Breathing-Adapted Imaging Techniques for Rapid 4-Dimensional Lung Tomosynthesis.

Purpose: This article presents enhancements to a 4-dimensional (4D) lung digital tomosynthesis (DTS) model introduced in a 2018 paper. That model was proposed as an adjunct to 4D computed tomography (4DCT) to improve tumor localization through artifact reduction achieved by imaging the entire lung in all projections, reducing the projection collection time duration for each phase compared with 4DCT, and requiring only a single-breath cycle to capture all phases. This is applicable to SABR treatment planning. Enhancements comprise customized patient 4D-DTS x-ray scanning parameters. Methods and Materials: Imaging parameters derived with the 4D-DTS model were arc duration, frames per second, pulse duration, and tube current normalized to single-chest radiographic milliampere-seconds (mA/mAsAEC). Optimized phase-specific DTS projections imaging parameters were derived for volunteer respiration-tracking surrogate waveforms and for sinusoidal waveforms. These parameters are temporally matched to the respiratory surrogate waveform and presented as continuous data plots during a period of 20 seconds. Comparison is made between surrogate excursions during a single-phase CT and 4D-DTS reconstructions. Results: 4D-DTS imaging techniques were customized to volunteer respiratory waveforms and sinusoidal waveforms. Technique settings at the highest velocity portions of the volunteer waveforms were arc duration 0.066 seconds, frame rate 921 Hz, pulse duration 1.076 ms, and normalized tube current 76.2 s-1. Technique settings at the highest velocity portions of the sinusoidal waveforms were arc duration 0.029 seconds, frame rate 2074 Hz, pulse duration 0.472 ms, and normalized tube current 173.6 s-1. Sinusoidal surrogate excursion distance at the highest velocity portion of the waveform during a CT rotation of 0.5 seconds ranged from 2.68 to 21.09 mm, all greater than the limiting excursion distance chosen in the 4D-DTS model. Conclusions: 4D-DTS image technique settings can be customized to individual patient breathing patterns so that captured range of motion satisfies an operator-selected value.

p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis.

The autophagy-lysosome pathway and apoptosis constitute vital determinants of cell fate and engage in a complex interplay in both physiological and pathological conditions. Central to this interplay is the archetypal autophagic cargo adaptor p62/SQSTM1/Sequestosome-1 which mediates both cell survival and endoplasmic reticulum stress-induced apoptosis via aggregation of ubiquitinated caspase-8. Here, we investigated the role of p62-mediated apoptosis in head and neck squamous cell carcinoma (HNSCC), which can be divided into two groups based on human papillomavirus (HPV) infection status. We show that increased autophagic flux and defective apoptosis are associated with radioresistance in HPV(-) HNSCC, whereas HPV(+) HNSCC fail to induce autophagic flux and readily undergo apoptotic cell death upon radiation treatments. The degree of radioresistance and tumor progression of HPV(-) HNSCC respectively correlated with autophagic activity and cytosolic levels of p62. Pharmacological activation of the p62-ZZ domain using small molecule ligands sensitized radioresistant HPV(-) HNSCC cells to ionizing radiation by facilitating p62 self-polymerization and sequestration of cargoes leading to apoptosis. The self-polymerizing activity of p62 was identified as the essential mechanism by which ubiquitinated caspase-8 is sequestered into aggresome-like structures, without which irradiation fails to induce apoptosis in HNSCC. Our results suggest that harnessing p62-dependent sequestration of ubiquitinated caspase-8 provides a novel therapeutic avenue in patients with radioresistant tumors.

Photodynamic Therapy as a Potent Radiosensitizer in Head and Neck Squamous Cell Carcinoma.

Despite recent advances in therapeutic modalities such as radiochemotherapy, the long-term prognosis for patients with advanced head and neck squamous cell carcinoma (HNSCC), especially nonviral HNSCC, remains very poor, while survival of patients with human papillomavirus (HPV)-associated HNSCC is greatly improved after radiotherapy. The goal of this study is to develop a mechanism-based treatment protocol for high-risk patients with HPV-negative HNSCC. To achieve our goal, we have investigated molecular mechanisms underlying differential radiation sensitivity between HPV-positive and -negative HNSCC cells. Here, we found that autophagy is associated with radioresistance in HPV-negative HNSCC, whereas apoptosis is associated with radiation sensitive HPV-positive HNSCC. Interestingly, we found that photodynamic therapy (PDT) directed at the endoplasmic reticulum (ER)/mitochondria initially induces paraptosis followed by apoptosis. This led to a substantial increase in radiation responsiveness in HPV-negative HNSCC, while the same PDT treatment had a minimal effect on HPV-positive cells. Here, we provide evidence that the autophagic adaptor p62 mediates signal relay for the induction of apoptosis, promoting ionizing radiation (XRT)-induced cell death in HPV-negative HNSCC. This work proposes that ER/mitochondria-targeted PDT can serve as a radiosensitizer in intrinsically radioresistant HNSCC that exhibits an increased autophagic flux.

