Radiosensitising effect of electrochemotherapy with bleomycin in LPB sarcoma cells and tumors in mice

BACKGROUND: Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system – electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo. METHODS: LPB sarcoma cells and tumors were treated either with bleomycin, electroporation or ionizing radiation, and combination of these treatments. In vitro, response to different treatments was determined by colony forming assay, while in vivo, treatment effectiveness was determined by local tumor control (TCD(50)). Time dependence of partial oxygen pressure in LPB tumors after application of electric pulses was measured by electron paramagnetic oxyimetry. RESULTS: Electroporation of cells in vitro increased radiosensitising effect of bleomycin for 1.5 times, in vivo radiation response of tumors was enhanced by 1.9 fold compared to response of tumors that were irradiated only. Neither treatment of tumors with bleomycin nor application of electric pulses only, affected radiation response of tumors. Application of electric pulses to the tumors induced profound but transient reduction of tumor oxygenation. Although tumor oxygenation after electroporation partially restored at the time of irradiation, it was still reduced at the level of radiobiologically relevant hypoxia. CONCLUSION: Our study shows that application of electric pulses to cells and tumors increases radiosensitising effect of bleomycin. Furthermore, our results demonstrate that the radiobiologically relevant hypoxia induced by electroporation of tumors did not counteract the pronounced radiosensitising effect of electrochemotherapy with bleomycin

A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans.

RATIONALE AND OBJECTIVES: The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies. MATERIALS AND METHODS: We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography-computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts. RESULTS: XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT. CONCLUSIONS: In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system

Characteristics of very high‐energy electron beams for the irradiation of deep‐seated targets

Driven by advances in accelerator technology and the potential of exploiting the FLASH effect for the treatment of deep-seated targets (&gt;5 cm), there is an active interest in the construction of devices to deliver very high-energy electron (VHEE) beams for radiation therapy. The application of novel VHEE devices, however, requires an assessment of the tradeoffs between the different beam parameter choices including beam energies, beam divergences, and maximal field sizes. This study systematically examines the dosimetric beam properties of VHEE beams, determining their clinical usefulness while marking their limits of applications for different beam configurations. We performed Monte Carlo simulations of the dose distributions of electron beams for different energies (25-250 MeV), source-to-surface distances (SSD) (50 cm, 100 cm, parallel), and field sizes (2 cm &lt;sup&gt;2&lt;/sup&gt; × 2 cm &lt;sup&gt;2&lt;/sup&gt; to 15 cm &lt;sup&gt;2&lt;/sup&gt; × 15 cm &lt;sup&gt;2&lt;/sup&gt; ) in water using a research version of the RayStation treatment planning system (RaySearch Labs 9A IONPG). The beam was simulated using a monoenergetic point source and perfect collimation. Central axis percentage depth dose (PDD) and transverse dose profiles at multiple depths were evaluated and compared to those of MV photon beams. Profile characteristics including therapeutic range (TR) at 90%, proximal fall-off (PFO) at 90%, lateral penumbra (LP) at 90%-10%, and field width (FW) at 90% were obtained. Very high-energy electrons beams with SSD 100 cm and parallel beams (infinite SSD) exhibit a linear to near-linear increase of TR as a function of energy in the simulated energy range and reach values well beyond the typical depths of lesions encountered in clinics (&lt;20 cm). Their TR show a marked field size dependence only for field sizes &lt;10 cm &lt;sup&gt;2&lt;/sup&gt; × 10 cm &lt;sup&gt;2&lt;/sup&gt; . For VHEE beams with SSD 50 cm, TR are largely reduced (4-8 cm). For beam energies &gt;150 MeV with large SSD (&gt;100 cm), for many configurations, there is no substantial difference in PDD when adding an opposed beam. This may potentially reduce the number of VHEE beams needed for treatment by a factor of two compared to a treatment using lower energies and lower SSD. In order to cover deep-seated targets homogeneously, VHEE devices with a parallel beam must provide a maximum field size up to several centimeters larger than the tumor size. For the investigated diverging beams, there is not such a significant field width reduction with depth for larger fields as it is compensated by divergence. Penumbrae of VHEE beams are smaller than those of clinical MV photon beams for lower depths (&lt;5 cm) but increase quickly for larger depths. There is only a relatively small dependence of penumbra on the SSD of the beam. The findings presented in this study assess the performance of VHEE beams and offer a first estimate of treatment indications and tradeoffs for a given design of a VHEE device. SSD &gt;100 cm results in clinically more favorable PDD. Beam energies of 100 MeV and above are needed to cover common tumors (5-15 cm in-depth) conformally. Higher energies provide an additional benefit specifically for small and deep-seated lesions due to their reduced lateral penumbrae