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ObjectiveRegorafenib 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.DesignPatients with RAS 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 (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-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). RAS 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).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Hearing loss is a major health burden, often caused by ototoxic drugs such as cisplatin and gentamicin. Effective therapy is limited by the poor penetrability of drugs into inner ear compartments. This study aimed to develop and test magnetic cationic liposomes as nanocarriers for targeted corticosteroid delivery to auditory hair cells. Carboxymethyl chitosan–coated liposomes were prepared by the lipid film hydration method, incorporating magnetic nanoparticles and dexamethasone phosphate in their aqueous core. The optimal liposomal formulation, in terms of size, zeta potential, and drug leakage over time, was selected and tested in an in vitro model of drug-induced ototoxicity. HEI-OC1 cells exposed to cisplatin or gentamicin were co-treated with the liposomal formulations, and viability, mitochondrial membrane potential, and β-galactosidase activity were assessed. The results demonstrated that magnetic, polymer-coated liposomes protected against cytotoxicity by preserving mitochondrial function and significantly reducing senescence. These findings provide a proof of concept for magnetically responsive liposomal systems as potential therapeutic platforms for preventing or treating drug-associated hearing loss.

Curcumin (CRC) is a natural active principle with important anti-inflammatory, antioxidant, antibacterial, and antitumor properties but has some limitations, such as poor bioavailability, low water solubility, and rapid metabolism. To preserve CRC’s benefits and eliminate its limitations, novel CRC-loaded core-shell electrospun nanofibers were designed. The nanofibers were prepared by co-axial electrospinning method using poly(vinyl alcohol)/CRC as core and poly(vinyl alcohol)/sodium alginate as shell. Polymer coating protects the CRC, increasing its stability. The swelling degree of CRCloaded nanofibers at pH 5.4 was around 326% higher than at pH 7.4 (297%) due to the repulsions of the anion-anion COO–groups. The release efficiency of CRC at pH 7.4 was 81%, while at pH 5.4 was about 96%. In the first 6 h, there was a slower release of CRC from the nanofibers in both acidic and slightly alkaline environments. Nanofibers showed good hemocompatibility, the values being between 2.36–3.22% after the first 90 min of contact, and after 180 min of treatment, the degree of erythrocyte lysis was between 3.78 and 4.93%. Cell viability assay on V79-4 Chinese hamster fibroblasts demonstrated that treatment with free CRC led to a value of 39% whereas for CRC-loaded nanofibers, the cell viability value increased to 59.66%. The results of the present study indicated that CRC-loaded electrospun nanofibers can have great potential for biomedical applications.

Background Deep-learning (DL) reconstructions could improve image quality and reduce acquisition time in diffusion-weighted imaging (DWI). This study assessed, qualitatively and quantitatively, DL-DWI in liver metastasis of colorectal cancer patients. Methods This prospective study enrolled 50 participants from June to November 2022. Phantom and participant data were acquired on a 1.5T MR scanner using a free-breathing DL-DWI research application sequence. Three DWIs were compared: a moderately-accelerated DL-DWI (DL-1), a corresponding standard reconstruction (Standard-1) and a highly-accelerated DL-DWI (DL-2). Image quality (four features on b750 images and one feature on ADC map) was assessed by two radiologists. Region of interest (ROI) based ADC measurements were performed at three locations: liver, spleen, liver metastasis. Across the three series, median scores and ADC values were assessed using a Friedman non-parametric test and post-hoc analysis (pairwise Wilcoxon tests with Bonferroni correction). A p-value < 0.05 was considered statistically significant. Results Fifty participants with metastatic colorectal cancer (mean age 62 years, range 36–88 years, 26 males) were evaluated. ROIs were delineated in liver ( N  = 50), spleen ( N  = 48), and liver metastasis ( N  = 11). Qualitatively, across both readers, DL-1 method received the highest scores for 5/8 features on the b750 images; all methods scored similarly on ADC maps for both readers. Quantitatively, ADCs were significantly different between DL-1 and Standard-1 series across all three organs, with DL-1-based ADC always higher ( p  < 0.01). This ADC increase was small: 8.9% (liver), 3.4% (spleen), 4.5% (liver metastasis). Conclusions This study suggests that a DL-based reconstruction is a promising technique to enable acceleration of liver DWI considering both qualitative and quantitative results. Trial registration NCT05118555 (Evaluation of New Magnetic Resonance Techniques); study date of registration (first submitted: 2021-10-18).