Characteristics of an Impaired PDT Response.

A concurrent human papilloma virus (HPV) infection potentiates the efficacy of ionizing radiation for treatment of head and neck cancer by promoting apoptosis. Studies in cell culture indicated an opposite effect for photodynamic therapy (PDT) when this leads to mitochondrial and ER photodamage. The explanation for this difference in PDT efficacy remains to be established. While apoptosis was impaired in HPV(-) cells, such cells can be killed via photodamage directed at the ER: this leads to a nonapoptotic death pathway termed paraptosis. No differences in photosensitizer uptake or reactive oxygen species (ROS) production were observed in HPV(+) vs. HPV(-) tumors. We now provide evidence that death pathways initiated by ER/mitochondrial photodamage leading to either paraptosis or apoptosis are impaired in an HPV(+) head and neck cell line. These results illustrate the complex determinants of PDT efficacy, a topic that has yet to be fully explored.

Combined Adjuvant Chemotherapy and Radiation Therapy Improves Disease-Free Survival for Uterine Serous Cancer.

PURPOSE: Uterine serous carcinoma (USC) is a rare but aggressive endometrial cancer histology. We reviewed outcomes for patients with USC to identify the best adjuvant treatment strategy. METHODS AND MATERIALS: We retrospectively identified 162 patients with The International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA USC treated at our institution. Baseline characteristics, treatment details, clinical outcomes, and toxicity data were recorded. RESULTS: Median follow-up was 3.4 years (0.3-26 years). A variety of adjuvant therapy strategies were employed: 14% no adjuvant therapy, 28% radiation alone, 15% chemotherapy alone, and 43% combined chemotherapy and radiation. Distant metastasis was the most common type of recurrence (37% at 5 years). For patients with stage I-IVA disease, there were no significant differences in outcomes by treatment type. For patients with stage I-II disease (70% of the cohort), disease-free survival was significantly higher after chemotherapy (alone or with radiation therapy, P = .005) and after combined chemotherapy and radiation compared with all other treatments (P = .025). Toxicity outcomes were favorable, with minimal grade 3 and no grade 4 or 5 events. CONCLUSIONS: Patients with USC experience high rates of recurrence and mortality. Distant metastasis is the most common pattern of failure for all stages. For patients with early-stage disease, combined chemotherapy and radiation improves 5-year disease-free survival compared with either single adjuvant treatment alone or no adjuvant treatment. The relatively large group of patients with USC included in this study may account for our ability to detect this improvement whereas clinical trials have failed to do so, possibly owing to the relatively small percentages of patients with USC enrolled.

Outcomes After Salvage Radiation Therapy for Recurrent Endometrial Cancer in Patients With No Prior Adjuvant Therapy: An Institutional Review.

PURPOSE: After definitive surgery, women with early-stage, low-risk endometrial cancer are observed. However, some will require salvage radiation therapy for recurrence. The purpose of this study was to evaluate our experience using salvage radiation for recurrent endometrial cancer in patients who did not receive upfront adjuvant therapy. METHODS AND MATERIALS: Twenty-eight women with endometrial cancer who had undergone initial definitive hysterectomy without adjuvant therapy developed isolated local or regional recurrence and were treated with salvage radiation in our department from 2004 to 2018. Salvage radiation included whole pelvic radiation, vaginal brachytherapy, or both. Patient and tumor characteristics, treatment details, and toxicities were recorded and analyzed. RESULTS: The median time to first recurrence was 1.7 years. First recurrences consisted of local recurrence in 23 patients, regional recurrence in 4, and both in 1. The median times from hysterectomy to first recurrence, local and regional, were 1.2 and 4.0 years, respectively. All patients underwent salvage radiation for management of their first recurrence. The median total equivalent dose in 2 Gy fractions for this treatment was 67.6 Gy (37.5-81.8 Gy). Two second recurrences occurred following salvage treatment, both local recurrence, at 6.5 and 13.5 months after radiation. The 2-year rates of local control, disease-free survival, and overall survival were 93%, 80%, and 88%, respectively. Treatment was well-tolerated, with low rates of gastrointestinal and genitourinary toxicity. CONCLUSIONS: In this group of patients, salvage radiation therapy for local or regional recurrence of endometrial cancer resulted in excellent control with low rates of acute and chronic toxicities.

