Integrating local and distant radiation-induced lung injury: Development and validation of a predictive model for ventilation loss.

BACKGROUND: Investigations on radiation-induced lung injury (RILI) have predominantly focused on local effects, primarily those associated with radiation damage to lung parenchyma. However, recent studies from our group and others have revealed that radiation-induced damage to branching serial structures such as airways and vessels may also have a substantial impact on post-radiotherapy (RT) lung function. Furthermore, recent results from multiple functional lung avoidance RT trials, although promising, have demonstrated only modest toxicity reduction, likely because they were primarily focused on dose avoidance to lung parenchyma. These observations emphasize the critical need for predictive dose-response models that effectively incorporate both local and distant RILI effects. PURPOSE: We develop and validate a predictive model for ventilation loss after lung RT. This model, referred to as P+A, integrates local (parenchyma [P]) and distant (central and peripheral airways [A]) radiation-induced damage, modeling partial (narrowing) and complete (collapse) obstruction of airways. METHODS: In an IRB-approved prospective study, pre-RT breath-hold CTs (BHCTs) and pre- and one-year post-RT 4DCTs were acquired from lung cancer patients treated with definitive RT. Up to 13 generations of airways were automatically segmented on the BHCTs using a research virtual bronchoscopy software. Ventilation maps derived from the 4DCT scans were utilized to quantify pre- and post-RT ventilation, serving, respectively, as input data and reference standard (RS) in model validation. To predict ventilation loss solely due to parenchymal damage (referred to as P model), we used a normal tissue complication probability (NTCP) model. Our model used this NTCP-based estimate and predicted additional loss due radiation-induced partial or complete occlusion of individual airways, applying fluid dynamics principles and a refined version of our previously developed airway radiosensitivity model. Predictions of post-RT ventilation were estimated in the sublobar volumes (SLVs) connected to the terminal airways. To validate the model, we conducted a k-fold cross-validation. Model parameters were optimized as the values that provided the lowest root mean square error (RMSE) between predicted post-RT ventilation and the RS for all SLVs in the training data. The performance of the P+A and the P models was evaluated by comparing their respective post-RT ventilation values with the RS predictions. Additional evaluation using various receiver operating characteristic (ROC) metrics was also performed. RESULTS: We extracted a dataset of 560 SLVs from four enrolled patients. Our results demonstrated that the P+A model consistently outperformed the P model, exhibiting RMSEs that were nearly half as low across all patients (13 ± 3 percentile for the P+A model vs. 24 ± 3 percentile for the P model on average). Notably, the P+A model aligned closely with the RS in ventilation loss distributions per lobe, particularly in regions exposed to doses ≥13.5 Gy. The ROC analysis further supported the superior performance of the P+A model compared to the P model in sensitivity (0.98 vs. 0.07), accuracy (0.87 vs. 0.25), and balanced predictions. CONCLUSIONS: These early findings indicate that airway damage is a crucial factor in RILI that should be included in dose-response modeling to enhance predictions of post-RT lung function.

Evaluation of Number Density of Tumor-Associated Macrophages by Immunohistochemistry and Semiquantitative Scoring in Invasive Breast Cancer: An Indian Study.

Context: Tumor microenvironment is emerging as a critical factor for progression of breast cancer. Tumor-associated macrophages (TAMs) play an important role in promoting tumor growth. Aim: This study was aimed at correlation of number density (ND) of TAMs with invasive ductal carcinoma (IDC) grading utilizing an image morphometric technique. We also sought to compare the TAMs and ND in the tumoral area and stromal region. We also explored the relationship between the clinical and pathological prognostic parameters. Subjects and Methods: The study included 75 cases of IDC that had undergone modified radical mastectomy. The Institutional Ethics Committee approved the study. Samples were classified as Grade 1, 2, and 3. Cases were graded as per the modified Bloom and Richardson criterion. Mean with standard deviation was calculated for each group. We utilized CD68 and CD163 immunostained sections for determining the ND of TAMs. TAMs were evaluated using computerized digital photomicrograph system with image analyzing software. ND was defined as the number of TAMs in total number of TAMs in five high-power fields/total area of five fields. ND was calculated separately in tumor and tumor stroma (TS). Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2/neu (HER2/neu) were scored in accordance with recommendations. Ki-67 was scored as per the recommended guidelines. Statistical Analysis Used: Data were tabulated in Microsoft Excel. SPSS version 20.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. To determine the relationship between macrophage density and clinicopathologic parameters, we used the independent t-test. To determine the differences in the parameters, analysis of variance (ANOVA) was utilized. Results: Age of the patients ranged from 34 to 58 years (mean: 55.5). One-way ANOVA between various grades of tumor indicating significant differences in terms of CD68 and CD163 densities in tumor and stroma (P < 0.0001). i.e., significant increased density of CD68 and CD163 was observed in Grade 3 tumor as compared to other two groups. A greater histological grade, ER, PR negative status, and a high Ki-67 index were all associated with TAM ND. There was no relation to HER2/neu status. Result of unpaired t-test indicates increased density in stroma as compared to tumor among various grades of IDC. Conclusions: We analyzed images with a software using photographs of the stained slides. This helped in quantitative analysis of TAMs on the CD68 and CD163 stained sections. This approach standardizes and reproducibly counts TAMs per unit area. We found significant difference between the number densities of TAMs in grades of invasive breast carcinoma. There were statistically significant differences in numerical densities of TAMs with ER, PR negativity, and Ki-67. There was no correlation with HER2/neu. Densities of CD68 and CD163 densities are more prevalent in TS as compared to intratumoral region.

