Ramesh C. Tailor

Energy dependence and dose response of Gafchromic EBT2 film over a wide range of photon, electron, and proton beam energies.

PURPOSE Since the Gafchromic film EBT has been recently replaced by the newer model EBT2, its characterization, especially energy dependence, has become critically important. The energy dependence of the dose response of Gafchromic EBT2 film is evaluated for a broad range of energies from different radiation sources used in radiation therapy. METHODS The beams used for this study comprised of kilovoltage x rays (75, 125, and 250 kVp), 137Cs gamma (662 KeV), 60Co gamma (1.17-1.33 MeV), megavoltage x rays (6 and 18 MV), electron beams (6 and 20 MeV), and proton beams (100 and 250 MeV). The films response to each of the above energies was measured over the dose range of 0.4-10 Gy, which corresponds to optical densities ranging from 0.05 to 0.74 for the film reader used. RESULTS The energy dependence of EBT2 was found to be relatively small within measurement uncertainties (1 sigma = +/- 4.5%) for all energies and modalities. CONCLUSION For relative and absolute dosimetry of radiation therapy beams, the weak energy dependence of the EBT2 makes it most suitable for clinical use compared to other films.

Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

UNLABELLED We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach. FROM THE CLINICAL EDITOR The ability of gold nanoparticles (AuNPs) to enhance the effect of physical radiation dose on tumor cells is known. This radiosensitization effect is thought to result from an increased number of photoelectric absorption events and the increased number of electrons present in gold. The authors here sought to further increase the amount and specificity of gold accumulation in prostatic cancer cells by conjugating gold nanorods to goserelin, a synthetic luteinizing hormone releasing hormone (LHRH) analogue that would bind to the LHRH receptor overexpressed in prostate cancers. It was shown that tumour cells were more sensitive to megavoltage radiation therapy. It is hoped that there would be eventual clinical translation of this approach.

Report of AAPM Therapy Physics Committee Task Group 74: in-air output ratio, Sc, for megavoltage photon beams.

The concept of in-air output ratio (Sc) was introduced to characterize how the incident photon fluence per monitor unit (or unit time for a Co-60 unit) varies with collimator settings. However, there has been much confusion regarding the measurement technique to be used that has prevented the accurate and consistent determination of Sc. The main thrust of the report is to devise a theoretical and measurement formalism that ensures interinstitutional consistency of Sc. The in-air output ratio, Sc, is defined as the ratio of primary collision water kerma in free-space, Kp, per monitor unit between an arbitrary collimator setting and the reference collimator setting at the same location. Miniphantoms with sufficient lateral and longitudinal thicknesses to eliminate electron contamination and maintain transient electron equilibrium are recommended for the measurement of Sc. The authors present a correction formalism to extrapolate the correct Sc from the measured values using high-Z miniphantom. Miniphantoms made of high-Z material are used to measure Sc for small fields (e.g., IMRT or stereotactic radiosurgery). This report presents a review of the components of Sc, including headscatter, source-obscuring, and monitor-backscattering effects. A review of calculation methods (Monte Carlo and empirical) used to calculate Sc for arbitrary shaped fields is presented. The authors discussed the use of Sc in photon dose calculation algorithms, in particular, monitor unit calculation. Finally, a summary of Sc data (from RPC and other institutions) is included for QA purposes.

A generic off-axis energy correction for linac photon beam dosimetry

Cooperative clinical trial group protocols frequently require off-axis point dose calculations. The Radiological Physics Center uses the calculative technique developed by Hanson et al. [Med. Phys. 7, 145-146 (1980); 7, 147-150 (1980)] to verify these calculations. In order to correct for off-axis energy changes, this technique requires off-axis half-value layer data, HVL, as a function of off-axis ray angle for the specific beam. This paper presents a formulism based on HVL mesurements on a limited number of therapy beams, which allows the calculation of an off-axis energy-correction factor for any clinical photon beam created by a linear accelerator using conventional flattening filters.

EBT2 film as a depth-dose measurement tool for radiotherapy beams over a wide range of energies and modalities

PURPOSE One of the fundamental parameters used for dose calculation is percentage depth-dose, generally measured employing ionization chambers. There are situations where use of ion chambers for measuring depth-doses is difficult or problematic. In such cases, radiochromic film might be an alternative. The EBT-2 model GAFCHROMIC™ film was investigated as a potential tool for depth-dose measurement in radiotherapy beams over a broad range of energies and modalities. METHODS Pieces of the EBT-2 model GAFCHROMIC™ EBT2 film were exposed to x-ray, electron, and proton beams used in radiotherapy. The beams employed for this study included kilovoltage x-rays (75 kVp), (60)Co gamma-rays, megavoltage x-rays (18 MV), electrons (7 and 20 MeV), and pristine Bragg-peak proton beams (126 and 152 MeV). At each beam quality, film response was measured over the dose range of 0.4-8.0 Gy, which corresponds to optical densities ranging from 0.05 to 0.4 measured with a flat-bed document scanner. To assess precision in depth-dose measurements with the EBT-2 model GAFCHROMIC™ film, uncertainty in measured optical density was investigated with respect to variation in film-to-film and scanner-bed uniformity. RESULTS For most beams, percentage depth-doses measured with the EBT-2 model GAFCHROMIC™ film show an excellent agreement with those measured with ion chambers. Some discrepancies are observed in case of (i) kilovoltage x-rays at larger depths due to beam-hardening, and (ii) proton beams around Bragg-peak due to quenching effects. For these beams, an empirical polynomial correction produces better agreement with ion-chamber data. CONCLUSIONS The EBT-2 model GAFCHROMIC™ film is an excellent secondary dosimeter for measurement of percentage depth-doses for a broad range of beam qualities and modalities used in radiotherapy. It offers an easy and efficient way to measure beam depth-dose data with a high spatial resolution.