Sequencing of Adjuvant Chemoradiation for Advanced Stage Endometrial Cancer: Outcomes and Toxicity Profiles.

OBJECTIVES: Radiation is frequently added to chemotherapy for adjuvant treatment of advanced stage endometrial cancer. Multiple adjuvant therapy sequencing options exist, and little data is available to compare these. We compared outcomes and toxicities after "sandwich" chemoradiation (chemotherapy, then radiation, then chemotherapy) and nonsandwich sequences (chemotherapy then radiation, radiation then chemotherapy, or concurrent chemoradiation). MATERIALS AND METHODS: We recorded baseline characteristics, adjuvant treatment details, clinical outcomes, and toxicities for stage III to IVA patients who underwent surgical staging followed by both adjuvant chemotherapy and radiation therapy at our institution. Effects of adjuvant treatment order (sandwich or nonsandwich) on these outcomes were analyzed. Toxicities were graded according to CTCAE v4.0. RESULTS: We identified 107 patients with a median follow-up of 3.2 years. Five-year local, regional, and distant recurrence were 7%, 15%, and 33%; disease-free and overall survival were 61% and 68%, respectively. Outcomes did not differ by sequence group. The overall rate of acute toxicity did not differ by sequence group. The overall rate of chronic toxicity was significantly lower for sandwich patients (P<0.001), as were overall rates of chronic genitourinary (P=0.048) and gynecologic (P<0.001) toxicities. There were no grade 4 or 5 acute or chronic toxicities. CONCLUSIONS: Advanced stage endometrial cancer is an aggressive disease and adjuvant chemotherapy and radiation therapy are indicated. Clinical outcomes were similar amongst the different sequences; however, sandwich therapy led to less chronic toxicity, offering an opportunity for improved quality of life in survivorship.

Effects of HPV Status on Responsiveness to Ionizing Radiation vs Photodynamic Therapy in Head and Neck Cancer Cell lines.

Efficacy of ionizing radiation (I/R) was compared with phototoxic effects of photodynamic therapy (PDT) in vitro using two cell lines derived from patients with head and neck squamous cell carcinoma (HNSCC). A cell line derived from a donor with a human papilloma virus (HPV) infection was more responsive to I/R but significantly less responsive to PDT than a cell line derived from an HPV-free patient. Cell death after I/R in the HPV(+) cell line was associated with increased DEVDase activity, a hallmark of apoptosis. The HPV(-) line was considerably less responsive to I/R, with DEVDase activity greatly reduced, suggesting an impaired apoptotic program. In contrast, the HPV(-) cells were readily killed by PDT when the ER was among the targets for photodamage. While DEVDase activity was enhanced, the death pathway appears to involve paraptosis until the degree of photodamage reached the LD99 range. These data suggest that PDT-induced paraptosis can be a death pathway for cells with an impaired apoptotic program.

Isoflavone-mediated radioprotection involves regulation of early endothelial cell death and inflammatory signaling in Radiation-Induced lung injury.

Purpose: Vascular damage and inflammation are limiting toxic effects of lung cancer radiotherapy, which lead to pneumonitis and pulmonary fibrosis. We have demonstrated that soy isoflavones (SIF) mitigate these toxic effects at late time points after radiation. However, the process by which SIF impacts the onset of radiation-induced inflammation remains to be elucidated. We have now investigated early events of radiation-induced inflammation and identified cellular and molecular signaling patterns by endothelial cells that could be modified by SIF to control vascular damage and the initiation of lung inflammation.Materials and methods: Histopathological, cellular and molecular studies were performed on mouse lungs from C57Bl/6 mice treated with 10 Gy of thoracic radiation (XRT) in conjunction with daily oral SIF treatment given prior and after radiation. Parallel studies were performed in-vitro using EA.hy926 endothelial cell line with SIF and radiation. Immunohistochemistry, western blots analysis, and flow cytometry were performed on lung tissue or EA.hy926 cells to analyze endothelial cells, their patterns of cell death or survival, and signaling molecules involved in inflammatory events.Results: Histopathological differences in inflammatory infiltrates and vascular injury in lungs, including vascular endothelial cells, were observed with SIF treatment at early time points post-XRT. XRT-induced expression of proinflammatory adhesion molecule ICAM-1 cells was reduced by SIF in-vitro and in-vivo in endothelial cells. Molecular changes in endothelial cells with SIF treatment in conjunction with XRT included increased DNA damage, reduced cell viability and cyclin B1, and inhibition of nuclear translocation of NF-κB. Analysis of cell death showed that SIF treatment promoted apoptotic endothelial cell death and decreased XRT-induced type III cell death. In-vitro molecular studies indicated that SIF + XRT increased apoptotic caspase-9 activation and production of IFNß while reducing the release of inflammatory HMGB-1 and IL-1α, the cleavage of pyroptotic gasdermin D, and the release of active IL-1ß, which are all events associated with type III cell death.Conclusions: SIF + XRT caused changes in patterns of endothelial cell death and survival, proinflammatory molecule release, and adhesion molecule expression at early time points post-XRT associated with early reduction of immune cell recruitment. These findings suggest that SIF could mediate its radioprotective effects in irradiated lungs by limiting excessive immune cell homing via vascular endothelium into damaged lung tissue and curtailing the overall inflammatory response to radiation.

