Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Evaluation of a compact multicontrast and multiresolution X-ray phase contrast edge illumination system for small animal imaging.

PURPOSE: In this work the performance of a compact multiresolution and multicontrast x-ray phase system based on edge illumination is investigated. It has been designed for small animal imaging and with a limited footprint for ease of deployment in laboratories. METHODS: The presented edge illumination system is based on a compact microfocus tungsten x-ray source combined with a flat panel detector. The source has a maximum output of 10 W when the minimum spot size of about 15 µm is used. The system has an overall length of 70 cm. A new double sample mask design, obtained by arranging both skipped and nonskipped configurations on the same structure, provides dual resolution capability. To test the system, we carried out computed tomography (CT) scans of a plastic phantom with different source settings using both single-image and multi-image acquisition schemes at different spatial resolutions. In addition, CT scans of an ex-vivo mouse specimen were acquired at the best identified working conditions to demonstrate the application of the presented system to small animal imaging. RESULTS: We found this system delivers good image quality, allowing for an efficient material separation and improving detail visibility in small animals thanks to the higher signal-to-noise ratio (SNR) of phase contrast with respect to conventional attenuation contrast. The system offers high versatility in terms of spatial resolution thanks to the double sample mask design integrated into a single scanner. The availability of both multi- and single-image acquisition schemes coupled with their dedicated retrieval algorithms, allows different working modes which can be selected based on user preference. Multi-image acquisition provides quantitative separation of the real and imaginary part of the refractive index, however, it requires a long scanning time. On the other hand, the single image approach delivers the best material separation and image quality at all the investigated source settings with a shorter scanning time but at the cost of quantitativeness. Finally, we also observed that the single image approach combined with a high-power x-ray source may result in a fast acquisition protocol compatible with in-vivo imaging.

A Preliminary Investigation into the Use of Edge Illumination X-ray Phase Contrast Micro-CT for Preclinical Imaging.

PURPOSE: To enable a preliminary assessment of the suitability of edge illumination (EI) x-ray phase contrast (XPC) micro x-ray computed tomography (micro-CT) to preclinical imaging. Specifically, to understand how different acquisition schemes and their combination with dedicated data processing affect contrast-to-noise ratio (CNR) and spatial resolution, while providing control over scan time and radiation dose delivery. PROCEDURES: Deceased mice (n = 3) were scanned with an EI XPC micro-CT setup operated under different settings, leading to scan times between 18 h and 13 min. For the shortest scan, the entrance dose was measured with a calibrated PTW 23344 ion chamber. Different data processing methods were applied, retrieving either separate attenuation and phase images, or hybrid (combined attenuation and phase) images. A quantitative comparison was performed based on CNR and spatial resolution measurements for a soft tissue interface. RESULTS: All phase-based images have led to a higher CNR for the considered soft tissue interface than the attenuation image, independent of scan time. The best relative CNR (a sixfold increase) was observed in one of the hybrid images. Spatial resolution was found to be connected to scan time, with a resolution of approximately 20 µm and 60 µm achieved for the longest and shortest scans, respectively. An entrance dose of approximately 300 mGy was estimated for the scan performed within 13 min. CONCLUSIONS: Despite their preliminary nature, our results suggest that EI XPC bears potential for enhancing the utility of preclinical micro-CT, and, pending further research and development, could ultimately become a valuable technique in this field.