PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation.

Cellular senescence is a permanent cell cycle arrest that can be triggered by both internal and external genotoxic stressors, such as telomere dysfunction and DNA damage. The execution of senescence is mainly by two pathways, p16/RB and p53/p21, which lead to CDK4/6 inhibition and RB activation to block cell cycle progression. While the regulation of p53/p21 signaling in response to DNA damage and other insults is well-defined, the regulation of the p16/RB pathway in response to various stressors remains poorly understood. Here, we report a novel function of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, as a potent inhibitor of p16 expression and senescence induction by ionizing radiation (IR), such as γ-rays. The results show that ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced senescence. Conversely, PR55α-knockdown by shRNA in pancreatic cancer cells elevates p16 transcription, reduces RB phosphorylation, and triggers senescence induction after IR. Furthermore, this PR55α function in the regulation of p16 and senescence is p53-independent because it was unaffected by the mutational status of p53. Moreover, PR55α only affects p16 expression but not p14 (ARF) expression, which is also transcribed from the same CDKN2A locus but from an alternative promoter. In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.

Commissioning and initial validation of Eclipse eMC algorithm for the electron FLASH research extension (FLEX) system for pre-clinical studies.

PURPOSE: To investigate the feasibility of commissioning the 16 MeV electron FLASH Extension (FLEX) in the commercial treatment planning system (TPS) for biomedical research with cell and mouse models, and in silico treatment planning studies. METHODS: To commission the FLEX system with the electron Monte Carlo (eMC) algorithm in the commercial TPS, radiochromic film was used to measure the vendor-recommended beam data. Once the beam model was generated for the eMC algorithm, supplemental measurements were collected for validation purposes and compared against the TPS-calculated results. Additionally, the newly commissioned 16 MeV FLASH beam was compared to the corresponding 16 MeV conventional electron beam. RESULTS: The eMC algorithm effectively modeled the FLEX system. The eMC-calculated PDDs and profiles for the 16 MeV electron FLASH beam agreed with measured values within 1%, on average, for 6 × 6 cm2 and 10 × 10 cm2 applicators. Flatness and symmetry deviated by less than 1%, while FWHM and penumbra agreed within 1 mm for both eMC-calculated and measured profiles. Additionally, the small field (i.e., 2-cm diameter cutout) that was measured for validation purposes agreed with TPS-calculated results within 1%, on average, for both the PDD and profiles. The FLASH and conventional dose rate 16 MeV electron beam were in agreement in regard to energy, but the profiles for larger field sizes began to deviate (>10 × 10 cm2) due to the forward-peaked nature of the FLASH beam. For cell irradiation experiments, the measured and eMC-calculated in-plane and cross-plane absolute dose profiles agreed within 1%, on average. CONCLUSIONS: The FLEX system was successfully commissioned in the commercial TPS using the eMC algorithm, which accurately modeled the forward-peaked nature of the FLASH beam. A commissioned TPS for FLASH will be useful for pre-clinical cell and animal studies, as well as in silico FLASH treatment planning studies for future clinical implementation.

Structural Design of 3D Current Collectors for Lithium Metal Anodes: A Review.

Due to the ultrahigh theoretical specific capacity (3860 mAh g-1) and low redox potential (-3.04 V vs. standard hydrogen electrode), Lithium (Li) metal anode (LMA) received increasing attentions. However, notorious dendrite and volume expansion during the cycling process seriously hinder the development of high energy density Li metal batteries. Constructing three-dimensional (3D) current collectors for Li can fundamentally solve the intrinsic drawback of hostless for Li. Therefore, this review systematically introduces the design and synthesis engineering and the current development status of different 3D collectors in recent years (the current collectors are divided into two major parts: metal-based current collectors and carbon-based current collectors). In the end, some perspectives of the future promotion for LMA application are also presented.

Cell Signaling Pathways That Promote Radioresistance of Cancer Cells.

Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.

p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase.

