Model refinement increases confidence levels and clinical agreement when commissioning a three-dimensional secondary dose calculation system.

PURPOSE: Evaluate custom beam models for a second check dose calculation system using statistically verifiable passing criteria for film analysis, DVH, and 3D gamma metrics. METHODS: Custom beam models for nine linear accelerators for the Sun Nuclear Dose Calculator algorithm (SDC, Sun Nuclear) were evaluated using the AAPM-TG119 test suite (5 Intensity Modulated Radiation Therapy (IMRT) and 5 Volumetric Modulated Arc Therapy (VMAT) plans) and a set of clinical plans. Where deemed necessary, adjustments to Multileaf Collimator (MLC) parameters were made to improve results. Comparisons to the Analytic Anisotropic Algorithm (AAA), and gafchromic film measurements were performed. Confidence intervals were set to 95% per TG-119. Film gamma criteria were 3%/3 mm (conventional beams) or 3%/1 mm (Stereotactic Radiosurgery [SRS] beams). Dose distributions in solid water phantom were evaluated based on DVH metrics (e.g., D95, V20) and 3D gamma criteria (3%/3 mm or 3%/1 mm). Film passing rates, 3D gamma passing rates, and DVH metrics were reported for HD MLC machines and Millennium MLC Machines. RESULTS: For HD MLC machines, SDC gamma film agreement was 98.76% ± 2.30% (5.74% CL) for 6FFF/6srs (3%/1 mm), and 99.80% ± 0.32% (0.83% CL) for 6x (3%/3 mm). For Millennium MLC machines, film passing rates were 98.20% ± 3.14% (7.96% CL), 99.52% ± 1.14% (2.71% CL), and 99.69% ± 0.82% (1.91% CL) for 6FFF, 6x, and 10x, respectively. For SDC to AAA comparisons: HD MLC Linear Accelerators (LINACs); DVH point agreement was 0.97% ± 1.64% (4.18% CL) and 1.05% ± 2.12% (5.20% CL); 3D gamma agreement was 99.97% ± 0.14% (0.30% CL) and 100.00% ± 0.02% (0.05% CL), for 6FFF/6srs and 6x, respectively; Millennium MLC LINACs: DVH point agreement was 0.77% ± 2.40% (5.47% CL), 0.80% ± 3.40% (7.47% CL), and 0.07% ± 2.15% (4.30% CL); 3D gamma agreement was 99.97% ± 0.13% (0.29% CL), 99.97% ± 0.17% (0.36% CL), and 99.99% ± 0.06% (0.12% CL) for 6FFF, 6x, and 10x, respectively. CONCLUSION: SDC shows agreement well within TG119 CLs for film and redundant dose calculation comparisons with AAA. In some models (SRS), this was achieved using stricter criteria. TG119 plans can be used to help guide model adjustments and to establish clinical baselines for DVH and 3D gamma criteria.

The influence of beam optics asymmetric distribution on dose in scanning carbon-ion radiotherapy.

PURPOSE: To quantify the influence of beam optics asymmetric distribution on dose. METHODS: Nine reference cubic targets and corresponding plans with modulation widths (M) of 3, 6, and 9 cm and with center depths (CDs) of 6, 12, and 24 cm were generated by the treatment planning system (TPS). The Monte Carlo code FLUKA was used for simulating the dose distribution from the aforementioned original plans and the dose perturbation by varying ±5%, ±15%, ±20%, ±25%, and ±40% in spot full width half maximum to the X-direction while keeping consistent in the Y-direction. The dosimetric comparisons in dose deviation, γ-index analysis, lateral penumbra, and flatness were evaluated. RESULTS: The largest 3D absolute mean deviation was 15.0% ± 20.9% (mean ± standard deviation) in M3CD6, whereas with the variation from -15% to +20%, the values were below 5% for all cube plans. The lowest 2D γ-index passing rate was 80.6% with criteria of 2%-2 mm by a +40% variation in M3CD6. For the M9CD24 with a -40% variation, the maximum 1D dose deviations were 5.6% and 15.7% in the high-dose region and the edge of the radiation field, respectively. The maximum deviations of penumbra and flatness were 3.4 mm and 11.4%, respectively. CONCLUSIONS: The scenario of beam optics asymmetric showed relatively slight influence on the global dose distribution but severely affected dose on the edge of the radiation field. For scanning carbon-ion therapy facilities, beam spot lateral profile settings in TPS base data should be properly handled when beam optics asymmetry variation is over 15%.