A study of skin marker alignment using different diamond-shaped light fields for prone breast external-beam radiation therapy.

For breast cancer patients treated in the prone position with tangential fields, a diamond-shaped light field (DSLF) can be used to align with corresponding skin markers for image-guided radiation therapy (IGRT). This study evaluates and compares the benefits of different DSLF setups. Seventy-one patients who underwent daily tangential kilovoltage (kV) IGRT were categorized retrospectively into four groups: (1) DSLF field size (FS) = 10 × 10 cm2 , gantry angle = 90° (right breast)/270° (left breast), with the same isocenter as treatment tangential beams; (2) same as group 1, except DSLF FS = 4 × 4 cm2 ; (3) DSLF FS = 4 × 4-6 × 8 cm2 , gantry angle = tangential treatment beam, off-isocenter so that the DSLF was at the approximate breast center; and (4) No-DSLF. We compared their total setup time (including any DSLF/marker-based alignment and IGRT) and relative kV-based couch shift corrections. For groups 1-3, DSLF-only dose distributions (excluding kV-based correction) were simulated by reversely shifting the couch positions from the computed tomography plans, which were assumed equivalent to the delivered dose when both DSLF and IGRT were used. For patient groups 1-4, the average daily setup time was 2.6, 2.5, 5.0, and 8.3 min, respectively. Their mean and standard deviations of daily kV-based couch shifts were 0.64 ± 0.4, 0.68 ± 0.3, 0.8 ± 0.6, and 1.0 ± 0.6 cm. The average target dose changes after excluding kV-IGRT for groups 1-3 were-0.2%, -0.1%, and +0.4%, respectively, whereas DSLF-1 was most efficient in sparing heart and chest wall, DSLF-2 had lowest lung Dmax ; and DSLF-3 maintained the highest target coverage at the cost of highest OAR dose. In general, the use of DSLF greatly reduces patient setup time and may result in smaller IGRT corrections. If IGRT is limited, different DSLF setups yield different target coverage and OAR dose sparing. Our findings will help DSLF setup optimization in the prone breast treatment setting.

Is a weekly qualitative picket fence test sufficient? A proposed alternate EPID-based weekly MLC QA program.

PURPOSE: Well-designed routine multileaf collimator (MLC) quality assurance (QA) is important to assure external-beam radiation treatment delivery accuracy. This study evaluates the clinical necessity of a comprehensive weekly (C-Weekly) MLC QA program compared to the American Association of Physics in Medicinerecommended weekly picket fence test (PF-Weekly), based on our seven-year experience with weekly MLC QA. METHODS: The C-Weekly MLC QA program used in this study includes 5 tests to analyze: (1) absolute MLC leaf position; (2) interdigitation MLC leaf position; (3) picket fence MLC leaf positions at static gantry angle; (4) minimum leaf-gap setting; and (5) volumetric-modulated arc therapy delivery. A total of 20,226 QA images from 16,855 tests (3,371 tests × 5) for 11 linacs at 5 photon clinical sites from May 2014 to June 2021 were analyzed. Failure mode and effects analysis was performed with 5 failure modes related to the 5 tests. For each failure mode, a risk probability number (RPN) was calculated for a C-Weekly and a PF-Weekly MLC QA program. The probability of occurrence was evaluated from statistical analyses of the C-Weekly MLC QA. RESULTS: The total number of failures for these 16,855 tests was 143 (0.9%): 39 (27.3%) for absolute MLC leaf position, 13 (9.1%) for interdigitation position, 9 (6.3%) for static gantry picket fence, 2 (1.4%) for minimum leaf-gap setting, and 80 (55.9%) for VMAT delivery. RPN scores for PF-Weekly MLC QA ranged from 60 to 192 and from 48 to 96 for C-Weekly MLC QA. CONCLUSION: RPNs for the 5 failure modes of MLC QA tests were quantitatively determined and analyzed. A comprehensive weekly MLC QA is imperative to lower the RPNs of the 5 failure modes to the desired level (<125); those from the PF-Weekly MLC QA program were found to be higher (>125). This supports the clinical necessity for comprehensive weekly MLC QA.