We have previously reported an important role of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, in the support of critical oncogenic pathways required for oncogenesis and the malignant phenotype of pancreatic cancer. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor inhibits the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins. Our studies show that inactivation of p53 by siRNA-knockdown, gene-deletion, HPV-E6-mediated degradation, or expression of the loss-of-function mutant p53R175H results in increased PR55α protein stability, which is accompanied by reduced protein expression of FBXL20 and decreased ubiquitination of PR55α. Subsequent studies demonstrate that knockdown of FBXL20 by siRNA mimics p53 deficiency, reducing PR55α ubiquitination and increasing PR55α protein stability. Functional tests indicate that ectopic p53R175H or PR55α expression results in an increase of c-Myc protein stability with concomitant dephosphorylation of c-Myc-T58, which is a PR55α substrate, whose phosphorylation otherwise promotes c-Myc degradation. A significant increase in anchorage-independent proliferation is also observed in normal human pancreatic cells expressing p53R175H or, to a greater extent, overexpressing PR55α. Consistent with the common loss of p53 function in pancreatic cancer, FBXL20 mRNA expression is significantly lower in pancreatic cancer tissues compared to pancreatic normal tissues and low FBXL20 levels correlate with poor patient survival. Collectively, these studies delineate a novel mechanism by which the p53/FBXL20 axis negatively regulates PR55α protein stability.

Medical Physics Practice Guideline (MPPG) 11.a: Plan and chart review in external beam radiotherapy and brachytherapy.

A therapeutic medical physicist is responsible for reviewing radiation therapy treatment plans and patient charts, including initial treatment plans and new chart review, on treatment chart (weekly) review, and end of treatment chart review for both external beam radiation and brachytherapy. Task group report TG 275 examined this topic using a risk-based approach to provide a thorough analysis and guidance for best practice. Considering differences in resources and workflows of various clinical practice settings, the Professional Council of the American Association of Physicists in Medicine assembled this task group to develop a practice guideline on the same topic to provide a minimum standard that balances an appropriate level of safety and resource utilization. This medical physics practice guidelines (MPPG) thus provides a concise set of recommendations for medical physicists and other clinical staff regarding the review of treatment plans and patient charts while providing specific recommendations about who to be involved, and when/what to check in the chart review process. The recommendations, particularly those related to the initial plan review process, are critical for preventing errors and ensuring smooth clinical workflow. We believe that an effective review process for high-risk items should include multiple layers with collective efforts across the department. Therefore, in this report, we make specific recommendations for various roles beyond medical physicists. The recommendations of this MPPG have been reviewed and endorsed by the American Society of Radiologic Technologists and the American Association of Medical Dosimetrists.

Associations between Statin/Omega3 Usage and MRI-Based Radiomics Signatures in Prostate Cancer.

Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer deaths among American men. Statins and omega-3 are two medications recently found to correlate with prostate cancer risk and aggressiveness, but the observed associations are complex and controversial. We therefore explore the novel application of radiomics in studying statin and omega-3 usage in prostate cancer patients. On MRIs of 91 prostate cancer patients, two regions of interest (ROIs), the whole prostate and the peripheral region of the prostate, were manually segmented. From each ROI, 944 radiomic features were extracted after field bias correction and normalization. Heatmaps were generated to study the radiomic feature patterns against statin or omega-3 usage. Radiomics models were trained on selected features and evaluated with 500-round threefold cross-validation for each drug/ROI combination. On the 1500 validation datasets, the radiomics model achieved average AUCs of 0.70, 0.74, 0.78, and 0.72 for omega-3/prostate, omega-3/peripheral, statin/prostate, and statin/peripheral, respectively. As the first study to analyze radiomics in relation to statin and omega-3 uses in prostate cancer patients, our study preliminarily established the existence of imaging-identifiable tissue-level changes in the prostate and illustrated the potential usefulness of radiomics for further exploring these medications' effects and mechanisms in prostate cancer.

Using flattening filter free beams in electronic tissue compensation whole breast irradiation with deep inspiration breath hold.