A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery.

OBJECTIVE: To determine which non-narcotic analgesic, acetaminophen (Ofirmev®) or ketorolac (Toradol®), provides better post-operative pain control when combined with an opioid patient-controlled analgesia (PCA) pump. Secondary objectives include comparisons of the rates of ileus, post-operative bleeding, transfusions, and length-of-hospitalization (LOH). METHODS: A prospective, randomized trial of acetaminophen (A) 1-g intravenous (IV) every 6-h or ketorolac (K) 15-mg IV every 6-h from post-operative day 1-3 in addition to an opioid PCA for patients undergoing benign or malignant gynecologic laparotomy procedures was performed. Abstracted data included pain levels via visual analogue pain scales (VAS), amount of narcotic used, hepatic enzyme levels, hemoglobin, urine output, blood transfusions, time to return of flatus and LOH. RESULTS: One-hundred patients were accrued and underwent 55 benign gynecologic laparotomies and 45 cancer-related laparotomies. VAS pain levels (3.3 K, 3.5 A) and morphine PCA use (79.1 oral morphine equivalents [OME] K vs. 84.5 A) were not different, however dilaudid PCA usage was less by K patients (84.4 OME K and 136.8 OME A, p < 0.001). There was a significant hemoglobin change between the two groups (2.6 g K vs. 2 g A, p = 0.015), however blood transfusions were equal (28% K, 22% A, p > 0.05). Return of flatus was 2.7-days for K vs. 3.4-days for A (p = 0.011) and LOH was not different (4.4-days K vs. 5.1-days A, p = 0.094). CONCLUSIONS: Both intravenous ketorolac and acetaminophen provide similar post-operative analgesia through VAS pain scales and total usage of morphine via PCA pumps. Use of ketorolac with dilaudid PCA was associated with less dependence on dilaudid and a quicker return of bowel function than acetaminophen, however length of stay and transfusion rates were not different.

Model evaluation of rapid 4-dimensional lung tomosynthesis.

PURPOSE: This is an investigation of a lung motion digital tomosynthesis (DTS) model using combined stationary detector and stationary cold cathode x-ray sources at projection acquisition rates that exceed the present norms. The intent is to reduce anatomical uncertainties from artifacts inherent in thoracic 4-dimensional computed tomography (CT). METHODS AND MATERIALS: Parameters necessary to perform rapid lung 4-dimensional DTS were studied using a conventional radiographic system with linear motion of the x-ray source and a simple hypothetical hardware performance model. Hypothetical rapid imaging parameters of sweep duration, projections per second, pulse duration, and tube current (mA) were derived on the basis of 0.5 mm and 1 mm motion captures per phase, 10 and 15 breaths per minute (bpm), 10 to 40 mm breathing amplitude, and 2 signal-to-noise ratio (SNR) levels. Anterior-posterior and lateral projection images of a normal size anthropomorphic thorax phantom with iodine contrast inserts were collected and reconstructed with an algebraic algorithm to study the effects of reduced x-ray output associated with field emission cold cathodes composed of carbon nanotubes or metal Spindt-type. Radiographic projections were collected at 3 SNR levels that were set at standard clinical DTS milliampere-seconds (mAs) and reduced corresponding to 50% and 25% standard DTS mAs to simulate a reduced x-ray output. RESULTS: The DTS SNR of the inserts was superior in all reconstructions at clinical mAs versus automatic exposure-control radiographs and superior in 3 of 4 at the 50% and 25% mAs levels. The most demanding performance parameters corresponding to 40 mm amplitude, 15 bpm, 0.5 mm motion capture limit, and 61 projections were sweep duration (10.4 msec), projection rate (5862 projections per second), pulse duration (0.161 msec), current 189 mA anterior-posterior, and 653 mA lateral. CONCLUSIONS: Feasibility depends on the output performance of stationary cold cathode hardware being developed for DTS. Present image receptor technology can accommodate frame acquisition rates.