Combining Serial and Parallel Functionality in Functional Lung Avoidance Radiation Therapy.

PURPOSE: Functional lung avoidance (FLA) radiation therapy (RT) aims to minimize post-RT pulmonary toxicity by preferentially avoiding dose to high-functioning lung (HFL) regions. A common limitation is that FLA approaches do not consider the conducting architecture for gas exchange. We previously proposed the functionally weighted airway sparing (FWAS) method to spare airways connected to HFL regions, showing that it is possible to substantially reduce risk of radiation-induced airway injury. Here, we compare the performance of FLA and FWAS and propose a novel method combining both approaches. METHODS: We used breath-hold computed tomography (BHCT) and simulation 4-dimensional computed tomography (4DCT) from 12 lung stereotactic ablative radiation therapy patients. Four planning strategies were examined: (1) Conventional: no sparing other than clinical dose-volume constraints; (2) FLA: using a 4DCT-based ventilation map to delineate the HFL, plans were optimized to reduce mean dose and V13.50 in HFL; (3) FWAS: we autosegemented 11 to 13 generations of individual airways from each patient's BHCT and assigned priorities based on the relative contribution of each airway to total ventilation. We used these priorities in the optimization along with airway dose constraints, estimated as a function of airway diameter and 5% probability of collapse; and (4) FLA + FWAS: we combined information from the 2 strategies. We prioritized clinical dose constraints for organs at risk and planning target volume in all plans. We performed the evaluation in terms of ventilation preservation accounting for radiation-induced damage to both lung parenchyma and airways. RESULTS: We observed average ventilation preservation for FLA, FWAS, and FLA + FWAS as 3%, 8.5%, and 14.5% higher, respectively, than for Conventional plans for patients with ventilation preservation in Conventional plans <90%. Generalized estimated equations showed that all improvements were statistically significant (P ≤ .036). We observed no clinically relevant improvements in outcomes of the sparing techniques in patients with ventilation preservation in Conventional plans ≥90%. CONCLUSIONS: These initial results suggest that it is crucial to consider the parallel and the serial nature of the lung to improve post-radiation therapy lung function and, consequently, quality of life for patients.

Comparison of the dosimetric accuracy of proton breast treatment plans delivered with SGRT and CBCT setups.

PURPOSE: To compare the dosimetric accuracy of surface-guided radiation therapy (SGRT) and cone-beam computed tomography (CBCT) setups in proton breast treatment plans. METHODS: Data from 30 patients were retrospectively analyzed in this IRB-approved study. Patients were prescribed 4256-5040 cGy in 16-28 fractions. CBCT and AlignRT (SGRT; Vision RT Ltd.) were used for treatment setup during the first three fractions, then daily AlignRT and weekly CBCT thereafter. Each patient underwent a quality assurance CT (QA-CT) scan midway through the treatment course to assess anatomical and dosimetric changes. To emulate the SGRT and CBCT setups during treatment, the planning CT and QA-CT images were registered in two ways: (1) by registering the volume within the CTs covered by the CBCT field of view; and (2) by contouring and registering the surface surveyed by the AlignRT system. The original plan was copied onto these two datasets and the dose was recalculated. The clinical treatment volume (CTV): V95% ; heart: V25Gy , V15Gy , and mean dose; and ipsilateral lung: V20Gy , V10Gy , and V5Gy , were recorded. Multi and univariate analyses of variance were performed to assess the differences in dose metric values between the planning CT and the SGRT and CBCT setups. RESULTS: The CTV V95% and lung V20Gy , V10Gy , and V5Gy dose metrics were all significantly (p < 0.01) lower on the QA-CT in both the CBCT and SGRT setup. The differences were not clinically significant and were, on average, 1.4-1.6% lower for CTV V95% and 1.8%-6.0% lower for the lung dose metrics. When comparing the lung and CTV V95% dose metrics between the CBCT and SGRT setups, no significant difference was observed. This indicates that the SGRT setup provides similar dosimetric accuracy as CBCT. CONCLUSION: This study supports the daily use of SGRT systems for the accurate dose delivery of proton breast treatment plans.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio and Their Role as Predictors of Disease Severity of Coronavirus Disease 2019 (COVID-19).

