Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

Development of a collapsed cone convolution/superposition dose calculation algorithm with a mass density-specific water kernel for magnetic resonance-guided radiotherapy.

This study aimed to develop and validate a collapsed cone convolution for magnetic resonance-guided radiotherapy (CCCMR). The 3D energy deposition kernels (EDKs) were generated in water in a 1.5-T transverse magnetic field. The CCCMR corrects the inhomogeneity in simulation geometry by referring to the EDKs according to the mass density between the interaction and energy deposition points in addition to density scaling. Dose distributions in a water phantom and in slab phantoms with inserted inhomogeneities were calculated using the Monte Carlo (MC) and CCCMR. The percentage depth dose (PDD) and off-axis ratio (OAR) were compared, and the gamma passing rate (3%/2 mm) was evaluated. The CCCMR simulated asymmetric dose distributions in the simulation phantoms, especially the water phantom, and all PDD and OAR profiles were in good agreement with the findings of the MC. The gamma passing rates were >99% for each field size and for the entire region. In the inhomogeneity phantoms, although the CCCMR underestimated dose in the low mass density regions, it could reconstruct dose changes at mass density boundaries. The gamma passing rate for the entire region was >95% for the field size of 2 × 2 cm2, but it was 68.9-86.7% for the field sizes of ≥5 × 5 cm2. Conclusively, in water, the CCCMR can obtain dose distributions comparable to those with the MC. Although the dose differences between them were mainly in inhomogeneity regions, the possibility of the effective use of the CCCMR in small field sizes was demonstrated.

Evaluation of the electron transport algorithm in magnetic field in EGS5 Monte Carlo code.

PURPOSE: To evaluate the accuracy of electron transport in the magnetic field of Electron Gamma Shower version 5 (EGS5) by using the special Fano cavity test. METHODS: To simulate electron transport in the magnetic field, the trajectory of the electron was reconstructed with a short step length to restrict fractional energy loss, and the maximum user step length (mxustep) was set at 0.01 cm or 0.001 cm. For the special Fano cavity test, three-layer slab Fano test geometry was used, and uniform and isotropic per unit mass mono-energetic electrons with 0.01, 0.1, 1.0, and 10 MeV were permitted from the central axis of geometry in 0.35 T and 1.5 T. Furthermore, the magnetic field strength was scaled based on the mass density of the material. The relative difference between the calculated dose to gap and the theoretical value was evaluated. Furthermore, the special Fano cavity test was also performed using EGSnrc with the electron-enhanced electric and magnetic field macros under the same conditions, and the results were compared with those of EGS5. RESULTS: Deviations in 0.35 T were within 0.3% regardless of the parameter settings. In 1.5 T, stable results within 0.3% were obtained using 0.001 cm as the mxustep, except for one at 10 MeV. Further, the accuracy of EGSnrc was within 0.2%, except for 10 MeV for a 0.2-cm gap in 1.5 T. CONCLUSIONS: EGS5 with the appropriate parameter settings enable electron transport in magnetic fields similar with the accuracy of EGSnrc.

Assessment and agreement of the CT appearance pattern and its severity grading of radiation-induced lung injury after stereotactic body radiotherapy for lung cancer.

PURPOSE: Radiographic severity of radiation-induced lung injury (RILI) has not been well-studied. The goal of this study was to assess the CT appearance pattern and severity of RILI without consideration of the clinical presentation. MATERIAL AND METHODS: A total of 49 patients, 41 with primary lung cancer and 8 with metastatic lung cancer, were treated by 4-fraction stereotactic body radiotherapy (SBRT). RILI after SBRT was separately assessed by two observers. The early and late CT appearance patterns and CT-based severity grading were explored. RESULTS: The median follow-up period was 39.0 months. In the early CT findings of observers 1 and 2, there was diffuse consolidation in 15 and 8, diffuse ground glass opacity (GGO) in 0 and 0, patchy consolidation and GGO in 17 and 20, patchy GGO in 3 and 3, and no changes in 10 and 14, respectively (kappa = 0.61). In late CT findings of observer 1 and 2, there were modified conventional pattern in 28 and 24, mass-like pattern in 8 and 11, scar-like pattern in 12 and 12, and no changes in 1 and 2, respectively (kappa = 0.63). In the results of the CT-based grading by observers 1 and 2, there were grade 0 in 1 and 2, grade 1 in 10 and 14, grade 2 in 31 and 29, grade 3 in 7 and 4, and none of grade 4 or more, respectively (kappa = 0.66). According to multivariate analyses (MVA), the significant predicting factors of grade 2 or more CT-based RILI were age (p = 0.01), oxygen dependence (p = 0.03) and interstitial shadow (p = 0.03). CONCLUSIONS: The agreement of the CT appearance and CT-based grading between two observers was good. These indicators may be able to provide us with more objective information and a better understanding of RILI.