Percent depth doses and X-ray beam characterizations of a fluoroscopic system incorporating copper filtration.

PURPOSE: In this investigation, we sought to characterize X-ray beam qualities and quantitate percent depth dose (PDD) curves for fluoroscopic X-ray beams incorporating added copper (Cu) filtration, such as those commonly used in fluoroscopically guided interventions (FGI). The intended application of this research is for dosimetry in soft tissue from FGI procedures using these data. METHODS: All measurements in this study were acquired on a Siemens (Erlangen, Germany) Artis zeego fluoroscope. X-ray beam characteristics of first half-value layer (HVL), second HVL, homogeneity coefficients (HCs), backscatter factors (BSFs) and kVp accuracy and precision were determined to characterize the X-ray beams used for the PDD measurements. A scanning water tank was used to measure PDD curves for 60, 80, 100, and 120 kVp X-ray beams with Cu filtration thicknesses of 0.0, 0.1, 0.3, 0.6, and 0.9 mm at 11 cm, 22 cm, and 42 cm nominal fields of view, in water depths of 0 to 150 mm. RESULTS: X-ray beam characteristics of first HVLs and HCs differed from previous published research of fluoroscopic X-ray beam qualities without Cu filtration. PDDs for 60, 80, 100, and 120 kVp with 0 mm of Cu filtration were comparable to previous published research, accounting for differences in fluoroscopes, geometric orientation, type of ionization chamber, X-ray beam quality, and the water tank used for data collection. PDDs and X-ray beam characteristics for beam qualities with Cu filtration are presented, which have not been previously reported. CONCLUSIONS: The data sets of X-ray beam characteristics and PDDs presented in this study can be used to estimate organ or soft tissue doses at depth involving similar beam qualities or to compare with mathematical models.

Radiotherapy and MVA-MUC1-IL-2 vaccine act synergistically for inducing specific immunity to MUC-1 tumor antigen.

BACKGROUND: We previously demonstrated that tumor irradiation potentiates cancer vaccines using genetic modification of tumor cells in murine tumor models. To investigate whether tumor irradiation augments the immune response to MUC1 tumor antigen, we have tested the efficacy of tumor irradiation combined with an MVA-MUC1-IL2 cancer vaccine (Transgene TG4010) for murine renal adenocarcinoma (Renca) cells transfected with MUC1. METHODS: Established subcutaneous Renca-MUC1 tumors were treated with 8 Gy radiation on day 11 and peritumoral injections of MVA-MUC1-IL2 vector on day 12 and 17, or using a reverse sequence of vaccine followed by radiation. Growth delays were monitored by tumor measurements and histological responses were evaluated by immunohistochemistry. Specific immunity was assessed by challenge with Renca-MUC1 cells. Generation of tumor-specific T cells was detected by IFN-γ production from splenocytes stimulated in vitro with tumor lysates using ELISPOT assays. RESULTS: Tumor growth delays observed by tumor irradiation combined with MVA-MUC1-IL-2 vaccine were significantly more prolonged than those observed by vaccine, radiation, or radiation with MVA empty vector. The sequence of cancer vaccine followed by radiation two days later resulted in 55-58% complete responders and 60% mouse long-term survival. This sequence was more effective than that of radiation followed by vaccine leading to 24-30% complete responders and 30% mouse survival. Responding mice were immune to challenge with Renca-MUC1 cells, indicating the induction of specific tumor immunity. Histology studies of regressing tumors at 1 week after therapy, revealed extensive tumor destruction and a heavy infiltration of CD45+ leukocytes including F4/80+ macrophages, CD8+ cytotoxic T cells and CD4+ helper T cells. The generation of tumor-specific T cells by combined therapy was confirmed by IFN-γ secretion in tumor-stimulated splenocytes. An abscopal effect was measured by rejection of an untreated tumor on the contralateral flank to the tumor treated with radiation and vaccine. CONCLUSIONS: These findings suggest that cancer vaccine given prior to local tumor irradiation augments an immune response targeted at tumor antigens that results in specific anti-tumor immunity. These findings support further exploration of the combination of radiotherapy with cancer vaccines for the treatment of cancer.

Extrapolation Ionization Chamber Dosimetry of Fluorescent X-Ray Energies from 4.5 to 19.6 keV.