Context Due to the wide spectrum of clinical illness in coronavirus disease 2019 (COVID-19) patients, it is important to stratify patients into severe and nonsevere categories. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been evaluated rapidly by a few studies worldwide for its association with severe disease, but practically none have been conducted in the Indian population. This study was undertaken to examine the role of NLR and PLR in predicting severe disease in Indian patients. Objectives The objective was to study the association of NLR and PLR observed at the time of admission with maximum disease severity during hospitalization and to study their role in predicting disease severity. Material and Methods A total of 229 COVID-19 patients were admitted at the center during the study period. After applying inclusion and exclusion criteria, 191 patients were included in the study. The demographic, clinical, and laboratory (complete blood count, NLR, and PLR) data of all patients were obtained at the time of admission. Maximum disease severity of all patients was assessed during hospitalization. Statistical Analysis Chi-square and Mann-Whitney U tests were used to assess statistical significance. Receiver operating characteristic curve (ROC) was plotted for NLR and PLR to estimate the cutoff values and sensitivity and specificity using Youden's index for predicting severe disease. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals. Results Mean NLR and PLR were significantly higher in severe patients (NLR = 7.41; PLR = 204) compared with nonsevere patients (NLR = 3.30; PLR = 121). ROC analysis showed that NLR, in comparison to PLR, had a higher area under the curve (AUC) of 0.779, with a larger OR of 1.237 and cutoff of 4.1, and showed 69% sensitivity and 78% specificity in predicting severe disease. Cut off for PLR was 115.3, which showed 79% sensitivity and 62% specificity in predicting severe disease. Conclusion NLR and PLR, both showing acceptable AUCs, can be used as screening tools to predict disease severity. However, NLR was a better predictor of disease severity.

Performance measurement tools for consultation-liaison psychiatry services must consider feasibility.

This editorial describes an effort by 9 consultation-liaison (C-L) psychiatry service leaders in the United States to incorporate routine performance measurement into their service workflows. Although C-L psychiatry is an essential clinical service in general hospitals, performance metrics for this service have not been broadly accepted or implemented. Meanwhile, the performance metrics that have been developed rely on an investment in resources and/or new workflows that C-L psychiatry services may not be prepared to make on a widespread level. Our group sought to determine the feasibility of incorporating routine performance measurement into the workflows of a diverse sample of C-L psychiatry services using only existing resources via three collection methods: timestamp review, chart auditing, and survey administration. No methods were broadly successful across the 9 services. We argue that for routine performance measurement to gain wider traction in the field of C-L psychiatry, the ready availability-or automatability-of performance data must be taken into account.

Evaluation of Computed Tomography Scanners for Feasibility of Using Averaged Hounsfield Unit-to-Stopping Power Ratio Calibration Curve.

PURPOSE: The purpose of this study was to quantify the variability of stoichiometric calibration curves for different computed tomography (CT) scanners and determine whether an averaged Hounsfield unit (HU)-to-stopping power ratio (SPR) calibration curve can be used across multiple CT scanners. MATERIALS AND METHODS: Five CT scanners were used to scan an electron density phantom to establish HU values of known material plugs. A stoichiometric calibration curve was calculated for CT scanners and for the average curve. Animal tissue surrogates were used to compare the water-equivalent thickness (WET) of the animal tissue surrogates calculated by the treatment planning system (TPS) and the WET values measured with a multilayered ionization chamber. The calibration curves were optimized to reduce the percentage of difference between measured and TPS-calculated WET values. A second set of tissue surrogates was then used to evaluate the overall range of uncertainty for the optimized CT-specific and average calibration curves. RESULTS: Overall, the average variation in HU for all 6 calibration curves before optimization was 8.3 HU. For both the averaged and CT-specific calibrations, the root mean square error (RMSE) of the percentage of difference between TPS-calculated and measured WET values before optimization was 4%. The RMSE of the percentage of difference for the TPS-calculated and multilayered ionization chamber measured WET values after the optimization for both averaged and CT-specific calibration curves was reduced to less than 1.5%. The overall RMSE of the TPS and the measured WET percentage of difference after optimization was 2.1% for both averaged and CT-specific calibration curves. CONCLUSION: Averaged CT calibration curves can be used to map the HU-to-SPR in TPSs, if the variations in HU values across all scanners is relatively small. Performing tissue surrogate optimization of the HU-to-SPR calibration curve has been shown to reduce the overall uncertainty of the calibration for averaged and CT-specific calibration curves and is recommended, especially if an averaged HU-to-SPR calibration curve is used.

Use of local noise power spectrum and wavelet analysis in quantitative image quality assurance for EPIDs.