Background BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. Methods 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). Results Seventy-three patients received BAL101553 at doses of 15–80 mg/m 2 (phase 1, n  = 24; phase 2a, n  = 49). The MTD was 60 mg/m 2 ; DLTs observed at doses ≥60 mg/m 2 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 2 . The RP2D for 2-h intravenous infusion was 30 mg/m 2 . The overall disease control rate was 26.3% in the efficacy population. Conclusions 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. Clinical trial registration EudraCT: 2010-024237-23.

Hydrogels are a favorable alternative to accelerate the burn wound healing process and skin regeneration owing to their capability of absorbing contaminated exudates. The bacterial infections that occur in burn wounds might be treated using different topically applied materials, but bacterial resistance to antibiotics has become a major problem worldwide. Therefore, the use of non-antibiotic treatments represents a major interest in current research. In this study, new antibiocomposite hydrogels with anti-inflammatory and antimicrobial properties based on hyaluronic acid (HA) and sodium alginate (AG) were obtained using 4-(4,6-dimethoxy-1,3,5-triazinyl-2)-4-methylmorpholinium chloride as an activator. The combination of Ibuprofen, a non-steroidal anti-inflammatory drug commonly used to reduce inflammation, fever and pain in the body, with zinc oxide nanoparticles (ZnO NPs) was used in this study aimed at creating a complex hydrogel with anti-inflammatory and antimicrobial action and capable of improving the healing process of wounds caused by burns. FTIR spectra confirmed the cross-linking of AG with HA as well as the successful incorporation of ZnO NPs. Using electronic microscopy, it was noticed that the morphology of hydrogels is influenced by the incorporation of ZnO nanoparticles. Moreover, the incorporation of ZnO nanoparticles into hydrogels also has an influence on the swelling behavior at both pH 7.4 and 5.4. In fact, the swelling rate is lower when the amounts of the activator, HA and ZnO NPs are high. A drug release rate of almost 100% was observed for hydrogels without ZnO NPs, whereas the addition of nanoparticles to hydrogels led to a decrease in the release rate to 68% during 24 h. Cellular viability tests demonstrated the non-cytotoxic behavior of the hydrogels without the ZnO NPs, whereas a weak to moderate cytotoxic effect was noticed for hydrogels with ZnO NPs. The hydrogels containing 4% and 5% ZnO NPs, respectively, showed good antimicrobial activity against the S. aureus strain. These preliminary data prove that these types of hydrogels can be of interest as biomaterials for the treatment of burn wounds.

BackgroundThe Myeloma Response Assessment and Diagnosis System (MY-RADS) guidelines establish a standardised acquisition and analysis pipeline for whole-body MRI (WB-MRI) in patients with myeloma. This is the first study to assess image quality in a multi-centre prospective trial using MY-RADS.MethodsThe cohort consisted of 121 examinations acquired across ten sites with a range of prior WB-MRI experience, three scanner manufacturers and two field strengths. Image quality was evaluated qualitatively by a radiologist and quantitatively using a semi-automated pipeline to quantify common artefacts and image quality issues. The intra- and inter-rater repeatability of qualitative and quantitative scoring was also assessed.ResultsQualitative radiological scoring found that the image quality was generally good, with 94% of examinations rated as good or excellent and only one examination rated as non-diagnostic. There was a significant correlation between radiological and quantitative scoring for most measures, and intra- and inter-rater repeatability were generally good.When the quality of an overall examination was low, this was often due to low quality diffusion-weighted imaging (DWI), where signal to noise ratio (SNR), anterior thoracic signal loss and brain geometric distortion were found as significant predictors of examination quality.ConclusionsIt is possible to successfully deliver a multi-centre WB-MRI study using the MY-RADS protocol involving scanners with a range of manufacturers, models and field strengths. Quantitative measures of image quality were developed and shown to be significantly correlated with radiological assessment. The SNR of DW images was identified as a significant factor affecting overall examination quality.Trial registrationClinicalTrials.gov, NCT03188172, Registered on 15 June 2017.Critical relevance statementGood overall image quality, assessed both qualitatively and quantitatively, can be achieved in a multi-centre whole-body MRI study using the MY-RADS guidelines.Key points• A prospective multi-centre WB-MRI study using MY-RADS can be successfully delivered.• Quantitative image quality metrics were developed and correlated with radiological assessment.• SNR in DWI was identified as a significant predictor of quality, allowing for rapid quality adjustment.