PURPOSE: In order to reduce heart dose, DIBH has become a common practice in left-sided whole breast irradiation. This technique involves a significant strain on patients due to the breath-hold requirements. We hereby investigate the dosimetric and delivery feasibility of using flattening filter free (FFF) energies with electronic tissue compensation (ECOMP) planning technique to reduce the required breath-hold lengths and increase patient compatibility. METHODS: Fifteen left-sided, postlumpectomy patients previously receiving DIBH whole-breast radiotherapy (266cGy x 16fx) were retrospectively planned using ECOMP for both 6X and 6X-FFF. A dosimetric comparison was made between the two plans for each patient using various dosimetric constraints. Delivery feasibility was analyzed by recalculating the 6X ECOMP plan with 6X-FFF without replanning (6X-FFF QA) and delivering both plans for a one-to-one comparison using Gamma analysis. Beam-on times for the 6X and 6X-FFF plans were measured. For all tests, Wilcoxon signed-rank test was used with P < 0.05 as significant. RESULTS: No statistical difference was observed between 6X and 6X-FFF plans for most dosimetric endpoints except contralateral breast Dmax (P = 0.0008) and skin Dmax (p = 0.03) and Dmin (P = 0.01) for which 6X-FFF showed favorable results when compared with 6X. 6X-FFF significantly reduced beam-on times for all patients by 22%-42% (average 32%). All plan QAs passed departmental gamma criteria (10% low-dose threshold, 3%/3mm, >95% passing). CONCLUSION: ECOMP planning with FFF was found feasible for left-sided breast patients with DIBH. Plan quality is comparable, if not better, than plans using flattened beams. FFF ECOMP could significantly reduce beam-on time and required breath-hold lengths thereby increasing patient compatibility for this treatment while offering satisfactory plan quality and delivery accuracy.

Minimum dose rate estimation for pulsed FLASH radiotherapy: A dimensional analysis.

PURPOSE/OBJECTIVES: To provide an order of magnitude estimate of the minimum dose rate ( R min ) required by pulsed ultra-high dose rate radiotherapy (FLASH RT) using dimensional analysis. MATERIALS/METHODS: In this study, we postulate that radiation-induced transient hypoxia inside normal tissue cells during FLASH RT results in better normal tissue sparing over conventional dose rate radiotherapy. We divide the process of cell irradiation by an ultra-short radiation pulse into three sequential phases: (a) The radiation pulse interacts with the normal tissue cells and produces radiation-induced species. (b) The radiation-induced species react with oxygen molecules and reduce the cell environmental oxygen concentration ( O 2 ). (c) Oxygen molecules, from nearest capillaries, diffuse slowly back into the resulted low O 2 regions. By balancing the radiation-induced oxygen depletion in phase II and diffusion-resulted O 2 replenishment in phase III, we can estimate the maximum allowed pulse repetition interval to produce a pulse-to-pulse superimposed O 2 reduction against the baseline O 2 . If we impose a threshold in radiosensitivity reduction to achieve clinically observable radiotherapy oxygen effect and combine the processes mentioned above, we could estimate the R min required for pulsed FLASH RT through dimensional analysis. RESULTS: The estimated R min required for pulsed FLASH RT is proportional to the product of the oxygen diffusion coefficient and O 2 inside the cell, and inversely proportional to the product of the square of the oxygen diffusion distance and the drop of intracellular O 2 per unit radiation dose. Under typical conditions, our estimation matches the order of magnitude with the dose rates observed in the recent FLASH RT experiments. CONCLUSIONS: The R min introduced in this paper can be useful when designing a FLASH RT system. Additionally, our analysis of the chemical and physical processes may provide some insights into the FLASH RT mechanism.

Can the Student Outperform the Master? A Plan Comparison Between Pinnacle Auto-Planning and Eclipse knowledge-Based RapidPlan Following a Prostate-Bed Plan Competition.