PURPOSE: To investigate the use of local noise power spectrum (NPS) to characterize image noise and wavelet analysis to isolate defective pixels and inter-subpanel flat-fielding artifacts for quantitative quality assurance (QA) of electronic portal imaging devices (EPIDs). METHODS: A total of 93 image sets including custom-made bar-pattern images and open exposure images were collected from four iViewGT a-Si EPID systems over three years. Global quantitative metrics such as modulation transform function (MTF), NPS, and detective quantum efficiency (DQE) were computed for each image set. Local NPS was also calculated for individual subpanels by sampling region of interests within each subpanel of the EPID. The 1D NPS, obtained by radially averaging the 2D NPS, was fitted to a power-law function. The r-square value of the linear regression analysis was used as a singular metric to characterize the noise properties of individual subpanels of the EPID. The sensitivity of the local NPS was first compared with the global quantitative metrics using historical image sets. It was then compared with two commonly used commercial QA systems with images collected after applying two different EPID calibration methods (single-level gain and multilevel gain). To detect isolated defective pixels and inter-subpanel flat-fielding artifacts, Haar wavelet transform was applied on the images. RESULTS: Global quantitative metrics including MTF, NPS, and DQE showed little change over the period of data collection. On the contrary, a strong correlation between the local NPS (r-square values) and the variation of the EPID noise condition was observed. The local NPS analysis indicated image quality improvement with the r-square values increased from 0.80 ± 0.03 (before calibration) to 0.85 ± 0.03 (after single-level gain calibration) and to 0.96 ± 0.03 (after multilevel gain calibration), while the commercial QA systems failed to distinguish the image quality improvement between the two calibration methods. With wavelet analysis, defective pixels and inter-subpanel flat-fielding artifacts were clearly identified as spikes after thresholding the inversely transformed images. CONCLUSIONS: The proposed local NPS (r-square values) showed superior sensitivity to the noise level variations of individual subpanels compared with global quantitative metrics such as MTF, NPS, and DQE. Wavelet analysis was effective in detecting isolated defective pixels and inter-subpanel flat-fielding artifacts. The proposed methods are promising for the early detection of imaging artifacts of EPIDs.

A study of IMRT planning parameters on planning efficiency, delivery efficiency, and plan quality.

PURPOSE: To improve planning and delivery efficiency of head and neck IMRT without compromising planning quality through the evaluation of inverse planning parameters. METHODS: Eleven head and neck patients with pre-existing IMRT treatment plans were selected for this retrospective study. The Pinnacle treatment planning system (TPS) was used to compute new treatment plans for each patient by varying the individual or the combined parameters of dose∕fluence grid resolution, minimum MU per segment, and minimum segment area. Forty-five plans per patient were generated with the following variations: 4 dose∕fluence grid resolution plans, 12 minimum segment area plans, 9 minimum MU plans, and 20 combined minimum segment area∕minimum MU plans. Each plan was evaluated and compared to others based on dose volume histograms (DVHs) (i.e., plan quality), planning time, and delivery time. To evaluate delivery efficiency, a model was developed that estimated the delivery time of a treatment plan, and validated through measurements on an Elekta Synergy linear accelerator. RESULTS: The uncertainty (i.e., variation) of the dose-volume index due to dose calculation grid variation was as high as 8.2% (5.5 Gy in absolute dose) for planning target volumes (PTVs) and 13.3% (2.1 Gy in absolute dose) for planning at risk volumes (PRVs). Comparison results of dose distributions indicated that smaller volumes were more susceptible to uncertainties. The grid resolution of a 4 mm dose grid with a 2 mm fluence grid was recommended, since it can reduce the final dose calculation time by 63% compared to the accepted standard (2 mm dose grid with a 2 mm fluence grid resolution) while maintaining a similar level of dose-volume index variation. Threshold values that maintained adequate plan quality (DVH results of the PTVs and PRVs remained satisfied for their dose objectives) were 5 cm(2) for minimum segment area and 5 MU for minimum MU. As the minimum MU parameter was increased, the number of segments and delivery time were decreased. Increasing the minimum segment area parameter decreased the plan MU, but had less of an effect on the number of segments and delivery time. Our delivery time model predicted delivery time to within 1.8%. CONCLUSIONS: Increasing the dose grid while maintaining a small fluence grid allows for improved planning efficiency without compromising plan quality. Delivery efficiency can be improved by increasing the minimum MU, but not the minimum segment area. However, increasing the respective minimum MU and∕or the minimum segment area to any value greater than 5 MU and 5 cm(2) is not recommended because it degrades plan quality.

Status of O6 -methylguanine-DNA methyltransferase [MGMT] gene promoter methylation among patients with glioblastomas from India.

BACKGROUND: O6 -methylguanine DNA methyltransferase [MGMT] gene promoter methylation has emerged as a promising marker in determining resistance to temozolomide, used in the treatment of patients with glioblastomas. AIM: To determine the frequency of MGMT promoter methylation among patients with glioblastomas using methylation-specific polymerase chain reaction (MSP) and compare it to the results obtained by bisulfite sequencing of a subset of samples. MATERIALS AND METHODS: DNA obtained from the frozen tissue of 27 samples of glioblastomas and three other gliomas, were analyzed for MGMT promoter methylation using a nested MSP assay. Sixteen samples were also subjected to bisulfite sequencing to determine the methylation status of 27 CpG sites within the sequenced region of the MGMT promoter. Data with respect to radiation, chemotherapy and survival outcome was also collected. RESULTS: MGMT promoter methylation was seen in 67% of the cases included in the study using frozen tissues by MSP analysis, while 62% were methylated among glioblastomas alone. There was a 100% concordance between the results obtained by MSP analysis and bisulfite sequencing. Clinical outcome was known among 67% of cases and methylation was higher among those patients who had no recurrence, though it was not statistically significant [P=0.44]. CONCLUSION: The frequency of methylation seen in this study concurs with that reported earlier from the country. MSP was easy to perform and interpret. However, the utility of this testing system in a routine diagnostic setting is still being debated.

