Contrast-enhanced, conebeam CT-based, fractionated radiotherapy and follow-up monitoring of orthotopic mouse glioblastoma: a proof-of-concept study.

BACKGROUND: Despite aggressive treatment regimens comprising surgery and radiochemotherapy, glioblastoma (GBM) remains a cancer entity with very poor prognosis. The development of novel, combined modality approaches necessitates adequate preclinical model systems and therapy regimens that closely reflect the clinical situation. So far, image-guided, fractionated radiotherapy of orthotopic GBM models represents a major limitation in this regard. METHODS: GL261 mouse GBM cells were inoculated into the right hemispheres of C57BL/6 mice. Tumor growth was monitored by contrast-enhanced conebeam CT (CBCT) scans. When reaching an average volume of approximately 7 mm3, GBM tumors were irradiated with daily fractions of 2 Gy up to a cumulative dose of 20 Gy in different beam collimation settings. For treatment planning and tumor volume follow-up, contrast-enhanced CBCT scans were performed twice per week. Daily repositioning of animals was achieved by alignment of bony structures in native CBCT scans. When showing neurological symptoms, mice were sacrificed by cardiac perfusion. Brains, livers, and kidneys were processed into histologic sections. Potential toxic effects of contrast agent administration were assessed by measurement of liver enzyme and creatinine serum levels and by histologic examination. RESULTS: Tumors were successfully visualized by contrast-enhanced CBCT scans with a detection limit of approximately 2 mm3, and treatment planning could be performed. For daily repositioning of the animals, alignment of bony structures in native CT scans was well feasible. Fractionated irradiation caused a significant delay in tumor growth translating into significantly prolonged survival in clear dependence of the beam collimation setting and margin size. Brain sections revealed tumors of similar appearance and volume on the day of euthanasia. Importantly, the repeated contrast agent injections were well tolerated, as liver enzyme and creatinine serum levels were only subclinically elevated, and liver and kidney sections displayed normal histomorphology. CONCLUSIONS: Contrast-enhanced, CT-based, fractionated radiation of orthotopic mouse GBM represents a versatile preclinical technique for the development and evaluation of multimodal radiotherapeutic approaches in combination with novel therapeutic agents in order to accelerate translation into clinical testing.

Practical implications for the quality assurance of modulated radiation therapy techniques using point detector arrays.

PURPOSE: Linac parameters potentially influencing the delivery quality of IMRT and VMAT plans are investigated with respect to threshold ranges, consequently to be considered in a linac based quality assurance procedure. Three commercially available 2D arrays are used to further investigate the influence of the measurement device. METHODS: Using three commercially available 2D arrays (Mx: MatriXXevolution , Oc: Octavius1500 , Mc: MapCHECK2), simple static measurements, measurements for MLC characterization and dynamic interplay of gantry movement, MLC movement and variable dose rate were performed. The results were evaluated with respect to each single array as well as among each other. RESULTS: Simple static measurements showed different array responses to dose, dose rate and profile homogeneity and revealed instabilities in dose delivery and profile shape during linac ramp up. Using the sweeping gap test, all arrays were able to detect small leaf misalignments down to ±0.1 mm, but this test also demonstrated up to 15% dose deviation due to profile instabilities and fast accelerating leaves during linac ramp up. Tests including gantry rotation showed different stability of gantry mounts for each array. Including gantry movement and dose rate variability, differences compared to static delivery were smaller compared to dose differences when simultaneously controling interplay of gantry movement, leaf movement and dose rate variability. CONCLUSION: Linac based QA is feasible with the tested commercially available 2D arrays. Limitations of each array and the linac ramp up characteristics should be carefully considered during individual plan generation and regularly checked in linac QA. Especially the dose and dose profile during linac ramp up should be checked regularly, as well as MLC positioning accuracy using a sweeping gap test. Additionally, dynamic interplay tests including various gantry rotation speeds and angles, various leaf speeds and various dose rates should be included.

Ionoacoustic tomography of the proton Bragg peak in combination with ultrasound and optoacoustic imaging.

Ions provide a more advantageous dose distribution than photons for external beam radiotherapy, due to their so-called inverse depth dose deposition and, in particular a characteristic dose maximum at their end-of-range (Bragg peak). The favorable physical interaction properties enable selective treatment of tumors while sparing surrounding healthy tissue, but optimal clinical use requires accurate monitoring of Bragg peak positioning inside tissue. We introduce ionoacoustic tomography based on detection of ion induced ultrasound waves as a technique to provide feedback on the ion beam profile. We demonstrate for 20 MeV protons that ion range imaging is possible with submillimeter accuracy and can be combined with clinical ultrasound and optoacoustic tomography of similar precision. Our results indicate a simple and direct possibility to correlate, in-vivo and in real-time, the conventional ultrasound echo of the tumor region with ionoacoustic tomography. Combined with optoacoustic tomography it offers a well suited pre-clinical imaging system.

[Implants with 32P-foils for LDR-brachytherapy of benign stenosis in urology and gastroenterology]. / (32)P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie.

For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P-foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy.

Scanning irradiation device for mice in vivo with pulsed and continuous proton beams.

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 µm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.