PURPOSE: Pinnacle Auto-Planning and Eclipse RapidPlan are 2 major commercial automated planning engines that are fundamentally different: Auto-Planning mimics real planners in the iterative optimization, while RapidPlan generates static dose objectives from estimations predicted based on a prior knowledge base. This study objectively compared their performances on intensity-modulated radiotherapy planning for prostate fossa and lymphatics adopting the plan quality metric used in the 2011 American Association of Medical Dosimetrists Plan Challenge. METHODS: All plans used an identical intensity-modulated radiotherapy beam setup and a simultaneous integrated boost prescription (68 Gy/56 Gy to prostate fossa/lymphatics). Auto-Planning was used to retrospectively plan on 20 patients, which were subsequently employed as the library to build an RapidPlan model. To compare the 2 engines' performances, a test set including 10 patients and the Plan Challenge patient was planned by both Auto-Planning (master) and RapidPlan (student) without manual intervention except for a common dose normalization and evaluated using the plan quality metric that included 14 quantitative submetrics ranging over target coverage, spillage, and organ at risk doses. Plan quality metric scores were compared between the Auto-Planning and RapidPlan plans using the Mann-Whitney U test. RESULTS: There was no significant difference between the overall performance of the 2 engines on the 11 test cases ( P = .509). Among the 14 submetrics, Auto-Planning and RapidPlan showed no significant difference on most submetrics except for 2. On the Plan Challenge case, Auto-Planning scored 129.9 and RapidPlan scored 130.3 out of 150, as compared with the average score of 116.9 ± 16.4 (range: 58.2-142.5) among the 125 Plan Challenge participants. CONCLUSION: Using an innovative study design, an objective comparison has been conducted between 2 major commercial automated inverse planning engines. The 2 engines performed comparably with each other and both yielded plans at par with average human planners. Using a constant-performing planner (Auto-Planning) to train and to compare, RapidPlan was found to yield plans no better than but as good as its library plans.

Technical Assessment of an Automated Treatment Planning on Dose Escalation of Pancreas Stereotactic Body Radiotherapy.

BACKGROUND: Stereotactic body radiotherapy has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process and may impede further escalation of the prescription dose. PURPOSE: The present study aims to evaluate the consistency and efficiency of Pinnacle Auto-Planning for pancreas stereotactic body radiotherapy with original prescription and escalated prescription. METHODS: Twenty-four patients with pancreatic cancer treated with stereotactic body radiotherapy were studied retrospectively. The prescription is 40 Gy over 5 consecutive fractions. Most of patients (n = 21) also had 3 other different dose-level targets (6 Gy/fraction, 5 Gy/fraction, and 4 Gy/fraction). Two types of plans were generated by Pinnacle Auto-Planning with the original prescription (8 Gy/fraction, 6 Gy/fraction, 5 Gy/fraction, and 4 Gy/fraction) and escalated prescription (9 Gy/fraction, 7 Gy/fraction, 6 Gy/fraction, and 5 Gy/fraction), respectively. The same Auto-Planning template, including beam geometry, intensity-modulated radiotherapy objectives and intensity-modulated radiotherapy optimization parameters, were utilized for all the auto-plans in each prescription group. The intensity-modulated radiotherapy objectives do not include any manually created structures. Dosimetric parameters including percentage volume of PTV receiving 100% of the prescription dose, percentage volume of PTV receiving 93% of the prescription dose, and consistency of the dose-volume histograms of the target volumes were assessed. Dmax and D1 cc of highly radiosensitive organs were also evaluated. RESULTS: For all the pancreas stereotactic body radiotherapy plans with the original or escalated prescriptions, auto-plans met institutional dose constraints for critical organs, such as the duodenum, small intestine, and stomach. Furthermore, auto-plans resulted in acceptable planning target volume coverage for all targets with different prescription levels. All the plans were generated in a one-attempt manner, and very little human intervention is necessary to achieve such plan quality. CONCLUSIONS: Pinnacle3 Auto-Planning consistently and efficiently generate acceptable treatment plans for multitarget pancreas stereotactic body radiotherapy with or without dose escalation and may play a more important role in treatment planning in the future.

Radiomic feature stability across 4D respiratory phases and its impact on lung tumor prognosis prediction.