Low-Dose CT in Pelvic Imaging: Comparing Dose and Image Quality in Relation to Clinical Value in a Phantom Study.

OBJECTIVE. The aim of this phantom study was to determine whether low-dose CT of the pelvis can be performed using a dose similar to that used in a standard radio-graphic examination and to ascertain whether CT, with its better delineation of complex structures, has greater clinical value than radiography and therefore will result in improved patient care. Special consideration was given to CT performed using the tin filtration technique. MATERIALS AND METHODS. For dose comparison, an anthropomorphic phantom with 20 thermoluminescent dosimeters, two different CT scanners, and three conventional radiography devices were used. Seven CT protocols (including tin filtration) and four different radiographic examinations were performed. Dose calculations, objective and subjective evaluations of image quality, and figure-of-merit calculations were compared among the techniques. Furthermore, the images obtained were evaluated in a clinical context. Intraclass correlation was determined for the subjective results. RESULTS. The dose values of the tested low-dose CT protocols, in particular those using the tin filtration technique, corresponded to or were only slightly higher than the dose values of conventional pelvic radiographic images obtained in three views. Low-dose CT examinations were rated sufficient for consolidation control and had an informative value that was significantly higher than that of conventional radiography. Tin filtering showed the best results for low-dose CT in terms of combining dose and clinically relevant image quality. CONCLUSION. In this phantom study, low-dose CT was superior to radiography for visualizing and evaluating the dorsal pelvic ring, with only marginally higher radiation exposure occurring when the latest-generation CT systems were used. Tin filtration can improve image quality, create further dose reductions, or provide both benefits.

Clinical utility, dose determination, and safety of ocular contrast-enhanced ultrasonography in horses: A pilot study.

OBJECTIVE: To determine efficacy of contrast-enhanced ultrasonography (CEUS) using different sulfur hexafluoride (SF6) doses to assess blood flow and perfusion in equine eyes and to evaluate safety of SF6 in horses. PROCEDURES: Ocular B-mode and contrast-enhanced ultrasonography were performed bilaterally in nine sedated university-owned horses. Intravenous SonoVue® bolus injections of 5, 10, 15, 20, 25, and 30 mL were administered for 2/18, 5/18, 6/18, 3/18, 1/18, and 1/18 eyes, respectively. Doses were increased based on ascending bodyweight. Each eye within one horse was examined utilizing a different dose. Qualitative blood flow and quantitative perfusion were analyzed. Heart and respiratory rates were monitored nonsedated, sedated, and during first and second minutes of CEUS. RESULTS: Qualitative contrast enhancement (CE) was visible in 7/9 animals. Quantitative CE was measurable bilaterally in four horses, unilaterally in three individuals, and not detected in two animals. In all horses with unilateral CE, the positive eye received the higher dose. Fifteen mL dose resulted in significantly shorter time to peak than 10 mL (P < .05). Peak intensity, maximum signal increase, and corresponding area under the curve were significantly higher for 15 and 20 mL doses compared with 10 mL (P < .05). Uveal and retinal tissues were enhanced frequently. Twenty-five and 30 mL doses revealed no CE. Only sedation reduced heart rates significantly (P < .05). Clinically relevant changes in respiratory rates or adverse reactions following SF6 application were not observed. CONCLUSIONS: Contrast enhancement was in most instances dose-dependent. Fifteen mL appeared appropriate to assess equine ocular perfusion. The reliability in horses remains questionable; however, CEUS was well-tolerated.

Analysis of dose comparison techniques for patient-specific quality assurance in radiation therapy.