BackgroundWhole-body (WB) MRI, which includes diffusion-weighted imaging (DWI) and T1-w Dixon, permits sensitive detection of marrow disease in addition to qualitative and quantitative measurements of disease and response to treatment of bone marrow. We report on the first study to embed standardised WB-MRI within a prospective, multi-centre myeloma clinical trial (IMAGIMM trial, sub-study of OPTIMUM/MUKnine) to explore the use of WB-MRI to detect minimal residual disease after treatment.MethodsThe standardised MY-RADS WB-MRI protocol was set up on a local 1.5 T scanner. An imaging manual describing the MR protocol, quality assurance/control procedures and data transfer was produced and provided to sites. For non-identical scanners (different vendor or magnet strength), site visits from our physics team were organised to support protocol optimisation. The site qualification process included review of phantom and volunteer data acquired at each site and a teleconference to brief the multidisciplinary team. Image quality of initial patients at each site was assessed. ResultsWB-MRI was successfully set up at 12 UK sites involving 3 vendor systems and two field strengths. Four main protocols (1.5 T Siemens, 3 T Siemens, 1.5 T Philips and 3 T GE scanners) were generated. Scanner limitations (hardware and software) and scanning time constraint required protocol modifications for 4 sites. Nevertheless, shared methodology and imaging protocols enabled other centres to obtain images suitable for qualitative and quantitative analysis. ConclusionsStandardised WB-MRI protocols can be implemented and supported in prospective multi-centre clinical trials.Trial registration NCT 03188172 clinicaltrials.gov; registration date 15th June 2017 https://clinicaltrials.gov/ct2/show/study/NCT03188172

Background To compare liver image quality and lesion detection using an AI-augmented T1-weighted sequence on hepatobiliary-phase gadoxetate-enhanced magnetic resonance imaging (MRI). Methods Fifty patients undergoing gadoxetate-enhanced MRI were recruited. Two T1-weighted Dixon sequences were utilized: a 17-s breath-hold acquisition and an accelerated 12-s breath-hold acquisition (reduced phase resolution), both reconstructed using neural network (NN) and iterative denoising (ID), NN-alone, ID-alone, and the standard method. Contrast-to-noise ratio (CNR) was assessed quantitatively for all series (ANOVA). Two blinded radiologists independently analyzed three image sets: 17-s acquisition reconstructed with NN and ID (17-s NN + ID), 12-s acquisition reconstructed with NN and ID (12-s NN + ID), and 17-s acquisition with standard reconstruction (17-s standard). Overall image quality, qualitative CNR, lesion edge sharpness, vessel edge sharpness, and respiratory motion artifacts were scored (4-point Likert scale) and compared (Friedman test). Lesion detection was compared between 12-s NN + ID and 17-s standard reconstructions (Wilcoxon signed-rank test). Results Quantitative liver-to-portal vein CNR was significantly higher for 17-s NN + ID than 17-s standard or 17-s NN-alone images ( p  = 0.001). Scores for overall image quality, qualitative CNR, vessel edge sharpness, and lesion edge sharpness were significantly higher for 17-s NN + ID and 12-s NN + ID than standard reconstruction ( p  < 0.001); there was no significant difference between 17-s and 12-s NN + ID. There was no significant difference in respiratory motion artifacts and number of lesions or diameter of the smallest detected lesion using 12-s NN + ID or 17-s standard reconstruction. Conclusion AI-augmented reconstructions can improve image quality while reducing breath-hold duration in T1-weighted hepatobiliary-phase gadoxetate-enhanced MRI, without compromising lesion detection. Relevance statement AI-augmented reconstruction of T1-weighted MRI improves image quality and lesion detection in hepatobiliary phase liver imaging, reducing breath-hold duration without compromising clinical lesion detection. Key Points Liver-to-portal vein CNR was significantly higher for 17-s NN + ID. AI-augmented reconstructions scored higher for image quality, contrast-to-noise, vessel-edge, and lesion-edge sharpness. No significant difference in lesion detection between 12-s NN + ID and 17-s standard reconstructions. Graphical Abstract

Non-aqueous dispersions (NAD) with two types of polymeric nanoparticles (NPs), such as hydrophobic poly(ε-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 in vitro 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.