Radiomic analysis has recently demonstrated versatile uses in improving diagnostic and prognostic prediction accuracy for lung cancer. However, since lung tumors are subject to substantial motion due to respiration, the stability of radiomic features over the respiratory cycle of the patient needs to be investigated to better evaluate the robustness of the inter-patient feature variability for clinical applications, and its impact in such applications needs to be assessed. A full panel of 841 radiomic features, including tumor intensity, shape, texture, and wavelet features, were extracted from individual phases of a four-dimensional (4D) computed tomography on 20 early-stage non-small-cell lung cancer (NSCLC) patients. The stability of each radiomic feature was assessed across different phase images of the same patient using the coefficient of variation (COV). The relationship between individual COVs and tumor motion magnitude was inspected. Population COVs, the mean COVs of all 20 patients, were used to evaluate feature motion stability and categorize the radiomic features into 4 different groups. The two extremes, the Very Small group (COV≤5%) and the Large group (COV>20%), each accounted for about a quarter of the features. Shape features were the most stable, with COV≤10% for all features. A clinical study was subsequently conducted using 140 early-stage NSCLC patients. Radiomic features were employed to predict the overall survival with a 500-round bootstrapping. Identical multiple regression model development process was applied, and the model performance was compared between models with and without a feature pre-selection step based on 4D COV to pre-exclude unstable features. Among the systematically tested cutoff values, feature pre-selection with 4D COV≤5% achieved the optimal model performance. The resulting 3-feature radiomic model significantly outperformed its counterpart with no 4D COV pre-selection, with P = 2.16x10-27 in the one-tailed t-test comparing the prediction performances of the two models.

Application of statistical and computational methodology to predict brainstem dosimetry for trigeminal neuralgia stereotactic radiosurgery.

OBJECTIVES: To apply advanced statistical and computational methodology in evaluating the impact of anatomical and technical variables on normal tissue dosimetry of trigeminal neuralgia (TN) stereotactic radiosurgery (SRS). METHODS: Forty patients treated with LINAC-based TN SRS with 90 Gy maximum dose were randomly selected for the study. Parameters extracted from the treatment plans for the study included three dosimetric output variables: the maximum dose to the brainstem (BSmax), the volume of brainstem that received at least 10 Gy (V10BS), and the volume of normal brain that received at least 12 Gy (V12). We analyzed five anatomical variables: the incidence angle of the nerve with the brainstem surface (A), the nerve length (L), the nerve width as measured both axially (WA) and sagittally (WS), the distance measured along the nerve between the isocenter and the brainstem surface (D), and one technical variable: the utilized cone size (CS). Univariate correlation was calculated for each pair among all parameters. Multivariate regression models were fitted for the output parameters using the optimal input parameters selected by the Gaussian graphic model LASSO. Repeated twofold cross-validations were used to evaluate the models. RESULTS: Median BSmax, V10BS, and V12 for the 40 patients were 35.7 Gy, 0.14 cc, and 1.28 cc, respectively. Median A, L, WA, WS, D, and CS were 43.7°, 8.8 mm, 2.8 mm, 2.7 mm, 4.8 mm, and 6 mm, respectively. Of the three output variables, BSmax most strongly correlated with the input variables. Specifically, it had strong, negative correlations with the input anatomical variables and a positive correlation with CS. The correlation between D and BSmax at -0.51 was the strongest correlation between single input and output parameters, followed by that between CS and V10BS at 0.45, and that between A and BSmax at -0.44. V12 was most correlated with cone size alone, rather than anatomy. LASSO identified an optimal 3-feature combination of A, D, and CS for BSmax and V10BS prediction. Using cross-validation, the multivariate regression models with the three selected features yielded stronger correlations than the correlation between the BSmax and V10BS themselves. CONCLUSIONS: For the first time, an advanced statistical and computational methodology was applied to study the impact of anatomical and technical variables on TN SRS. The variables were found to impact brainstem doses, and reasonably strong correlation models were established using an optimized 3-feature combination including the nerve incidence angle, cone size, and isocenter-brainstem distance.

Does intensity modulation increase target dose calculation errors of conventional algorithms for lung SBRT?

