Long term safety and visibility of a novel liquid fiducial marker for use in image guided radiotherapy of non-small cell lung cancer.

Safety and clinical feasibility of injecting a novel liquid fiducial marker for use in image guided radiotherapy in 15 patients with non-small cell lung cancer are reported. No major safety or toxicity issues were encountered. Markers present at start of radiotherapy remained visible in cone beam computed tomography and fluoroscopy images throughout the treatment course and on computed tomography images during follow-up (0-38 months). Marker volume reduction was seen until 9 months after treatment, after which no further marker breakdown was found. No post-treatment migration or marker related complications were found.

Quantification of MRI visibility and artifacts at 3T of liquid fiducial marker in a pancreas tissue-mimicking phantom.

PURPOSE: X-ray-based position verification of the target volume in image-guided radiation therapy (IGRT) of patients with pancreatic ductal adenocarcinoma (PDAC) is currently performed on solid fiducial markers that are implanted under endoscopic ultrasonography. A new biodegradable liquid fiducial marker has recently been introduced. To assess its potential use for magnetic resonance imaging (MRI)-guided photon or proton radiotherapy of PDAC, the MRI visibility and artifacts of this marker were quantified and compared against solid gold markers. MATERIAL AND METHODS: Different spherical volumes (10 µL, 25 µL, 50 µL, and 100 µL) of a biodegradable liquid fiducial marker as well as seven differently sized and oriented solid gold (0.35 mm diameter; 5 mm and 10 mm length) and iron-gold alloy fiducial markers (0.28 mm diameter; 1 cm and 2 cm length) were implanted in a spherical gel phantom, mimicking the proton spin relaxation properties of healthy pancreatic tissue at 3 Tesla. MR relaxometry was performed to quantify the size and magnitude of the decrease in the effective transversal relaxation time T2∗ and relative proton density ρ(H) as a measure of potential visibility and to quantify the size and magnitude of the increase in magnetic field inhomogeneity ΔB0 as a measure of potential signal artifacts. The phantom was scanned in a 3.0 T PET/MR scanner with an eight-channel head coil. RESULTS: The solid fiducial markers showed a direct linear relationship between the potentially visible size and artifact size. The liquid fiducial marker showed a tendency toward a potentially visible size at smaller artifacts. Liquid markers from 25 to 100 µL generated visible volumes comparable to the size of the solid markers. The magnitude of visibility was the highest for the liquid fiducial marker with volumes of 25-100 µL showing no correlation with the magnitude of artifact. The solid markers showed a strong nonlinear correlation between magnitude of visibility and artifact, whereas the solid marker consisting of a gold-iron alloy induced the strongest artifacts. CONCLUSION: The liquid fiducial marker causes signal voids on MRI due to its absence of water hydrogen atoms without strongly affecting the magnetic field in the surrounding tissue. The alteration of the static magnetic field was found to be the main effect leading to the visibility of the solid fiducial markers. Hence, especially when a low level of image distortion is required, MRI characteristics of the liquid marker surpass those of solid gold markers currently being used for IGRT of PDAC.

Injectable iodine-125 labeled tissue marker for radioactive localization of non-palpable breast lesions.

We have developed a 125I-radiolabeled injectable fiducial tissue marker with the potential to replace current methods used for surgical guidance of non-palpable breast tumors. Methods in routine clinical use today such as radioactive seed localization, radio-guided occult lesion localization and wire-guided localization suffers from limitations that this injectable fiducial tissue marker offers solutions to. The developed 125I-radiolabeled injectable fiducial tissue marker is based on highly viscous sucrose acetate isobutyrate. The marker was readily inserted in NMRI mice and proved to be spatially well-defined and stable over a seven day period with excellent CT contrast (>1500 HU), enabling fluoroscopic visualization of the marker during placement. The radioactivity remains strongly associated with the marker during the implantation period, which limits exposure to healthy tissue. Biodistribution studies show that there is negligible radioactivity in all non-tumor tissues sampled, with the exception of the thyroid gland, where limited accumulation was observed (0.06% of injected dose after 7 days). Based on the excellent performance of the marker and the fact that it can be delivered through thin hypodermic needles (≥27G), the marker holds great promise for clinical application, since patient discomfort is reduced significantly compared to current methods. STATEMENT OF SIGNIFICANCE: A new type of tissue marker for local administration to non-palpable breast tumors has been developed. The surgical guidance marker is based on derivatives of the biomaterial sucrose acetate isobutyrate and unlike currently used markers it is injectable in the tissue using thin needles, reducing the discomfort to the patients significantly. The marker confers CT contrast and has radioactive properties, meaning it also could find use in brachytherapy. The design of the iodine-125 labeled fiducial tissue marker enables control of dosimetry as well as a choice of iodine isotope used. The marker is anticipated to be clinical applicable due to its contrast performance in mice and its potential for enhanced flexibility in surgical procedures, compared to current methods.

