolymers with different molar masses were studied, and a good correlation was noted between the micellar sizes and the total degree of polymerisation (DPn) of the copolymers. The micelles formed by Cop A PCL120-g-P(NVCL507-co-NVP128), with the lowest total DPn, have a Z-average value of 39 nm, whereas the micellar sizes for Cop B PCL120-g-P(NVCL1253-co-NVP139) are around 47 nm. These PMs were further used for the encapsulation of two drugs with applications for the treatment of eye diseases. After the encapsulation of Dorzolamide, a slight increase in micellar sizes was noted, whereas the encapsulation of Indomethacin led to a decrease in these sizes. Using dynamic light scattering, it was proved that both free and drug-loaded PMs are stable for 30 days of storage at 4 °C. Moreover, in vitro biological tests demonstrated that the obtained PMs are both haemo- and cytocompatible and thus can be used for further in vivo tests. The designed micellar system proved its ability to release the encapsulated drugs in vitro, and the results obtained were validated by in vivo tests carried out on experimental animals, which proved its high effectiveness in reducing intraocular pressure.
Diffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can ...also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response.
This prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm
diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters diffusion coefficient D (10
mm
/s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10
mm
/s), and their product fD* (mm
/s) and three DCE-MRI parameters volume transfer constant K
(min
), enhancement fraction EF (%), and their product KEF (min
) were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P<0.05 was considered significant). DCE-MRI and IVIM-DWI parameter correlations were evaluated with Spearman rank tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations.
Significant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P<0.001), KEF (0.095 to 0.045 min
, P<0.001) and K
(0.109 to 0.078 min
, P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10
mm
/s, P<0.001), while perfusion-related parameters showed no change. No strong correlations were found between DCE-MRI and IVIM-DWI parameters. A moderate correlation was found, after treatment, between K
and D* (r=0.60; P=0.002) and fD* (r=0.67; P<0.001). When compared to RECIST v.1.1 evaluations, KEF and D correctly identified most clinical responders, whilst non-responders were incorrectly identified.
IVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements.
NCT03010722 clinicaltrials.gov; registration date 6
January 2015.
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