PURPOSE: Conventional dose algorithms (Type A and Type B) for lung SBRT can display considerable target dose errors compared to Type-C algorithms. Intensity-modulated techniques (IMRT/VMAT) are increasingly being utilized for lung SBRT. Therefore, our study aimed to assess whether intensity modulation increased target dose calculation errors by conventional algorithms over conformal techniques. METHODS: Twenty lung SBRT patients were parallely planned with both IMRT and dynamic conformal arc (DCA) techniques using a Type-A algorithm, and another 20 patients were parallely planned with IMRT, VMAT, and DCA using a Type-B algorithm. All 100 plans were recalculated with Type-C algorithms using identical beam and monitor unit settings, with the Type-A/Type-B algorithm dose errors defined using Type-C recalculation as the ground truth. Target dose errors for PTV and GTV were calculated for a variety of dosimetric end points. Using Wilcoxon signed-rank tests (p < 0.05 for statistical significance), target dose errors were compared between corresponding IMRT/VMAT and DCA plans for the two conventional algorithms. The levels of intensity modulation were also evaluated using the ratios of MUs in the IMRT/VMAT plans to those in the corresponding DCA plans. Linear regression was used to study the correlation between intensity modulation and relative dose error magnitudes. RESULTS: Overall, larger errors were found for the Type-A algorithm than for the Type-B algorithm. However, the IMRT/VMAT plans were not found to have statistically larger dose errors from their corresponding DCA plans. Linear regression did not identify a significant correlation between the intensity modulation level and the relative dose error. CONCLUSION: Intensity modulation did not appear to increase target dose calculation errors for lung SBRT plans calculated with conventional algorithms.

Using weighted power mean for equivalent square estimation.

PURPOSE: Equivalent Square (ES) enables the calculation of many radiation quantities for rectangular treatment fields, based only on measurements from square fields. While it is widely applied in radiotherapy, its accuracy, especially for extremely elongated fields, still leaves room for improvement. In this study, we introduce a novel explicit ES formula based on Weighted Power Mean (WPM) function and compare its performance with the Sterling formula and Vadash/Bjärngard's formula. METHODS: The proposed WPM formula is ESWPMa,b=waα+1-wbα1/α for a rectangular photon field with sides a and b. The formula performance was evaluated by three methods: standard deviation of model fitting residual error, maximum relative model prediction error, and model's Akaike Information Criterion (AIC). Testing datasets included the ES table from British Journal of Radiology (BJR), photon output factors (Scp ) from the Varian TrueBeam Representative Beam Data (Med Phys. 2012;39:6981-7018), and published Scp data for Varian TrueBeam Edge (J Appl Clin Med Phys. 2015;16:125-148). RESULTS: For the BJR dataset, the best-fit parameter value α = -1.25 achieved a 20% reduction in standard deviation in ES estimation residual error compared with the two established formulae. For the two Varian datasets, employing WPM reduced the maximum relative error from 3.5% (Sterling) or 2% (Vadash/Bjärngard) to 0.7% for open field sizes ranging from 3 cm to 40 cm, and the reduction was even more prominent for 1 cm field sizes on Edge (J Appl Clin Med Phys. 2015;16:125-148). The AIC value of the WPM formula was consistently lower than its counterparts from the traditional formulae on photon output factors, most prominent on very elongated small fields. CONCLUSION: The WPM formula outperformed the traditional formulae on three testing datasets. With increasing utilization of very elongated, small rectangular fields in modern radiotherapy, improved photon output factor estimation is expected by adopting the WPM formula in treatment planning and secondary MU check.

A comprehensive dosimetric study on switching from a Type-B to a Type-C dose algorithm for modern lung SBRT.