PURPOSE: Gamma evaluation is the most commonly used technique for comparison of dose distributions for patient-specific pretreatment quality assurance in radiation therapy. Alternative dose comparison techniques have been developed but not widely implemented. This study aimed to compare and evaluate the performance of several previously published alternatives to the gamma evaluation technique, by systematically evaluating a large number of patient-specific quality assurance results. METHODS: The agreement indices (or pass rates) for global and local gamma evaluation, maximum allowed dose difference (MADD) and divide and conquer (D&C) techniques were calculated using a selection of acceptance criteria for 429 patient-specific pretreatment quality assurance measurements. Regression analysis was used to quantify the similarity of behavior of each technique, to determine whether possible variations in sensitivity might be present. RESULTS: The results demonstrated that the behavior of D&C gamma analysis and MADD box analysis differs from any other dose comparison techniques, whereas MADD gamma analysis exhibits similar performance to the standard global gamma analysis. Local gamma analysis had the least variation in behavior with criteria selection. Agreement indices calculated for 2%/2 mm and 2%/3 mm, and 3%/2 mm and 3%/3 mm were correlated for most comparison techniques. CONCLUSION: Radiation oncology treatment centers looking to compare between different dose comparison techniques, criteria or lower dose thresholds may apply the results of this study to estimate the expected change in calculated agreement indices and possible variation in sensitivity to delivery dose errors.

Radiation exposure related to cardiovascular CT examination: comparison between conventional 64-MDCT and third-generation dual-source MDCT.

PURPOSE: To compare radiation exposure associated with daily practice cardiovascular (CV) examinations performed on two different multidetector computed tomography (MDCT) scanners, a conventional 64-MDCT and a third-generation dual-source (DS) MDCT. MATERIALS AND METHODS: In this retrospective study, 1458 patients who underwent CV examinations between January 2017 and August 2018 were enrolled. A single-source 64-MDCT (Lightspeed VCT, GE) scan was performed in 705 patients from January to August 2017 (207 coronary examinations and 498 vascular examinations) and 753 patients underwent third-generation 192 × 2-DSCT (Somatom FORCE, Siemens) scan from January to August 2018 (302 coronary examinations and 451 vascular examinations). Volume CT dose index (CTDIvol), dose length product (DLP), effective dose (ED), tube voltage (TV) and exposure time (ET), pitch factor (PF) were registered for each patient. Student's t test was used to compare mean values between each corresponding group of MDCT and DSCT. RESULTS: In coronary examinations with DSCT, CTDIvol was 24.4% lower (23.1 mGy vs 30.6 mGy, p < 0.0001) and DLP and ED reductions were 35.6% than with MDCT (465.0 mGy * cm vs 732.3 mGy * cm and 6.5 mSv and 10.3 mSv; vs p < 0.0001). Concerning scan parameters, kVp and ET reductions were 12.7% and 69.4%, respectively (p < 0.0001); PF increase was 73.8% (p < 0.0001). In all vascular studies, DSCT, compared with MDCT, permitted to reduce CTDIvol from 43.5 to 70.6%; DLP and ED reductions were from 50.3 to 73.1%; kVp and ET decreases were from 10.7 to 32.5% and from 26.3 to 68.7%. PF increase was from 16.7 to 58.1% (all differences with p < 0.0001). CONCLUSIONS: In daily practice, CV examinations CTDI, DLP, ED, ET and TV were lower and PF was higher with 192 × 2-DSCT compared to 64-MDCT.

Relamorelin Reduces Vomiting Frequency and Severity and Accelerates Gastric Emptying in Adults With Diabetic Gastroparesis.

BACKGROUND & AIMS: Gastroparesis is an important complication of diabetes. We investigated the effects of relamorelin (a pentapeptide-selective agonist of the ghrelin receptor that speeds gastric emptying in patients with diabetes) in patients with diabetic gastroparesis. METHODS: We performed a double-blind trial of 204 patients (78% Caucasian; 67% female; mean age, 55 y; 88% with type 2 diabetes) with diabetic gastroparesis with moderate to severe symptoms and delayed gastric emptying at 27 clinical centers, from June 2012 until August 2013. Patients were assigned randomly (1:1:1) to groups given placebo or subcutaneous relamorelin 10 µg once or twice daily. The primary end point was the half-time of gastric emptying. Secondary end points included nausea, abdominal pain, bloating, early satiety, as well as the composite score of these 4 subjective symptoms and vomiting frequency and severity. RESULTS: Twice-daily relamorelin significantly accelerated gastric emptying (P < .03) and reduced vomiting frequency (by ∼60%) and severity vs placebo (P ≤ .033). Compared with placebo, relamorelin did not improve other gastrointestinal symptoms, such as abdominal pain and satiety. In the 119 patients (58.3%) with baseline vomiting, twice-daily relamorelin significantly reduced the half-time of gastric emptying and vomiting, as well as nausea, abdominal pain, bloating, and early satiety compared with placebo (composite score, P = .043). No overall safety concerns were identified. CONCLUSIONS: In a clinical trial of patients with diabetic gastroparesis, relamorelin (10 µg twice daily) significantly accelerated gastric emptying and significantly reduced vomiting, compared with placebo. Among patients with baseline vomiting, relamorelin had prokinetic effects and significantly reduced vomiting and also improved other symptoms of diabetic gastroparesis compared with placebo. ClincialTrials.gov number: NCT01571297.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.