Use of a line-pair resolution phantom for comprehensive quality assurance of electronic portal imaging devices based on fundamental imaging metrics.

Image guided radiation therapy solutions based on megavoltage computed tomography (MVCT) involve the extension of electronic portal imaging devices (EPIDs) from their traditional role of weekly localization imaging and planar dose mapping to volumetric imaging for 3D setup and dose verification. To sustain the potential advantages of MVCT, EPIDs are required to provide improved levels of portal image quality. Therefore, it is vital that the performance of EPIDs in clinical use is maintained at an optimal level through regular and rigorous quality assurance (QA). Traditionally, portal imaging QA has been carried out by imaging calibrated line-pair and contrast resolution phantoms and obtaining arbitrarily defined QA indices that are usually dependent on imaging conditions and merely indicate relative trends in imaging performance. They are not adequately sensitive to all aspects of image quality unlike fundamental imaging metrics such as the modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE) that are widely used to characterize detector performance in radiographic imaging and would be ideal for QA purposes. However, due to the difficulty of performing conventional MTF measurements, they have not been used for routine clinical QA. The authors present a simple and quick QA methodology based on obtaining the MTF, NPS, and DQE of a megavoltage imager by imaging standard open fields and a bar-pattern QA phantom containing 2 mm thick tungsten line-pair bar resolution targets. Our bar-pattern based MTF measurement features a novel zero-frequency normalization scheme that eliminates normalization errors typically associated with traditional bar-pattern measurements at megavoltage x-ray energies. The bar-pattern QA phantom and open-field images are used in conjunction with an automated image analysis algorithm that quickly computes the MTF, NPS, and DQE of an EPID system. Our approach combines the fundamental advantages of linear systems metrics such as robustness, sensitivity across the full spatial frequency range of interest, and normalization to imaging conditions (magnification, system gain settings, and exposure), with the simplicity, ease, and speed of traditional phantom imaging. The algorithm was analyzed for accuracy and sensitivity by comparing with a commercial portal imaging QA method (PIPSPRO, Standard Imaging, Middleton, WI) on both first-generation lens-coupled and modern a-Si flat-panel based clinical EPID systems. The bar-pattern based QA measurements were found to be far more sensitive to even small levels of degradation in spatial resolution and noise. The bar-pattern based QA methodology offers a comprehensive image quality assessment tool suitable for both commissioning and routine EPID QA.

Analysis of the kinestatic charge detection system as a high detective quantum efficiency electronic portal imaging device.

Megavoltage x-ray imaging suffers from reduced image quality due to low differential x-ray attenuation and large Compton scatter compared with kilovoltage imaging. Notwithstanding this, electronic portal imaging devices (EPIDs) are now widely used in portal verification in radiotherapy as they offer significant advantages over film, including immediate digital imaging and superior contrast range. However video-camera-based EPIDs (VEPIDs) are limited by problems of low light collection efficiency and significant light scatter, leading to reduced contrast and spatial resolution. Indirect and direct detection-based flat-panel EPIDs have been developed to overcome these limitations. While flat-panel image quality has been reported to exceed that achieved with portal film, these systems have detective quantum efficiency (DQE) limited by the thin detection medium and are sensitive to radiation damage to peripheral read-out electronics. An alternative technology for high-quality portal imaging is presented here: kinesatic charge detection (KCD). The KCD is a scanning tri-electrode ion-chamber containing high-pressure noble gas (xenon at 100 atm) used in conjunction with a strip-collimated photon beam. The chamber is scanned across the patient, and an external electric field is used to regulate the cation drift velocity. By matching the scanning velocity with that of the cation (i.e., ion) drift velocity, the cations remain static in the object frame of reference, allowing temporal integration of the signal. The KCD offers several advantages as a portal imaging system. It has a thick detector geometry with an active detection depth of 6.1 cm, compared to the sub-millimeter thickness of the phosphor layer in conventional phosphor screens, leading to an order of magnitude advantage in quantum efficiency (>0.3). The unique principle of and the use of the scanning strip-collimated x-ray beam provide further integration of charges in time, reduced scatter, and a significantly reduced imaging dose, enhancing the imaging signal-to-noise ratio (SNR) and leading to high DQE. While thick detectors usually suffer from reduced spatial resolution, the KCD provides good spatial resolution due to high gas pressure that limits the spread of scattered electrons, and a strip-collimated beam that significantly reduces the inclusion of scatter in the imaging signal. A 10 cm wide small-field-of-view (SFOV) prototype of the KCD is presented with a complete analysis of its imaging performance. Measurements of modulation transfer function (MTF), noise power spectrum (NPS), and DQE were in good agreement with Monte Carlo simulations. Imaging signal loss from recombination within the KCD chamber was measured at different gas pressures, ion drift velocities, and strip-collimation widths. Image quality for the prototype KCD was also observed with anthropomorphic phantom imaging in comparison with various commercial and research portal imaging systems, including VEPID, flat-panel imager, and conventional and high contrast film systems. KCD-based imaging provided very good contrast and good spatial resolution at very low imaging dose (0.1 cGy per image). For the prototype KCD, measurements yielded DQE(0)=0.19 and DQE(1 cy/mm)=0.004.