A photon source model based on particle transport in a parameterized accelerator structure for Monte Carlo dose calculations.

PURPOSE: An accurate source model of a medical linear accelerator is essential for Monte Carlo (MC) dose calculations. This study aims to propose an analytical photon source model based on particle transport in parameterized accelerator structures, focusing on a more realistic determination of linac photon spectra compared to existing approaches. METHODS: We designed the primary and secondary photon sources based on the photons attenuated and scattered by a parameterized flattening filter. The primary photons were derived by attenuating bremsstrahlung photons based on the path length in the filter. Conversely, the secondary photons were derived from the decrement of the primary photons in the attenuation process. This design facilitates these sources to share the free parameters of the filter shape and be related to each other through the photon interaction in the filter. We introduced two other parameters of the primary photon source to describe the particle fluence in penumbral regions. All the parameters are optimized based on calculated dose curves in water using the pencil-beam-based algorithm. To verify the modeling accuracy, we compared the proposed model with the phase space data (PSD) of the Varian TrueBeam 6 and 15 MV accelerators in terms of the beam characteristics and the dose distributions. The EGS5 Monte Carlo code was used to calculate the dose distributions associated with the optimized model and reference PSD in a homogeneous water phantom and a heterogeneous lung phantom. We calculated the percentage of points passing 1D and 2D gamma analysis with 1%/1 mm criteria for the dose curves and lateral dose distributions, respectively. RESULTS: The optimized model accurately reproduced the spectral curves of the reference PSD both on- and off-axis. The depth dose and lateral dose profiles of the optimized model also showed good agreement with those of the reference PSD. The passing rates of the 1D gamma analysis with 1%/1 mm criteria between the model and PSD were 100% for 4 × 4, 10 × 10, and 20 × 20 cm2 fields at multiple depths. For the 2D dose distributions calculated in the heterogeneous lung phantom, the 2D gamma pass rate was 100% for 6 and 15 MV beams. The model optimization time was less than 4 min. CONCLUSION: The proposed source model optimization process accurately produces photon fluence spectra from a linac using valid physical properties, without detailed knowledge of the geometry of the linac head, and with minimal optimization time.

Impact of a commercially available model-based dose calculation algorithm on treatment planning of high-dose-rate brachytherapy in patients with cervical cancer.

We evaluated the impact of model-based dose calculation algorithms (MBDCAs) on high-dose-rate brachytherapy (HDR-BT) treatment planning for patients with cervical cancer. Seven patients with cervical cancer treated using HDR-BT were studied. Tandem and ovoid applicators were used in four patients, a vaginal cylinder in one, and interstitial needles in the remaining two patients. MBDCAs were applied to the Advanced Collapsed cone Engine (ACE; Elekta, Stockholm, Sweden). All plans, which were originally calculated using TG-43, were re-calculated using both ACE and Monte Carlo (MC) simulations. Air was used as the rectal material. The mean difference in the rectum D2cm3 between ACErec-air and MCrec-air was 8.60 ± 4.64%, whereas that in the bladder D2cm3 was -2.80 ± 1.21%. Conversely, in the small group analysis (n = 4) using water instead of air as the rectal material, the mean difference in the rectum D2cm3 between TG-43 and ACErec-air was 11.87 ± 2.65%, whereas that between TG-43 and ACErec-water was 0.81 ± 2.04%, indicating that the use of water as the rectal material reduced the difference in D2cm3 between TG-43 and ACE. Our results suggested that the differences in the dose-volume histogram (DVH) parameters of TG-43 and ACE were large for the rectum when considerable air (gas) volume was present in it, and that this difference was reduced when the air (gas) volume was reduced. Also, ACE exhibited better dose calculation accuracy than that of TG-43 in this situation. Thus, ACE may be able to calculate the dose more accurately than TG-43 for HDR-BT in treating cervical cancers, particularly for patients with considerable air (gas) volume in the rectum.

Assessment of myocardial metabolic disorder associated with mediastinal radiotherapy for esophageal cancer -a pilot study.