BACKGROUND: Type-C dose algorithms provide more accurate dosimetry for lung SBRT treatment planning. However, because current dosimetric protocols were developed based on conventional algorithms, its applicability for the new generation algorithms needs to be determined. Previous studies on this issue used small sample sizes and reached discordant conclusions. Our study assessed dose calculation of a Type-C algorithm with current dosimetric protocols in a large patient cohort, in order to demonstrate the dosimetric impacts and necessary treatment planning steps of switching from a Type-B to a Type-C dose algorithm for lung SBRT planning. METHODS: Fifty-two lung SBRT patients were included, each planned using coplanar VMAT arcs, normalized to D95% = prescription dose using a Type-B algorithm. These were compared against three Type-C plans: re-calculated plans (identical plan parameters), re-normalized plans (D95% = prescription dose), and re-optimized plans. Dosimetric endpoints were extracted and compared among the four plans, including RTOG dosimetric criteria: (R100%, R50%, D2cm, V105%, and lung V20), PTV Dmin, Dmax, Dmean, V% and D90%, PTV coverage (V100%), homogeneity index (HI), and Paddick conformity index (PCI). RESULTS: Re-calculated Type-C plans resulted in decreased PTV Dmin with a mean difference of 5.2% and increased Dmax with a mean difference of 3.1%, similar or improved RTOG dose compliance, but compromised PTV coverage (mean D95% and V100% reduction of 2.5 and 8.1%, respectively). Seven plans had >5% D95% reduction (maximum reduction = 16.7%), and 18 plans had >5% V100% reduction (maximum reduction = 60.0%). Re-normalized Type-C plans restored target coverage, but yielded degraded plan conformity (average PCI reduction 4.0%), and RTOG dosimetric criteria deviation worsened in 11 plans, in R50%, D2cm, and R100%. Except for one case, re-optimized Type-C plans restored RTOG compliance achieved by the original Type-B plans, resulting in similar dosimetric values but slightly higher target dose heterogeneity (mean HI increase = 13.2%). CONCLUSIONS: Type-B SBRT lung plans considerably overestimate target coverage for some patients, necessitating Type-C re-normalization or re-optimization. Current RTOG dosimetric criteria appear to remain appropriate.

Still equivalent for dose calculation in the Monte Carlo era? A comparison of free breathing and average intensity projection CT datasets for lung SBRT using three generations of dose calculation algorithms.

PURPOSE: Inhomogeneity dose modeling and respiratory motion description are two critical technical challenges for lung stereotactic body radiotherapy, an important treatment modality for small size primary and secondary lung tumors. Recent studies revealed lung density-dependent target dose differences between Monte Carlo (Type-C) algorithm and earlier algorithms. Therefore, this study aimed to investigate the equivalence of the two most popular CT datasets for treatment planning, free breathing (FB) and average intensity projection (AIP) CTs, using Type-C algorithms, and comparing with two older generation algorithms (Type-A and Type-B). METHODS: Twenty patients (twenty-one lesions) were planned using a Type-A algorithm on the FB CT. Lung was contoured separately on FB and AIP CTs and compared. Dose comparison was obtained between the two CTs using four commercial dose algorithms including one Type-A (Pencil Beam Convolution - PBC), one Type-B (Analytical Anisotropic Algorithm - AAA), and two Type-C algorithms (Voxel Monte Carlo - VMC and Acuros External Beam - AXB). For each algorithm, the dosimetric parameters of the target (PTV, Dmin , Dmax , Dmean , D95, and D90) and lung (V5, V10, V20, V30, V35, and V40) were compared between the two CTs using the Wilcoxon signed rank test. Correlation between dosimetric differences and density differences for each algorithm were studied using linear regression and Spearman correlation, in which both global and local density differences were evaluated. RESULTS: Although the lung density differences on FB and AIP CTs were statistically significant (P = 0.003), the magnitude was small at 1.21 ± 1.45%. Correspondingly, for the two Type-C algorithms, target and lung dosimetric differences were small in magnitude and statistically insignificant (P > 0.05) for all but one instance, similar to the findings for the older generation algorithms. Nevertheless, a significant correlation was shown between the dosimetric and density differences for Type-C and Type-B algorithms, but not for the Type-A algorithm. CONCLUSIONS: With the capability to more accurately model inhomogeneity, Monte Carlo (Type-C) algorithms are sensitive to respiration-induced local and global tissue density changes and exhibit a strong correlation between dosimetric and density differences. However, FB and AIP CTs may still be considered equivalent for dose calculation in the Monte Carlo era, due to the small magnitude of lung density differences between these two datasets.