Superiority of fesoterodine 8 mg vs 4 mg in reducing urgency urinary incontinence episodes in patients with overactive bladder: results of the randomised, double-blind, placebo-controlled EIGHT trial.

OBJECTIVE: To assess the superiority of fesoterodine 8 mg vs 4 mg for improvement in urgency urinary incontinence (UUI) episodes and other diary variables, diary-dry rate (proportion of patients with >0 UUI episodes on baseline diary and 0 UUI episodes on post-baseline diary), and improvements in measures of symptom bother, health-related quality of life (HRQL), and other patient-reported outcomes (PROs). PATIENTS AND METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, multinational trial of men and women aged ≥18 years with overactive bladder (OAB) symptoms including UUI (ClinicalTrials.gov ID NCT01302067). Patients were randomised (2:2:1) to receive fesoterodine 8 mg, fesoterodine 4 mg, or placebo once daily; those randomised to fesoterodine 8 mg started with fesoterodine 4 mg once daily for 1 week, then 8 mg once daily for the remaining 11 weeks. Patients completed bladder diaries at baseline and weeks 4 and 12 and the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. The primary endpoint was change from baseline to week 12 in UUI episodes per 24 h. RESULTS: At week 12, patients receiving fesoterodine 8 mg (779 patients) had significantly greater reductions from baseline in UUI episodes, micturitions, and urgency episodes than patients receiving fesoterodine 4 mg (790) or placebo (386); diary-dry rate was significantly higher in the fesoterodine 8-mg group vs the fesoterodine 4-mg and placebo groups (all P < 0.05). At week 12, patients receiving fesoterodine 8 mg also had significantly greater improvements in scores on the PPBC, UPS, and all OAB-q scales and domains than patients receiving fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving fesoterodine 4 mg had significantly greater improvements in UUI episodes, urgency episodes, and micturitions; significantly higher diary-dry rates; and significantly greater improvement in PPBC scores and OAB-q scores than patients receiving placebo (all P < 0.05). Dry mouth was the most commonly reported adverse event (AE) in the fesoterodine groups (placebo group, 3.4%; fesoterodine 4-mg group, 12.9%; fesoterodine 8-mg group, 26.1%); most cases were mild or moderate in all treatment groups. Rates of serious AEs and discontinuations due to AEs were low in all groups. CONCLUSIONS: In a 12-week, prospectively designed, superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy vs fesoterodine 4 mg and placebo, as measured by reductions in UUI episodes and other diary variables, diary-dry dry rate, and improvements in measures of symptom bother, HRQL, and other PROs; clear evidence of dose-dependent efficacy is unique to fesoterodine among antimuscarinics and other oral agents for the treatment of OAB. Fesoterodine 4 mg was significantly more effective than placebo on all outcomes except for improvements in UPS scores. These data support the benefit of having two doses of fesoterodine in clinical practice, with the recommended starting dose of 4 mg for all patients and the fesoterodine 8-mg dose available for patients who require a higher dose to achieve optimal symptom relief.

Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Weight-bearing gantry-free cone-beam CT of the lumbar spine: Image quality analysis and dose efficiency.

PURPOSE: The effect of static forces under load limits the prognostic value of lumbar spine CT in a horizontal position. Using a gantry-free scanner architecture, this study was designed to assess the feasibility of weight-bearing cone-beam CT (CBCT) of the lumbar spine and to establish the most dose-effective combination of scan parameters. METHODS: Eight formalin-fixated cadaveric specimens were examined with a gantry-free CBCT system in upright position with the aid of a dedicated positioning backstop. Cadavers were scanned with eight combinations of tube voltage (102 or 117 kV), detector entrance dose level (high or low), and frame rates (16 or 30 fps). Five radiologists independently analyzed datasets for overall image quality and posterior wall assessability. Additionally, image noise and signal-to-noise ratio (SNR) were compared based on region-of-interest (ROI) measurements in the gluteal muscles. RESULTS: Radiation dose ranged from 6.8 ± 1.6 (117 kV, dose level low, 16 fps) to 24.3 ± 6.3 mGy (102 kV, dose level high, 30 fps). Both image quality and posterior wall assessability were favored with 30 over 16 fps (all p ≤ 0.008). In contrast, both tube voltage (all p > 0.999) and dose level (all p > 0.096) did not significantly impact reader assessment. Image noise decreased considerably with higher frame rates (all p ≤ 0.040), while SNR ranged from 0.56 ± 0.03 to 1.11 ± 0.30 without a significant difference between scan protocols (all p ≥ 0.060). CONCLUSIONS: Employing an optimized scan protocol, weight-bearing gantry-free CBCT of the lumbar spine allows for diagnostic imaging at reasonable radiation dose.