An empirical relationship for determining photon beam quality in TG-21 from a ratio of percent depth doses

A key component of the Radiological Physics Centers (RPC) on-site dosimetry review visits are photon beam calibrations for which determination of the energy of the x ray is a key element. The ratio of ionizations, TPR20/TPR10, for a 10 cm x 10 cm field at depths of 20 and 10 cm for a constant SCD is used as a quantitative measure of beam quality in the Task Group 21 protocol. The RPC has measured both TPR20/TPR10 and the corresponding ratio of percent depth dose (D20/D10) at a constant SSD for 685 photon beams (4-25 MV) for most makes and models if accelerators. A strong correlation between TPR20/TPR10 and D20/D10 is presented which allows the determination of the TPR ratio from the measurement of the ratio of percent depth doses. An analysis of the uncertainty introduced in the TG-21 factors (L/rho, Pwall, Prepl) caused by the spread in the measured data and translated into the determination of the TPR ratio results in an insignificant error (< 0.3%). This empirical relationship provides an alternate technique for quantifying the beam quality defined in the TG-21 protocol without surrendering any loss of precision in output calibration. This technique may be found by those who calibrate at a fixed SSD to be an easier and quicker method.

Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing.

PURPOSE To provide the foundation for combining immunotherapy to induce tumor antigen-specific T cells with proton radiation therapy to exploit the activity of those T cells. METHODS AND MATERIALS Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. RESULTS These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. CONCLUSIONS These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

A first order approximation of field-size and depth dependence of wedge transmission

The Radiological Physics Center, through its dosimetry review visits to participating institutions, is aware that many institutions ignore the field-size and depth dependence of wedge transmission values. Reference wedge transmission values are normally measured by the Radiological Physics Center for a 10 cm x 10 cm field at the calibration depth of 5 or 7 cm. Recently, additional measurements (1) for a 10 cm x 10 cm field at 20-cm depth and (2) for a 20 cm x 20 cm field at the calibration depth were included. The transmission under these two conditions was compared with that under reference conditions. The relative transmission values for 138 photon beams from 88 separate linear accelerators (4-25 MV) and 60Co units were measured. Our data suggest that the dependence of the wedge transmission on field-size and depth, in the first approximation, depends on the absolute value of the transmission under reference conditions. For wedges with a transmission value greater than 0.65%, field-size dependence and change in depth dose are typically less than 2%. However, for wedges with transmission values less than 0.65%, field-size dependence increases with decreasing reference wedge transmission. The change in wedge transmission with depth is significant (> 2%) only for photon energies less than or equal to 10 MV and can exceed 5% for thick wedges. Failure to include the depth and field-size dependencies of wedge transmission in patient dosimetry calculations can result in significant tumor-dose discrepancies.

Evaluation of hyperpolarized [1-13C]-pyruvate by magnetic resonance to detect ionizing radiation effects in real time

Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real-time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-13C] pyruvate HP-MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping.

Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys

Hormone suppression given before or after cytotoxic treatment stimulates the recovery of spermatogenesis from endogenous and transplanted spermatogonial stem cells (SSC) and restores fertility in rodents. To test whether the combination of hormone suppression and transplantation could enhance the recovery of spermatogenesis in primates, we irradiated (7 Gy) the testes of 12 adult cynomolgus monkeys and treated six of them with gonadotropin‐releasing hormone antagonist (GnRH‐ant) for 8 weeks. At the end of this treatment, we transfected cryopreserved testicular cells with green fluorescent protein‐lentivirus and autologously transplanted them back into one of the testes. The only significant effect of GnRH‐ant treatment on endogenous spermatogenesis was an increase in the percentage of tubules containing differentiated germ cells (tubule differentiation index; TDI) in the sham‐transplanted testes of GnRH‐ant–treated monkeys compared with radiation‐only monkeys at 24 weeks after irradiation. Although transplantation alone after irradiation did not significantly increase the TDI, detection of lentiviral DNA in the spermatozoa of one radiation‐only monkey indicated that some transplanted cells colonized the testis. However, the combination of transplantation and GnRH‐ant clearly stimulated spermatogenic recovery as evidenced by several observations in the GnRH‐ant–treated monkeys receiving transplantation: (i) significant increases (~20%) in the volume and weight of the testes compared with the contralateral sham‐transplanted testes and/or to the transplanted testes of the radiation‐only monkeys; (ii) increases in TDI compared to the transplanted testes of radiation‐only monkeys at 24 weeks (9.6% vs. 2.9%; p = 0.05) and 44 weeks (16.5% vs. 6.1%, p = 0.055); (iii) detection of lentiviral sequences in the spermatozoa or testes of five of the GnRH‐ant–treated monkeys and (iv) significantly higher sperm counts than in the radiation‐only monkeys. Thus hormone suppression enhances spermatogenic recovery from transplanted SSC in primates and may be a useful tool in conjunction with spermatogonial transplantation to restore fertility in men after cancer treatment.