Automatic planning on hippocampal avoidance whole-brain radiotherapy.

Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle3 Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present study is to evaluate the performance of the Pinnacle3 Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle3 Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D2% and D98% of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D100% and Dmax of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle3 Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The expedited quality planning achieved by Auto-Planning (AP) may facilitate protocol enrollment of patients to further investigate the hippocampal-sparing effect and be used to ensure timely start of palliative treatment in future clinical practice.

Prostate bed target interfractional motion using RTOG consensus definitions and daily CT on rails : Does target motion differ between superior and inferior portions of the clinical target volume?

PURPOSE: Using high-quality CT-on-rails imaging, the daily motion of the prostate bed clinical target volume (PB-CTV) based on consensus Radiation Therapy Oncology Group (RTOG) definitions (instead of surgical clips/fiducials) was studied. It was assessed whether PB motion in the superior portion of PB-CTV (SUP-CTV) differed from the inferior PB-CTV (INF-CTV). PATIENTS AND METHODS: Eight pT2-3bN0-1M0 patients underwent postprostatectomy intensity-modulated radiotherapy, totaling 300 fractions. INF-CTV and SUP-CTV were defined as PB-CTV located inferior and superior to the superior border of the pubic symphysis, respectively. Daily pretreatment CT-on-rails images were compared to the planning CT in the left-right (LR), superoinferior (SI), and anteroposterior (AP) directions. Two parameters were defined: "total PB-CTV motion" represented total shifts from skin tattoos to RTOG-defined anatomic areas; "PB-CTV target motion" (performed for both SUP-CTV and INF-CTV) represented shifts from bone to RTOG-defined anatomic areas (i. e., subtracting shifts from skin tattoos to bone). RESULTS: Mean (± standard deviation, SD) total PB-CTV motion was -1.5 (±â€¯6.0), 1.3 (±â€¯4.5), and 3.7 (±â€¯5.7) mm in LR, SI, and AP directions, respectively. Mean (±â€¯SD) PB-CTV target motion was 0.2 (±1.4), 0.3 (±2.4), and 0 (±3.1) mm in the LR, SI, and AP directions, respectively. Mean (±â€¯SD) INF-CTV target motion was 0.1 (±â€¯2.8), 0.5 (±â€¯2.2), and 0.2 (±â€¯2.5) mm, and SUP-CTV target motion was 0.3 (±â€¯1.8), 0.5 (±â€¯2.3), and 0 (±â€¯5.0) mm in LR, SI, and AP directions, respectively. No statistically significant differences between INF-CTV and SUP-CTV motion were present in any direction. CONCLUSION: There are no statistically apparent motion differences between SUP-CTV and INF-CTV. Current uniform planning target volume (PTV) margins are adequate to cover both portions of the CTV.

Estimation of internal organ motion-induced variance in radiation dose in non-gated radiotherapy.

In the delivery of non-gated radiotherapy (RT), owing to intra-fraction organ motion, a certain degree of RT dose uncertainty is present. Herein, we propose a novel mathematical algorithm to estimate the mean and variance of RT dose that is delivered without gating. These parameters are specific to individual internal organ motion, dependent on individual treatment plans, and relevant to the RT delivery process. This algorithm uses images from a patient's 4D simulation study to model the actual patient internal organ motion during RT delivery. All necessary dose rate calculations are performed in fixed patient internal organ motion states. The analytical and deterministic formulae of mean and variance in dose from non-gated RT were derived directly via statistical averaging of the calculated dose rate over possible random internal organ motion initial phases, and did not require constructing relevant histograms. All results are expressed in dose rate Fourier transform coefficients for computational efficiency. Exact solutions are provided to simplified, yet still clinically relevant, cases. Results from a volumetric-modulated arc therapy (VMAT) patient case are also presented. The results obtained from our mathematical algorithm can aid clinical decisions by providing information regarding both mean and variance of radiation dose to non-gated patients prior to RT delivery.