Study of a prototype high quantum efficiency thick scintillation crystal video-electronic portal imaging device.

Image quality in portal imaging suffers significantly from the loss in contrast and spatial resolution that results from the excessive Compton scatter associated with megavoltage x rays. In addition, portal image quality is further reduced due to the poor quantum efficiency (QE) of current electronic portal imaging devices (EPIDs). Commercial video-camera-based EPIDs or VEPIDs that utilize a thin phosphor screen in conjunction with a metal buildup plate to convert the incident x rays to light suffer from reduced light production due to low QE (<2% for Eastman Kodak Lanex Fast-B). Flat-panel EPIDs that utilize the same luminescent screen along with an a-Si:H photodiode array provide improved image quality compared to VEPIDs, but they are expensive and can be susceptible to radiation damage to the peripheral electronics. In this article, we present a prototype VEPID system for high quality portal imaging at sub-monitor-unit (subMU) exposures based on a thick scintillation crystal (TSC) that acts as a high QE luminescent screen. The prototype TSC system utilizes a 12 mm thick transparent CsI(Tl) (thallium-activated cesium iodide) scintillator for QE=0.24, resulting in significantly higher light production compared to commercial phosphor screens. The 25 X 25 cm2 CsI(Tl) screen is coupled to a high spatial and contrast resolution Video-Optics plumbicon-tube camera system (1240 X 1024 pixels, 250 microm pixel width at isocenter, 12-bit ADC). As a proof-of-principle prototype, the TSC system with user-controlled camera target integration was adapted for use in an existing clinical gantry (Siemens BEAMVIEW(PLUS)) with the capability for online intratreatment fluoroscopy. Measurements of modulation transfer function (MTF) were conducted to characterize the TSC spatial resolution. The measured MTF along with measurements of the TSC noise power spectrum (NPS) were used to determine the system detective quantum efficiency (DQE). A theoretical expression of DQE(0) was developed to be used as a predictive model to propose improvements in the optics associated with the light detection. The prototype TSC provides DQE(0)=0.02 with its current imaging geometry, which is an order of magnitude greater than that for commercial VEPID systems and comparable to flat-panel imaging systems. Following optimization in the imaging geometry and the use of a high-end, cooled charge-coupled-device (CCD) camera system, the performance of the TSC is expected to improve even further. Based on our theoretical model, the expected DQE(0)=0.12 for the TSC system with the proposed improvements, which exceeds the performance of current flat-panel EPIDs. The prototype TSC provides high quality imaging even at subMU exposures (typical imaging dose is 0.2 MU per image), which offers the potential for daily patient localization imaging without increasing the weekly dose to the patient. Currently, the TSC is capable of limited frame-rate fluoroscopy for intratreatment visualization of patient motion at approximately 3 frames/second, since the achievable frame rate is significantly reduced by the limitations of the camera-control processor. With optimized processor control, the TSC is expected to be capable of intratreatment imaging exceeding 10 frames/second to monitor patient motion.

Calcium dependence of proteinase-activated receptor 2 and cholecystokinin-mediated amylase secretion from pancreatic acini.