Helical tomotherapy and two types of volumetric modulated arc therapy: dosimetric and clinical comparison for several cancer sites.

Radiotherapy accelerators have undergone continuous technological developments. We investigated the differences between Radixact™ and VMAT treatment plans. Sixty patients were included in this study. Dosimetric comparison between the Radixact™ and VMAT plans was performed for six cancer sites: whole-brain, head and neck, lymphoma, lung, prostate, and rectum. The VMAT plans were generated with two Elekta linear accelerators (Synergy® and Versa HD™). The planning target volume (PTV) coverage, organs-at-risk dose constraints, and four dosimetric indexes were considered. The deliverability of the plans was assessed using quality assurance (gamma index evaluation) measurements; clinical judgment was included in the assessment. The mean AAPM TG218 (3%-2 mm, global normalization) gamma index values were 99.4%, 97.8%, and 96.6% for Radixact™, Versa HD™, and Synergy®, respectively. Radixact™ performed better than Versa HD™ in terms of dosimetric indexes, hippocampi D100%, spinal cord Dmax, rectum V38.4  Gy, bladder V30 Gy, and V40 Gy. Versa HD™ saved more of the (lungs-PTV) V5 Gy and (lungs-PTV) Dmean, heart Dmean, breasts V4 Gy, and bowel V45 Gy. Regarding Synergy®, the head and neck Radixact™ plan saved more of the parotid gland, oral cavity, and supraglottic larynx. From a clinical point of view, for the head and neck, prostate, and rectal sites, the Radixact™ and Versa HD™ plans were similar; Radixact™ plans were preferable for the head and neck and rectum to Synergy® plans. The quality of linac plans has improved, and differences with tomotherapy have decreased. However, tomotherapy continues to be an essential add-on in multi-machine departments.

Automated Non-coplanar Volumetric Modulated Arc Therapy Planning for Maxillary Sinus Carcinoma.

BACKGROUND/AIM: Dosimetric parameters in volumetric modulated arc therapy (VMAT), non-coplanar VMAT (NC-VMAT), and automated NC-VMAT (HyperArc, HA) were compared for patients with maxillary sinus carcinoma (MSC). PATIENTS AND METHODS: Twenty HA plans were generated to deliver 70.4, 64, and 46 Gy for planning target volumes with high (PTV1), intermediate (PTV2), and low risk (PTV3), respectively. The VMAT and NC-VMAT plans were retrospectively generated using the same optimized parameters as those used in the HA plans. RESULTS: For PTV1, the three treatment plans provided comparable target coverages. For PTV2, the D95%, D99%, and Dmin in the HA plans (64.7±1.2, 62.7±2.1 and 54.6±6.2 Gy, respectively) were significantly higher (p<0.05) than those in the VMAT plans (64.3±1.7, 61.9±2.4 and 52.9±6.4 Gy, respectively). The NC-VMAT and HA plans provided significantly higher (p<0.05) dosimetric parameters for PTV3 than those in the VMAT plans, and D99% in the HA was significantly higher than that in the NC-VMAT plans (52.5±3.0 vs. 51.8±2.7 Gy, p<0.05). The doses to the brain and brainstem were lowest in the HA plans (p<0.05). Moreover, dosimetric parameters of the contralateral organs (lens, optic nerve, retina, and parotid) were lower in the HA plans than in the VMAT and NC-VMAT plans. CONCLUSION: The HA plans provided the best target coverage and OAR sparing compared with VMAT and NC-VMAT plans for patients with MSC.