Characteristic X rays of energies less than approximately 20 keV are of interest in radiobiology and radiation oncology. There is evidence that these low-energy photons produce higher relative biological effectiveness (RBE) and lower oxygen enhancement ratio (OER) relative to higher energies. Lower energy X rays also offer the advantage of healthy tissue sparing beyond the target treatment depth. Electronic brachytherapy systems that can deliver characteristic and bremsstrahlung X rays of varying energy are in clinical use as well as under development. We performed low-energy extrapolation ionization chamber dosimetry using two methods: 1. the exposure-to-dose method; and 2. the Burlin theory method combined with the extrapolation chamber method of Klevenhagen. We investigated fluorescent X rays emitted from seven metals: titanium (Ti, Z = 22); chromium (Cr, Z = 24); iron (Fe, Z = 26); cobalt (Co, Z = 27); copper (Cu, Z = 29); zinc (Zn, Z = 30); and molybdenum (Mo, Z = 42). X rays were produced by irradiation of the metals with a 55 kVp, 45 mA silver anode spectrum. The data obtained were air kerma rate (cGy/min), and radiation dose rate (cGy/min) in phosphate-buffered saline (PBS) solution and water. Air kerma rates ranged from 3.55 ± 0.10 to 14.36 ± 0.39 cGy/min. Dose rates ranged from 3.85 ± 0.10 to 16.96 ± 0.46 cGy/min in PBS and 3.59 ± 0.10 to 16.06 ± 0.43 cGy/min in water. Dose-rate energy dependence of both models was examined by taking a ratio of measured to Monte Carlo calculated dose rates. Dosimetry method 1 exhibited a linear relationship across all energies with a slope of 0.0127 keV(-1) and R(2) of 0.9276. Method 2 exhibited a linear relationship across all energies with a slope of 0.0467 keV(-1) and R(2) of 0.9933. Method 1 or 2 may be used as a relative dosimetry system to derive dose rates to water by using a second reference ion chamber with a NIST-traceable calibration for the molybdenum spectrum.

Investigating ion recombination effects in a liquid-filled ionization chamber array used for IMRT QA measurements.

PURPOSE: PTW's Octavius 1000 SRS array performs IMRT quality assurance (QA) measurements with liquid-filled ionization chambers (LICs) to allow closer detector spacing and higher resolution, compared to air-filled QA devices. However, reduced ion mobility in LICs relative to air leads to increased ion recombination effects and reduced collection efficiencies that are dependent on Linac pulse frequency and pulse dose. These pulse parameters are variable during an IMRT delivery, which affects QA results. In this study, (1) 1000 SRS collection efficiencies were measured as a function of pulse frequency and pulse dose, (2) two methods were developed to correct changes in collection efficiencies during IMRT QA measurements, and the effects of these corrections on QA pass rates were compared. METHODS: To obtain collection efficiencies, the OCTAVIUS 1000 SRS was used to measure open fields of varying pulse frequency, pulse dose, and beam energy with results normalized to air-filled chamber measurements. Changes in ratios of 1000 SRS to chamber measured dose were attributed to changing collection efficiencies, which were then correlated to pulse parameters using regression analysis. The usefulness of the derived corrections was then evaluated using 6 MV and 10FFF SBRT RapidArc plans delivered to the OCTAVIUS 4D system using a TrueBeam (Varian Medical Systems) linear accelerator equipped with a high definition multileaf collimator. For the first correction, matlab software was developed that calculates pulse frequency and pulse dose for each detector, using measurement and DICOM RT Plan files. Pulse information is converted to collection efficiency, and measurements are corrected by multiplying detector dose by ratios of calibration to measured collection efficiencies. For the second correction the MU/min in the daily 1000 SRS calibration was chosen to match the average MU/min of the volumetric modulated arc therapy plan. Effects of the two corrections on QA results were examined by performing 3D gamma analysis comparing predicted to measured dose, with and without corrections. RESULTS: Collection efficiencies correlated linearly to pulse dose, while correlations with pulse frequency were less defined, generally increasing as pulse frequency decreased. After complex matlab corrections, average 3D gamma pass rates improved by [0.07%,0.40%,1.17%] for 6 MV and [0.29%,1.40%,4.57%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. Maximum changes in gamma pass rates were [0.43%,1.63%,3.05%] for 6 MV and [1.00%,4.80%,11.2%] for 10FFF using [3%/3 mm,2%/2 mm,1%/1 mm] criteria. On average, pass rates of simple daily calibration corrections were within 1% of complex matlab corrections. CONCLUSIONS: OCTAVIUS 1000 SRS ion recombination effects have little effect on 6 MV measurements. However, the effect could potentially be clinically significant for higher pulse dose unflattened beams when using tighter gamma tolerances, especially when small aperture sizes are used, as is common for SRS/SBRT. In addition, ion recombination effects are strongly correlated to changing MU/min, therefore MU/min used in daily 1000 SRS calibrations should be matched to the expected average MU/min of the IMRT plan.

