Mathematical modeling of intraperitoneal drug delivery: simulation of drug distribution in a single tumor nodule

The intraperitoneal (IP) administration of chemotherapy is an alternative treatment for peritoneal carcinomatosis, allowing for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration. Nevertheless, drug penetration depths are still limited to a few millimeters. It is thus necessary to better understand the limiting factors behind this poor penetration in order to improve IP chemotherapy delivery. By developing a three-dimensional computational fluid dynamics (CFD) model for drug penetration in a tumor nodule, we investigated the impact of a number of key parameters on the drug transport and penetration depth during IP chemotherapy. Overall, smaller tumors showed better penetration than larger ones, which could be attributed to the lower IFP in smaller tumors. Furthermore, the model demonstrated large improvements in penetration depth by subjecting the tumor nodules to vascular normalization therapy, and illustrated the importance of the drug that is used for therapy. Explicitly modeling the necrotic core had a limited effect on the simulated penetration. Similarly, the penetration depth remained virtually constant when the Darcy permeability of the tissue changed. Our findings illustrate that the developed parametrical CFD model is a powerful tool providing more insight in the drug transport and penetration during IP chemotherapy

MRI-only based radiotherapy treatment planning for the rat brain on a Small Animal Radiation Research Platform (SARRP)

Computed tomography (CT) is the standard imaging modality in radiation therapy treatment planning (RTP). However, magnetic resonance (MR) imaging provides superior soft tissue contrast, increasing the precision of target volume selection. We present MR-only based RTP for a rat brain on a small animal radiation research platform (SARRP) using probabilistic voxel classification with multiple MR sequences. Six rat heads were imaged, each with one CT and five MR sequences. The MR sequences were: T1-weighted, T2-weighted, zero-echo time (ZTE), and two ultra-short echo time sequences with 20 mu s (UTE1) and 2 ms (UTE2) echo times. CT data were manually segmented into air, soft tissue, and bone to obtain the RTP reference. Bias field corrected MR images were automatically segmented into the same tissue classes using a fuzzy c-means segmentation algorithm with multiple images as input. Similarities between segmented CT and automatic segmented MR (ASMR) images were evaluated using Dice coefficient. Three ASMR images with high similarity index were used for further RTP. Three beam arrangements were investigated. Dose distributions were compared by analysing dose volume histograms. The highest Dice coefficients were obtained for the ZTE-UTE2 combination and for the T1-UTE1-T2 combination when ZTE was unavailable. Both combinations, along with UTE1-UTE2, often used to generate ASMR images, were used for further RTP. Using 1 beam, MR based RTP underestimated the dose to be delivered to the target (range: 1.4%-7.6%). When more complex beam configurations were used, the calculated dose using the ZTE-UTE2 combination was the most accurate, with 0.7% deviation from CT, compared to 0.8% for T1-UTE1-T2 and 1.7% for UTE1-UTE2. The presented MR-only based workflow for RTP on a SARRP enables both accurate organ delineation and dose calculations using multiple MR sequences. This method can be useful in longitudinal studies where CT's cumulative radiation dose might contribute to the total dose

Temperature dependence of the LabPET small-animal PET scanner

INTRODUCTION In quantitative PET imaging it is important to correct for all image-degrading effects, for example detector efficiency variation. Detector efficiency variation depends on the stability of detector efficiency when operating conditions vary within normal limits. As the efficiency of APD-based light detection strongly depends on ambient temperature, temperature-dependent detector efficiency normalization may be needed in APD-based PET scanners. We have investigated the temperature dependence of the LabPET APD-based small-animal PET scanner. MATERIALS AND METHODS First a simulation study was performed to evaluate the effect of different APD temperature coefficients on the temperature dependence of scanner sensitivity. Five experiments were also performed. First the immediate effect of temperature changes on scanner sensitivity was evaluated. Second, the effect of temperature changes that have stabilized for a few hours was investigated. In a third experiment the axial sensitivity profile was acquired at 21 degrees C and 24 degrees C. Next, two acquisitions of the NEMA image quality phantom (at 21 degrees C and 23 degrees C) were performed and absolute quantification was done based on normalization scans acquired at the correct and incorrect temperature. Finally, the feasibility of maintaining a constant room temperature and the stability of the scanner sensitivity under constant room temperature was evaluated. RESULTS Simulations showed that the relation between temperature-dependent APD gain changes and scanner sensitivity is quite complex. A temperature deviation leading to a 1 % change in APD gain corresponds to a much larger change in scanner sensitivity due to the shape of the energy histogram. In the first and second experiment a strong correlation between temperature and scanner sensitivity was observed. Changes of 2.24 kcps/MBq and 1.64 kcps/MBq per degrees C were seen for immediate and stabilized temperature changes respectively. The NEMA axial sensitivity profile also showed a decrease in sensitivity at higher temperature. The quantification experiment showed that a larger quantification error (up to 13%) results when a normalization scan acquired at the incorrect temperature is used. In the last experiment, temperature variability was 0.19 degrees C and counts varied by 10.2 Mcts (1.33%). CONCLUSION The sensitivity of the LabPET small-animal PET scanner strongly depends on room temperature. Therefore, room temperature should be kept as stable as possible and temperature-dependent detector efficiency normalization should be used. However, with constant room temperature excellent scanner stability is observed. Temperature should be kept constant within 0.5 degrees C and weekly normalization scans are recommended

Magnetic resonance imaging-guided radiation therapy using animal models of glioblastoma