Dosimetric Comparison Study Between Free Breathing and Breath Hold Techniques in Patients Treated by Liver-Directed Stereotactic Body Radiation Therapy.

Background Breathing motion management is the key to delivering stereotactic body radiation therapy (SBRT) for liver lesions. This study aimed to compare the dosimetric parameters of liver SBRT using two different techniques: free breathing and breath hold. Method The study included 11 patients with liver metastases or hepatocellular carcinoma who underwent liver-directed SBRT. A dosimetric comparison was performed using dose-volume histogram analysis, evaluating parameters such as the maximum dose to 5 cc of bowel volume, mean liver dose (MLD), and liver V20 and V30. Statistical analyses were performed to compare results. Results The findings revealed that the breath hold technique resulted in significantly lower doses to the bowel and smaller volumes of normal liver tissue receiving 20 Gy (V20) and 30 Gy (V30) than the free breathing. Although there was no statistically significant difference in the MLD between the two techniques, the breath hold technique resulted in a lower MLD. Conclusion This dosimetric comparison study suggests that the breath hold technique is associated with lower radiation exposure to the bowel and normal liver tissues. Although this may not be feasible for all patients, it may be an appropriate procedure for selected individuals. Further research is needed to validate these findings in different patient populations and explore their impact on clinical outcomes and patient-reported quality of life.

Methylprednisolone Treatment in Brain Death-Induced Lung Inflammation-A Dose Comparative Study in Rats.

Background: The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response. Methods: BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining. Results: Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1ß tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats. Conclusion: We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.

Dose Calculation Comparisons between Three Modern Treatment Planning Systems.

PURPOSE: Monaco treatment planning system (TPS) version 5.1 uses a Monte-Carlo (MC)-based dose calculation engine. The aim of this study is to verify and compare the Monaco-based dose calculations with both Pinnacle3 collapsed cone convolution superposition (CCCS) and Eclipse anisotropic analytical algorithm (AAA) calculations. MATERIALS AND METHODS: For this study, 18 previously treated lung and head-and-neck (HN) cancer patients were chosen to compare the dose calculations between Pinnacle, Monaco, and Eclipse. Plans were chosen from those that had been treated using the Elekta VersaHD or a Novalis Tx linac. All of the treated volumetric-modulated arc therapy plans used 6 MV or 10 MV photon beams. The original plans calculated with CCCS or AAA along with the recalculated ones using MC from the three TPS were exported into Velocity software for intercomparison. RESULTS: To compare the dose calculations, Planning target volume (PTV) heterogeneity indexes and conformity indexes were calculated from the dose volume histograms (DVH) of all plans. While mean lung dose (MLD), lung V5 and V20 values were recorded for lung plans, the computed dose to parotids, brainstem, and mandible were documented for HN plans. In plan evaluation, percent differences of the above dosimetric values in Monaco computation were compared against each of the other TPS computations. CONCLUSION: It could be concluded through this research that there can be differences in the calculation of dose across different TPSs. Although relatively small, these differences could become apparent when compared using DVH. These differences most likely arise from the different dose calculation algorithms used in each TPS. Monaco employs the MC allowing it to have much more detailed calculations that result in it being seen as the most accurate and the gold standard.

Modeling Pathway Dynamics of the Skeletal Muscle Response to Intravenous Methylprednisolone (MPL) Administration in Rats: Dosing and Tissue Effects.

A model-based approach for the assessment of pathway dynamics is explored to characterize metabolic and signaling pathway activity changes characteristic of the dosing-dependent differences in response to methylprednisolone in muscle. To consistently compare dosing-induced changes we extend the principles of pharmacokinetics and pharmacodynamics and introduce a novel representation of pathway-level dynamic models of activity regulation. We hypothesize the emergence of dosing-dependent regulatory interactions is critical to understanding the mechanistic implications of MPL dosing in muscle. Our results indicate that key pathways, including amino acid and lipid metabolism, signal transduction, endocrine regulation, regulation of cellular functions including growth, death, motility, transport, protein degradation, and catabolism are dependent on dosing, exhibiting diverse dynamics depending on whether the drug is administered acutely of continuously. Therefore, the dynamics of drug presentation offer the possibility for the emergence of dosing-dependent models of regulation. Finally, we compared acute and chronic MPL response in muscle with liver. The comparison revealed systematic response differences between the two tissues, notably that muscle appears more prone to adapt to MPL.