Effect of fluoroscopic X-ray beam spectrum on air-kerma measurement accuracy: implications for establishing correction coefficients on interventional fluoroscopes with KAP meters.

The first goal of this study was to investigate the accuracy of the displayed reference plane air kerma (Ka,r) or air kerma-area product (Pk,a) over a broad spectrum of X-ray beam qualities on clinically used interventional fluoroscopes incorporating air kerma-area product meters (KAP meters) to measure X-ray output. The second goal was to investigate the accuracy of a correction coefficient (CC) determined at a single beam quality and applied to the measured Ka,r over a broad spectrum of beam qualities. Eleven state-of-the-art interventional fluoroscopes were evaluated, consisting of eight Siemens Artis zee and Artis Q systems and three Philips Allura FD systems. A separate calibrated 60 cc ionization chamber (external chamber) was used to determine the accuracy of the KAP meter over a broad range of clinically used beam qualities. For typical adult beam qualities, applying a single CC deter-mined at 100 kVp with copper (Cu) in the beam resulted in a deviation of < 5% due to beam quality variation. This result indicates that applying a CC determined using The American Association of Physicists in Medicine Task Group 190 protocol or a similar protocol provides very good accuracy as compared to the allowed ± 35% deviation of the KAP meter in this limited beam quality range. For interventional fluoroscopes dedicated to or routinely used to perform pediatric interventions, using a CC established with a low kVp (~ 55-60 kVp) and large amount of Cu filtration (~ 0.6-0.9 mm) may result in greater accuracy as compared to using the 100 kVp values. KAP meter responses indicate that fluoroscope vendors are likely normalizing or otherwise influencing the KAP meter output data. Although this may provide improved accuracy in some instances, there is the potential for large discrete errors to occur, and these errors may be difficult to identify.

Development and evaluation of an end-to-end test for head and neck IMRT with a novel multiple-dosimetric modality phantom.

A comprehensive end-to-end test for head and neck IMRT treatments was developed using a custom phantom designed to utilize multiple dosimetry devices. Initial end-to-end test and custom H&N phantom were designed to yield maximum information in anatomical regions significant to H&N plans with respect to: (i) geometric accuracy, (ii) dosimetric accuracy, and (iii) treatment reproducibility. The phantom was designed in collaboration with Integrated Medical Technologies. The phantom was imaged on a CT simulator and the CT was reconstructed with 1 mm slice thickness and imported into Varian's Eclipse treatment planning system. OARs and the PTV were contoured with the aid of Smart Segmentation. A clinical template was used to create an eight-field IMRT plan and dose was calculated with heterogeneity correction on. Plans were delivered with a TrueBeam equipped with a high definition MLC. Preliminary end-to-end results were measured using film, ion chambers, and optically stimulated luminescent dosimeters (OSLDs). Ion chamber dose measurements were compared to the treatment planning system. Films were analyzed with FilmQA Pro using composite gamma index. OSLDs were read with a MicroStar reader using a custom calibration curve. Final phantom design incorporated two axial and one coronal film planes with 18 OSLD locations adjacent to those planes as well as four locations for IMRT ionization chambers below inferior film plane. The end-to-end test was consistently reproducible, resulting in average gamma pass rate greater than 99% using 3%/3 mm analysis criteria, and average OSLD and ion chamber measurements within 1% of planned dose. After initial calibration of OSLD and film systems, the end-to-end test provides next-day results, allowing for integration in routine clinical QA. Preliminary trials have demonstrated that our end-to-end is a reproducible QA tool that enables the ongoing evaluation of dosimetric and geometric accuracy of clinical head and neck treatments.

Approaches to interventional fluoroscopic dose curves.

Modern fluoroscopes used for image-based guidance in interventional procedures are complex X-ray machines, with advanced image acquisition and processing systems capable of automatically controlling numerous parameters based on defined protocol settings. This study evaluated and compared approaches to technique factor modulation and air kerma rates in response to simulated patient thickness variations for four state-of-the-art and one previous-generation interventional fluoroscopes. A polymethyl methacrylate (PMMA) phantom was used as a tissue surrogate for the purposes of determining fluoroscopic reference plane air kerma rates, kVp, mA, and variable copper filter thickness over a wide range of simulated tissue thicknesses. Data were acquired for each fluoroscopic and acquisition dose curve within each vendor's default abdomen or body imaging protocol. The data obtained indicated vendor- and model-specific variations in the approach to technique factor modulation and reference plane air kerma rates across a range of tissue thicknesses. However, in the imaging protocol evaluated, all of the state-of-the-art systems had relatively low air kerma rates in the fluoroscopic low-dose imaging mode as compared to the previous-generation unit. Each of the newest-generation systems also employ Cu filtration within the selected protocol in the acquisition mode of imaging; this is a substantial benefit, reducing the skin entrance dose to the patient in the highest dose-rate mode of fluoroscope operation. Some vendors have also enhanced the radiation output capabilities of their fluoroscopes which, under specific conditions, may be beneficial; however, these increased output capabilities also have the potential to lead to unnecessarily high dose rates. Understanding how fluoroscopic technique factors are modulated provides insight into the vendor-specific image acquisition approach and may provide opportunities to optimize the imaging protocols for clinical practice.