BACKGROUND: To evaluate the dose-effect relations for myocardial metabolic disorders after mediastinal radiotherapy (RT) by performing iodine-123 ß-methyl-iodophenyl pentadecanoic acid (I-123 BMIPP) scintigraphy. METHODS: Between 2011 and 2012, we performed I-123 BMIPP scintigraphy for patients with esophageal cancer before and six months after curative mediastinal RT. Single photon emission computed tomography (SPECT) images of pre-RT and post-RT were registered into RT dose distributions. The myocardium was contoured, and the regional RT dose was calculated. Normalization is required to compare pre- and post-RT SPECT images because the uptake pattern is changed due to the breathing level. Normalization was applied on the mean of SPECT counts in regions of the myocardium receiving less than 5 Gy. Relative values in each dose region (interval of 5 Gy) were calculated on the basis of this normalization for each patient. The reduction in the percent of relative values was calculated. RESULTS: Five patients were enrolled in this study. None of the patients had a past history of cardiac disease. The left ventricle was partially involved in RT fields in all patients. The patients received RT with median total doses of 60-66 Gy for the primary tumor and metastatic lymph nodes. Concomitant chemotherapy consisting of cisplatin or nedaplatin and 5-fluorouracil with RT was performed in 4 patients. All patients had reduced uptake corresponding to RT fields. Dose-effect relations for reduced uptake tended to be observed at 6 months after RT with mean decreases of 8.96% in regions at 10-15 Gy, 12.6% in regions at 20-25 Gy, 15.6% in regions at 30-35 Gy, 19.0% in regions at 40-45 Gy and 16.0% in regions at 50-55 Gy. CONCLUSIONS: Dose-effect relations for myocardial metabolic disorders tended to be observed. We may need to make an effort to reduce high-dose mediastinal RT to the myocardium in RT planning.

Assessment of safety and efficacy of perinatal or peripubertal exposure to daidzein on bone development in rats.

Neonatal exposure to isoflavones improved bone health in thereafter in previous animal studies. However, since isoflavones possess hormonal activity, it may interfere with reproductive development. In the present study, we assessed the safety and efficiency of perinatal or peripubertal exposure to daidzein on bone and reproductive organ development at early adulthood in rats. Sprague-Dawley pregnant rats (n = 18) were divided into 3 groups: (1) dams and their offspring were fed the control diet. (2) Dams were fed the daidzein diet (0.5 g daidzein/kg diet) during pregnancy and then the control diet at postnatal day 13 and their offspring were fed the control diet. (3) Dams and their offspring were fed the daidzein diet through the experiment. While perinatal exposure to daidzein did not confer a positive effect on bone mineral density on postnatal day 35, peripubertal exposure to daidzein protected against a decline in bone mineral density. Meanwhile, exposure to daidzein during the perinatal or peripubertal period did not affect reproductive organ weights at early adulthood in rats. Further investigations should assess the mechanisms underlying these responses of bone metabolism to daidzein, as well as the safety of daidzein exposure during the perinatal period and throughout life.

A single-center study on predicting outcomes of primary androgen deprivation therapy for prostate cancer using the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score.

OBJECTIVE: Japan Cancer of the Prostate Risk Assessment scores are reportedly useful for predicting progression-free survival after primary androgen deprivation therapy of prostate cancer patients. This study validated the risk assessment at a single institution. METHODS: We studied 255 prostate cancer patients given primary androgen deprivation therapy. Progression-free survival, cause-specific survival and overall survival were analyzed according to Japan Cancer of the Prostate Risk Assessment score-based risk classification. Cases with lymph node or distant metastases were subdivided by the risk classification. RESULTS: Ages ranged from 50 to 90 years (median: 76.5). Observation periods were 2-199 (median: 46.5) months. Primary androgen deprivation therapy includes combined androgen blockade in 150 cases (58.8%), uncombined luteinizing hormone-releasing hormone agonist in 97 (38.0%) and uncombined anti-androgenic agent in 8 (3.2%). Risk classified by Japan Cancer of the Prostate Risk Assessment scores was low in 104 cases (40.8%), intermediate in 86 (33.7%) and high in 65 (25.5%). The 5-year/10-year progression-free survival rates were 100%/80.8% in the low-risk, 82.3%/69.5% in the intermediate-risk and 34.7%/16.5% in the high-risk group. The 5-year/10-year cause-specific survival rates were 100%/100% in the low-risk, 90.7%/58.2% in the intermediate-risk and 63%/30.8% in the high-risk group. The 5-year/10-year overall survival rates were 87.5%/78.5% in the low-risk, 76.2%/43.1% in the intermediate-risk and 54.9%/25.4% in the high-risk group. For lymph node metastasis, cause-specific survival differed minimally between the intermediate- and high-risk groups (P = 0.1118). For distant metastasis, cause-specific survival differed significantly between the intermediate- and high-risk groups (P = 0.0264). CONCLUSIONS: Japan Cancer of the Prostate Risk Assessment score-based risk classification is useful for predicting post-primary androgen deprivation therapy progression-free survival, cause-specific survival and overall survival. Subtyping patients based on Japan Cancer of the Prostate Risk Assessment scores is particularly useful for predicting cause-specific survival with distant metastasis from prostate cancer.