Quantitative comparison of pre-treatment predictive and post-treatment measured dosimetry for selective internal radiation therapy using cone-beam CT for tumor and liver perfusion territory definition.

BACKGROUND: Selective internal radiation therapy (SIRT) is a promising treatment for unresectable hepatic malignancies. Predictive dose calculation based on a simulation using 99mTc-labeled macro-aggregated albumin (99mTc-MAA) before the treatment is considered as a potential tool for patient-specific treatment planning. Post-treatment dose measurement is mainly performed to confirm the planned absorbed dose to the tumor and non-tumor liver volumes. This study compared the predicted and measured absorbed dose distributions. METHODS: Thirty-one patients (67 tumors) treated by SIRT with resin microspheres were analyzed. Predicted and delivered absorbed dose was calculated using 99mTc-MAA-SPECT and 90Y-TOF-PET imaging. The voxel-level dose distribution was derived using the local deposition model. Liver perfusion territories and tumors have been delineated on contrast-enhanced CBCT images, which have been acquired during the 99mTc-MAA work-up. Several dose-volume histogram (DVH) parameters together with the mean dose for liver perfusion territories and non-tumoral and tumoral compartments were evaluated. RESULTS: A strong correlation between the predicted and measured mean dose for non-tumoral volume was observed (r = 0.937). The ratio of measured and predicted mean dose to this volume has a first, second, and third interquartile range of 0.83, 1.05, and 1.25. The difference between the measured and predicted mean dose did not exceed 11 Gy. The correlation between predicted and measured mean dose to the tumor was moderate (r = 0.623) with a mean difference of - 9.3 Gy. The ratio of measured and predicted tumor mean dose had a median of 1.01 with the first and third interquartile ranges of 0.58 and 1.59, respectively. Our results suggest that 99mTc-MAA-based dosimetry could predict under or over dosing of the non-tumoral liver parenchyma for almost all cases. For more than two thirds of the tumors, a predictive absorbed dose correctly indicated either good tumor dose coverage or under-dosing of the tumor. CONCLUSION: Our results highlight the predictive value of 99mTc-MAA-based dose estimation to predict non-tumor liver irradiation, which can be applied to prescribe an optimized activity aiming at avoiding liver toxicity. Compared to non-tumoral tissue, a poorer agreement between predicted and measured absorbed dose is observed for tumors.

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing.

Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.

Whole-ventricular irradiation for intracranial germ cell tumors: Dosimetric comparison of pencil beam scanned protons, intensity-modulated radiotherapy and volumetric-modulated arc therapy.

BACKGROUND: Whole-ventricular radiotherapy (WV-RT) followed by a boost to the tumor bed (WV-RT/TB) is recommended for intracranial germ cell tumors (IGCT). As the critical brain areas are mainly in the target volume vicinity, it is unclear if protons indeed substantially spare neurofunctional organs at risk (NOAR). Therefore, a dosimetric comparison study of WV-RT/TB was conducted to assess whether proton or photon radiotherapy achieves better NOAR sparing. METHODS: Eleven children with GCT received 24 Gy(RBE) WV-RT and a boost up to 40 Gy(RBE) in 25 fractions of 1.6 Gy(RBE) with pencil beam scanning proton therapy (PBS-PT). Intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans were generated for these patients. NOAR were delineated and treatment plans were compared for target volume coverage (TVC), homogeneity index (HI), inhomogeneity coefficient (IC) and (N)OAR sparing. RESULTS: TVC was comparable for all three modalities. Compared to IMRT and VMAT, PBS-PT showed statistically significant optimized IC, as well as dose reduction, among others, in mean and integral dose to the: normal brain (-35.2%, -32.7%; -35.2%, -33.0%, respectively), cerebellum (-53.7%, -33.1%; -53.6%, -32.7%) and right temporal lobe (-14.5%, -31.9%; -14.7%, -29.9%). The Willis' circle was better protected with PBS-PT than IMRT (-7.1%; -7.8%). The left hippocampus sparing was higher with IMRT. Compared to VMAT, the dose to the hippocampi, amygdalae and temporal lobes was significantly decreased in the IMRT plans. CONCLUSIONS: Dosimetric comparison of WV-RT/TB in IGCT suggests PBS-PT's advantage over photons in conformality and NOAR sparing, whereas IMRT's superiority over VMAT, thus potentially minimizing long-term sequelae.