Glioblastoma is the most aggressive and most common malignant primary brain tumour in adults and has a high mortality and morbidity. Because local tumour control in glioblastoma patients is still elusive in the majority of patients, there is an urgent need for alternative treatment strategies. However, to implement changes to the existing clinical standard of care, research must be conducted to develop alternative treatment strategies. A novel approach in radiotherapy is the introduction of pre-clinical precision image-guided radiation research platforms. The aim of this review is to give a brief overview of the efforts that have been made in the field of radiation research using animal models of glioblastoma. Because MRI has become the reference imaging technique for treatment planning and assessment of therapeutic responses in glioblastoma patients, we will focus in this review on small animal radiotherapy combined with MRI

Studying in vivo dynamics of xylem-transported 11CO2 using positron emission tomography

Respired CO2 in woody tissues can build up in the xylem and dissolve in the sap solution to be transported through the plant. From the sap, a fraction of the CO2 can either be radially diffuse to the atmosphere or be assimilated in chloroplasts present in woody tissues. These processes occur simultaneously in stems and branches, making it difficult to study their specific dynamics. Therefore, an 11C-enriched aqueous solution was administered to young branches of Populus tremula L., which were subsequently imaged by positron emission tomography (PET). This approach allows in vivo visualization of the internal movement of CO2 inside branches at high spatial and temporal resolution, and enables direct measurement of the transport speed of xylem-transported CO2 (vCO2). Through compartmental modeling of the dynamic data obtained from the PET images, we (i) quantified vCO2 and (ii) proposed a new method to assess the fate of xylem-transported 11CO2 within the branches. It was found that a fraction of 0.49 min−1 of CO2 present in the xylem was transported upwards. A fraction of 0.38 min−1 diffused radially from the sap to the surrounding parenchyma and apoplastic spaces (CO2,PA) to be assimilated by woody tissue photosynthesis. Another 0.12 min−1 of the xylem-transported CO2 diffused to the atmosphere via efflux. The remaining CO2 (i.e., 0.01 min−1) was stored as CO2,PA, representing the build-up within parenchyma and apoplastic spaces to be assimilated or directed to the atmosphere. Here, we demonstrate the outstanding potential of 11CO2-based plant-PET in combination with compartmental modeling to advance our understanding of internal CO2 movement and the respiratory physiology within woody tissues

Absolute quantification for small-animal PET

Quantification is important in preclinical PET studies. To achieve absolute quantification, an accurate reconstruction algorithm is necessary. Such an algorithm includes corrections for different effects such as geometric sensitivity of the scanner, detection efficiency, attenuation, scatter and random coincidences. In this work we present a method for performing absolute quantification on the LabPET system. All acquisitions were done on a GE Triumph system. This tri-modality system consists of a micro-PET (LabPET), micro-CT (X-O) and micro-SPECT (X-SPECT) scanner. Three PET scans were done. In the first scan 5 vials with different activity concentrations of F-18-FDG were scanned. The total activity inside the scanner was 80 MBq. The second scan was performed after 4 hours when the total activity in the scanner had decayed to 20 MBq. In the third scan 3 vials and 1 sphere were scanned with a total activity of 20 MBq. Before each PET scan a micro-CT scan was acquired. Point sources with a known activity were placed inside the field of view. The counts obtained in these point sources are used to obtain a correction factor for absolute sensitivity. Reconstruction was done using a 3D ML-EM reconstruction with micro-CT based attenuation correction. VOIs were drawn over the vials and the sphere in the reconstructed images. The total activity in the VOIs was calculated using the correction factor for absolute sensitivity. It was compared to the activity measured in a dose calibrator. The average quantification error was 56 %, 6.4 % and 0.6 % for the first, second and third scan. The high error in the first scan is explained by count rate effects, as 80 MBq can be considered a high activity level for this system. The feasibility of absolute quantification on the LabPET system was demonstrated. When the count rate is below 20 MBq absolute quantification is possible with an average quantification error smaller than 6.4 %

Utilizing micro-computed tomography to evaluate bone structure surrounding dental implants: a comparison with histomorphometry

Although histology has proven to be a reliable method to evaluate the ossoeintegration of a dental implant, it is costly, time consuming, destructive, and limited to one or few sections. Microcomputed tomography (µCT) is fast and delivers three-dimensional information, but this technique has not been widely used and validated for histomorphometric parameters yet. This study compared µCT and histomorphometry by means of evaluating their accuracy in determining the bone response to two different implant materials. In total, 32 titanium (Ti) and 16 hydroxyapatite (HA) implants were installed in 16 lop-eared rabbits. After 2 and 4 weeks, the animals were scarified, and the samples retrieved. After embedding, the samples were scanned with µCT and analyzed three-dimensionally for bone area (BA) and bone-implant contact (BIC). Thereafter, all samples were sectioned and stained for histomorphometry. For the Ti implants, the mean BIC was 25.25 and 28.86% after 2 and 4 weeks, respectively, when measured by histomorphometry, while it was 24.11 and 24.53% when measured with µCT. BA was 35.4 and 31.97% after 2 and 4 weeks for histomorphometry and 29.06 and 27.65% for µCT. For the HA implants, the mean BIC was 28.49 and 42.51% after 2 and 4 weeks, respectively, when measured by histomorphometry, while it was 33.74 and 42.19% when measured with µCT. BA was 30.59 and 47.17% after 2 and 4 weeks for histomorphometry and 37.16 and 44.95% for µCT. Direct comparison showed that only the 2 weeks BA for the titanium implants was significantly different between µCT and histology (p = 0.008). Although the technique has its limitations, µCT corresponded well with histomorphometry and should be considered as a tool to evaluate bone structure around implants