Dosimetric properties of radiophotoluminescent glass detector in low-energy photon beams.

PURPOSE: A radiophotoluminescent glass rod dosimeter (RGD) has recently become commercially available. It is being increasingly used for dosimetry in radiotherapy to measure the absorbed dose including scattered low-energy photons on the body surface of a patient and for postal dosimetry audit. In this article, the dosimetric properties of the RGD, including energy dependence of the dose response, reproducibly, variation in data obtained by the RGD for each energy, and angular dependence in low-energy photons, are discussed. METHODS: An RGD (GD-301, Asahi Techno Glass Corporation, Shizuoka, Japan) was irradiated with monochromatic low-energy photon beams generated by synchrotron radiation at Photon Factory, High Energy Accelerator Research Organization (KEK). The size of GD-301 was 1.5 mm in diameter and 8.5 mm in length and the active dose readout volume being 1 mm diameter and 0.6 mm depth located 0.7 mm from the end of the detector. The energy dependence of the dose response and reproducibility and variation were investigated for RGDs irradiated with a plastic holder and those irradiated without the plastic holder. Response of the RGD was obtained by not only conventional single field irradiation but also bilateral irradiation. Angular dependence of the RGD was measured in the range of 0°-90° for 13, 17, 40, and 80 keV photon beams by conventional single field irradiation. RESULTS: The dose responses had a peak at around 40 keV. For the energy range of less than 25 keV, all dose response curves steeply decreased in comparison with the ratio of mass energy absorption coefficient of the RGD to that of air. As for the reproducibility and variation in data obtained by the RGD, the coefficient of variance increased with decrease in photon energy. Furthermore, the variation for bilateral irradiation was less than that for single field irradiation. Regarding angular dependence of the RGD, for energies of 13 and 17 keV, the response decreased with increase in the irradiation angle, and the minimum values were 93.5% and 86%, respectively. CONCLUSIONS: Our results showed the dosimetric properties of the RGD, including the energy dependence of the dose response, reproducibly, variation, and angular dependence in low-energy photons and suggest that the accuracy of the absorbed dose in low-energy photons is affected by the readout method and the distribution of radiophotoluminescence centers in the RGD.

External validation of the cancer of the prostate risk assessment score to predict biochemical relapse after radical prostatectomy for prostate cancer in Japanese patients.

OBJECTIVES: The aim of the present study was external validation to determine whether the Cancer of the Prostate Risk Assessment (CAPRA) score predicts biochemical relapse (BCR) after radical prostatectomy (RP) in Japanese patients. METHODS: From 1995 to 2008, 503 Japanese patients undergoing RP for clinically localized prostate cancer were included in the validation cohort. The BCR-free rate was estimated using the Kaplan-Meier method. Performance of the CAPRA score was assessed using Cox proportional hazards regression models, concordance index (c-index) and calibration plots. RESULTS: Unlike the results in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort, the BCR-free rate and the hazard ratio for CAPRA score 4 were inversely better than those for CAPRA scores 2 and 3 in Japanese patients. The c-index of the CAPRA score was 0.673. The calibration plot demonstrated that the CAPRA score was generally well calibrated. CONCLUSIONS: In Japanese patients, the CAPRA score can predict BCR after RP only to some degree. Although our c-index is comparable with the c-index of 0.66 in the original CaPSURE cohort, it is lower than the c-indices reported in other validation cohorts, which range from 0.68 to 0.81. The CAPRA score may not predict BCR after RP in Japanese patients as accurately as it did in Western patients.