Liquid fiducial marker applicability in proton therapy of locally advanced lung cancer.

BACKGROUND AND PURPOSE: We investigated the clinical applicability of a novel liquid fiducial marker (LFM) for image-guided pencil beam scanned (PBS) proton therapy (PBSPT) of locally advanced lung cancer (LALC). MATERIALS AND METHODS: The relative proton stopping power (RSP) of the LFM was calculated and measured. Dose perturbations of the LFM and three solid markers, in a phantom, were measured. PBSPT treatment planning on computer tomography scans of five patients with LALC with the LFM implanted was performed with 1-3 fields. RESULTS: The RSP was experimentally determined to be 1.164 for the LFM. Phantom measurements revealed a maximum relative deviation in dose of 4.8% for the LFM in the spread-out Bragg Peak, compared to 12-67% for the solid markers. Using the experimentally determined RSP, the maximum proton range error introduced by the LFM is about 1mm. If the marker was displaced at PBSPT, the maximum dosimetric error was limited to 2 percentage points for 3-field plans. CONCLUSION: The dose perturbations introduced by the LFM were considerably smaller than the solid markers investigated. The RSP of the fiducial marker should be corrected in the treatment planning system to avoid errors. The investigated LFM introduced clinically acceptable dose perturbations for image-guided PBSPT of LALC.

Liquid fiducial marker performance during radiotherapy of locally advanced non small cell lung cancer.

BACKGROUND AND PURPOSE: We analysed the positional and structural stability of a long-term biodegradable liquid fiducial marker (BioXmark) for radiotherapy in patients with locally advanced lung cancer. MATERIAL AND METHODS: Markers were injected via endoscopic- or endobronchial ultrasound in lymph nodes and reachable primary tumours. Marker volume and Hounsfield Units (HU) changing rates were estimated using breath-hold CBCT. Inter-fraction variation in marker position relative to gross tumour volume (GTV) position was established, as well as the inter-fraction variation in mediastinal marker registration relative to a carina registration through the treatment. RESULTS: Fifteen patients were included and 29 markers analysed. All markers that were in situ at planning were visible through the treatment. Mean HU was 902±165HU for lymph node and 991±219HU for tumour markers. Volume degradation rates were -5% in lymph nodes and -23% in primary tumours. Three-dimensional inter-fraction variation for marker position relative to the GTV position was -0.1±0.7mm in lymph nodes and -1.5±2.3mm in primary tumours. Inter-fraction variations in marker registration relative to carina registration were -0.4±1.2mm in left-right, 0.2±2.0mm in anterior-posterior and -0.5±2.0mm in cranio-caudal directions. CONCLUSIONS: The liquid fiducial markers were visible and stable in size and position throughout the treatment course.

Effective nanoparticle-based gene delivery by a protease triggered charge switch.

Gene carriers made from synthetic materials are of interest in relation to gene therapy but suffer from lack of transfection efficiency upon systemic delivery. To address this problem, a novel lipo-peptide-PEG conjugate constituted by a lipid-anchor, a peptide sensitive to proteases and a poly (ethylene glycol) (PEG) chain is investigated. Utilizing ethanol-mediated nucleic acid encapsulation to prepare lipo-nanoparticles (LNPs), LNPs that are stable in serum are obtained. The LNPs constitute a highly effective gene delivery systems in vitro and possess the right features for further investigation in vivo including a PEG layer and a net negative charge that should ensure long-circulating properties before being activated by proteases in diseased tissue. Protease activation leads to detachment of PEG and a charge switching where the LNPs become positive due to the presence of glutamates in the cleaved peptide moiety. The cationic lipid DOTAP is used mainly to complex DNA and proton titratable DODAP is used to increase endosomal escape and enhance transfection efficiency. The idea of using a mixture of permanently charged and titratable cationic lipids shielded by a protease sensitive negatively charged lipo-peptide-PEG coat appears to be a highly efficient solution for achieving effective non-viral gene delivery and the results warrant further investigations.