Soy Isoflavones Promote Radioprotection of Normal Lung Tissue by Inhibition of Radiation-Induced Activation of Macrophages and Neutrophils.

INTRODUCTION: Radiation therapy for lung cancer is limited by toxicity to normal lung tissue that results from an inflammatory process, leading to pneumonitis and fibrosis. Soy isoflavones mitigate inflammatory infiltrates and radiation-induced lung injury, but the cellular immune mediators involved in the radioprotective effect are unknown. METHODS: Mice received a single dose of 10 Gy radiation delivered to the lungs and daily oral treatment of soy isoflavones. At different time points, mice were either processed to harvest bronchoalveolar lavage fluid for differential cell counting and lungs for flow cytometry or immunohistochemistry studies. RESULTS: Combined soy and radiation led to a reduction in infiltration and activation of alveolar macrophages and neutrophils in both the bronchoalveolar and lung parenchyma compartments. Soy treatment protected F4/80CD11c interstitial macrophages, which are known to play an immunoregulatory role and are decreased by radiation. Furthermore, soy isoflavones reduced the levels of nitric oxide synthase 2 expression while increasing arginase-1 expression after radiation, suggesting a switch from proinflammatory M1 macrophage to an anti-inflammatory M2 macrophage phenotype. Soy also prevented the influx of activated neutrophils in lung caused by radiation. CONCLUSIONS: Soy isoflavones inhibit the infiltration and activation of macrophages and neutrophils induced by radiation in lungs. Soy isoflavones-mediated modulation of macrophage and neutrophil responses to radiation may contribute to a mechanism of resolution of radiation-induced chronic inflammation leading to radioprotection of lung tissue.

Sensitivity and variability of Presage dosimeter formulations in sheet form with application to SBRT and SRS QA.

PURPOSE: To measure sensitivity and stability of the Presage dosimeter in sheet form for various chemical concentrations over a range of clinical photon energies and examine its use for stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) QA. METHODS: Presage polymer dosimeters were formulated to investigate and optimize their sensitivity and stability. The dosimeter is composed of clear polyurethane base, leucomalachite green (LMG) reporting dye, and bromoform radical initiator in 0.9-1.0 mm thick sheets. The chemicals are mixed together for 2 min, cast in an aluminum mold, and left to cure at 60 psi for a minimum of two days. Dosimeter response was characterized at energies Co-60, 6 MV, 10 MV flattening-filter free, 15 MV, 50 kVp (mean 19.2 keV), and Ir-192. The dosimeters were scanned by a Microtek Scanmaker i800 at 300 dpi, 2(16) bit depth per color channel. Red component images were analyzed with ImageJ and rit. SBRT QA was done with gamma analysis tolerances of 2% and 2 mm DTA. RESULTS: The sensitivity of the Presage dosimeter increased with increasing concentration of bromoform. Addition of tin catalyst decreased curing time and had negligible effect on sensitivity. LMG concentration should be at least as high as the bromoform, with ideal concentration being 2% wt. Gamma Knife SRS QA measurements of relative output and profile widths were within 2% of manufacturer's values validated at commissioning, except the 4 mm collimator relative output which was within 3%. The gamma pass rate of Presage with SBRT was 73.7%, compared to 93.1% for EBT2 Gafchromic film. CONCLUSIONS: The Presage dosimeter in sheet form was capable of detecting radiation over all tested photon energies and chemical concentrations. The best sensitivity and photostability of the dosimeter were achieved with 2.5% wt. LMG and 8.2% wt. bromoform. Scanner used should not emit any UV radiation as it will expose the dosimeter, as with the Epson 10000 XL scanner. Presage dosimeter in this form was sensitive enough for use in SRS and SBRT QA. The lower gamma pass rate for Presage compared to Gafchromic film can be attributed to the simple equipment used in the fabrication process, which limited the dosimeter's sensitivity uniformity by agglomeration of air bubbles in the material, nonuniform concentration of chemicals throughout the material, and thickness variations. This demands improvements in mixing tools and molds.