Pancreatic acini secrete digestive enzymes in response to a variety of secretagogues including CCK and agonists acting via proteinase-activated receptor-2 (PAR2). We employed the CCK analog caerulein and the PAR2-activating peptide SLIGRL-NH(2) to compare and contrast Ca(2+) changes and amylase secretion triggered by CCK receptor and PAR2 stimulation. We found that secretion stimulated by both agonists is dependent on a rise in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and that this rise in [Ca(2+)](i) reflects both the release of Ca(2+) from intracellular stores and accelerated Ca(2+) influx. Both agonists, at low concentrations, elicit oscillatory [Ca(2+)](i) changes, and both trigger a peak plateau [Ca(2+)](i) change at high concentrations. Although the two agonists elicit similar rates of amylase secretion, the rise in [Ca(2+)](i) elicited by caerulein is greater than that elicited by SLIGRL-NH(2). In Ca(2+)-free medium, the rise in [Ca(2+)](i) elicited by SLIGRL-NH(2) is prevented by the prior addition of a supramaximally stimulating concentration of caerulein, but the reverse is not true; the rise elicited by caerulein is neither prevented nor reduced by prior addition of SLIGRL-NH(2). Both the oscillatory and the peak plateau [Ca(2+)](i) changes that follow PAR2 stimulation are prevented by the phospholipase C (PLC) inhibitor U73122, but U73122 prevents only the oscillatory [Ca(2+)](i) changes triggered by caerulein. We conclude that 1) both PAR2 and CCK stimulation trigger amylase secretion that is dependent on a rise in [Ca(2+)](i) and that [Ca(2+)](i) rise reflects release of calcium from intracellular stores as well as accelerated influx of extracellular calcium; 2) PLC mediates both the oscillatory and the peak plateau rise in [Ca(2+)](i) elicited by PAR2 but only the oscillatory rise in [Ca(2+)](i) elicited by CCK stimulation; and 3) the rate of amylase secretion elicited by agonists acting via different types of receptors may not correlate with the magnitude of the [Ca(2+)](i) rise triggered by those different types of secretagogue.

Protection against acute pancreatitis by activation of protease-activated receptor-2.

Protease-activated receptor-2 (PAR-2) is a widely expressed tethered ligand receptor that can be activated by trypsin and other trypsin-like serine proteases. In the exocrine pancreas, PAR-2 activation modulates acinar cell secretion of digestive enzymes and duct cell ion channel function. During acute pancreatitis, digestive enzyme zymogens, including trypsinogen, are activated within the pancreas. We hypothesized that trypsin, acting via PAR-2, might regulate the severity of that disease, and to test this hypothesis, we examined the effect of either genetically deleting or pharmacologically activating PAR-2 on the severity of secretagogue-induced experimental pancreatitis. We found that experimental acute pancreatitis is more severe in PAR-2(-/-) than in wild-type mice and that in vivo activation of PAR-2, achieved by parenteral administration of the PAR-2-activating peptide SLIGRL-NH2, reduces the severity of pancreatitis. In the pancreas during the early stages of pancreatitis, the MAPK ERK1/2 is activated and translocated to the nucleus, but nuclear translocation is reduced by activation of PAR-2. Our findings indicate that PAR-2 exerts a protective effect on pancreatitis and that activation of PAR-2 ameliorates pancreatitis, possibly by inhibiting ERK1/2 translocation to the nucleus. Our observations suggest that PAR-2 activation may be of therapeutic value in the treatment and/or prevention of severe clinical pancreatitis, and they lead us to speculate that, from a teleological standpoint, PAR-2 may have evolved in the pancreas as a protective mechanism designed to dampen the injurious effects of intrapancreatic trypsinogen activation.

Verification of multileaf collimator leaf positions using an electronic portal imaging device.

An automated method is presented for determining individual leaf positions of the Siemens dual focus multileaf collimator (MLC) using the Siemens BEAMVIEW(PLUS) electronic portal imaging device (EPID). Leaf positions are computed with an error of 0.6 mm at one standard deviation (sigma) using separate computations of pixel dimensions, image distortion, and radiation center. The pixel dimensions are calculated by superimposing the film image of a graticule with the corresponding EPID image. A spatial correction is used to compensate for the optical distortions of the EPID, reducing the mean distortion from 3.5 pixels (uncorrected) per localized x-ray marker to 2 pixels (1 mm) for a rigid rotation and 1 pixel for a third degree polynomial warp. A correction for a nonuniform dosimetric response across the field of view of the EPID images is not necessary due to the sharp intensity gradients across leaf edges. The radiation center, calculated from the average of the geometric centers of a square field at 0 degrees and 180 degrees collimator angles, is independent of graticule placement error. Its measured location on the EPID image was stable to within 1 pixel based on 3 weeks of repeated extensions/retractions of the EPID. The MLC leaf positions determined from the EPID images agreed to within a pixel of the corresponding values measured using film and ionization chamber. Several edge detection algorithms were tested: contour, Sobel, Roberts, Prewitt, Laplace, morphological, and Canny. These agreed with each other to within < or = 1.2 pixels for the in-air EPID images. Using a test pattern, individual MLC leaves were found to be typically within 1 mm of the corresponding record-and-verify values, with a maximum difference of 1.8 mm, and standard deviations of <0.3 mm in the daily reproducibility. This method presents a fast, automatic, and accurate alternative to using film or a light field for the verification and calibration of the MLC.