MIDOS: a novel stochastic model towards a treatment planning system for microsphere dosimetry in liver tumors.

PURPOSE: Transarterial radioembolization (TARE) procedures treat liver tumors by injecting radioactive microspheres into the hepatic artery. Currently, there is a critical need to optimize TARE towards a personalized dosimetry approach. To this aim, we present a novel microsphere dosimetry (MIDOS) stochastic model to estimate the activity delivered to the tumor(s), normal liver, and lung. METHODS: MIDOS incorporates adult male/female liver computational phantoms with the hepatic arterial, hepatic portal venous, and hepatic venous vascular trees. Tumors can be placed in both models at user discretion. The perfusion of microspheres follows cluster patterns, and a Markov chain approach was applied to microsphere navigation, with the terminal location of microspheres determined to be in either normal hepatic parenchyma, hepatic tumor, or lung. A tumor uptake model was implemented to determine if microspheres get lodged in the tumor, and a probability was included in determining the shunt of microspheres to the lung. A sensitivity analysis of the model parameters was performed, and radiation segmentectomy/lobectomy procedures were simulated over a wide range of activity perfused. Then, the impact of using different microspheres, i.e., SIR-Sphere®, TheraSphere®, and QuiremSphere®, on the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), and mean absorbed dose was analyzed. RESULTS: Highly vascularized tumors translated into increased TNR. Treatment results (TNR and LSF) were significantly more variable for microspheres with high particle load. In our scenarios with 1.5 GBq perfusion, TNR was maximum for TheraSphere® at calibration time in segmentectomy/lobar technique, for SIR-Sphere® at 1-3 days post-calibration, and regarding QuiremSphere® at 3 days post-calibration. CONCLUSION: This novel approach is a decisive step towards developing a personalized dosimetry framework for TARE. MIDOS assists in making clinical decisions in TARE treatment planning by assessing various delivery parameters and simulating different tumor uptakes. MIDOS offers evaluation of treatment outcomes, such as TNR and LSF, and quantitative scenario-specific decisions.

Detailed dosimetric evaluation of inter-fraction and respiratory motion in lung stereotactic body radiation therapy based on daily 4D cone beam CT images.

Objective. Periodic respiratory motion and inter-fraction variations are sources of geometric uncertainty in stereotactic body radiation therapy (SBRT) of pulmonary lesions. This study extensively evaluates and validates the separate and combined dosimetric effect of both factors using 4D-CT and daily 4D-cone beam CT (CBCT) dose accumulation scenarios.Approach. A first cohort of twenty early stage or metastatic disease lung cancer patients were retrospectively selected to evaluate each scenario. The planned-dose (3DRef) was optimized on a 3D mid-position CT. To estimate the dosimetric impact of respiratory motion (4DRef), inter-fractional variations (3DAcc) and the combined effect of both factors (4DAcc), three dose accumulation scenarios based on 4D-CT, daily mid-cone beam CT (CBCT) position and 4D-CBCT were implemented via CT-CT/CT-CBCT deformable image registration (DIR) techniques. Each scenario was compared to 3DRef.A separate cohort of ten lung SBRT patients was selected to validate DIR techniques. The distance discordance metric (DDM) was implemented per voxel and per patient for tumor and organs at risk (OARs), and the dosimetric impact for CT-CBCT DIR geometric errors was calculated.Main results.Median and interquartile range (IQR) of the dose difference per voxel were 0.05/2.69 Gy and -0.12/2.68 Gy for3DAcc-3DRefand4DAcc-3DRef.For4DRef-3DRefthe IQR was considerably smaller -0.15/0.78 Gy. These findings were confirmed by dose volume histogram parameters calculated in tumor and OARs. For CT-CT/CT-CBCT DIR validation, DDM (95th percentile) was highest for heart (6.26 mm)/spinal cord (8.00 mm), and below 3 mm for tumor and the rest of OARs. The dosimetric impact of CT-CBCT DIR errors was below 2 Gy for tumor and OARs.Significance. The dosimetric impact of inter-fraction variations were shown to dominate those of periodic respiration in SBRT for pulmonary lesions. Therefore, treatment evaluation and dose-effect studies would benefit more from dose accumulation focusing on day-to-day changes then those that focus on respiratory motion.

IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction.

BACKGROUND: The quality and quantity of tumor neoantigens derived from tumor mutations determines the fate of the immune response in cancer. Frameshift mutations elicit better tumor neoantigens, especially when they are not targeted by nonsense-mediated mRNA decay (NMD). For tumor progression, malignant cells need to counteract the immune response including the silencing of immunodominant neoantigens (antigen immunoediting) and promoting an immunosuppressive tumor microenvironment. Although NMD inhibition has been reported to induce tumor immunity and increase the expression of cryptic neoantigens, the possibility that NMD activity could be modulated by immune forces operating in the tumor microenvironment as a new immunoediting mechanism has not been addressed. METHODS: We study the effect of SMG1 expression (main kinase that initiates NMD) in the survival and the nature of the tumor immune infiltration using TCGA RNAseq and scRNAseq datasets of breast, lung and pancreatic cancer. Different murine tumor models were used to corroborate the antitumor immune dependencies of NMD. We evaluate whether changes of SMG1 expression in malignant cells impact the immune response elicited by cancer immunotherapy. To determine how NMD fluctuates in malignant cells we generated a luciferase reporter system to track NMD activity in vivo under different immune conditions. Cytokine screening, in silico studies and functional assays were conducted to determine the regulation of SMG1 via IL-6/STAT3 signaling. RESULTS: IL-6/STAT3 signaling induces SMG1, which limits the expression of potent frameshift neoantigens that are under NMD control compromising the outcome of the immune response. CONCLUSION: We revealed a new neoantigen immunoediting mechanism regulated by immune forces (IL-6/STAT3 signaling) responsible for silencing otherwise potent frameshift mutation-derived neoantigens.

A method using 4D dose accumulation to quantify the interplay effect in lung stereotactic body radiation therapy.

The purpose of this study was to devise and evaluate a method to quantify the dosimetric uncertainty produced by the interplay between the movement of multileaf collimator and respiratory motion in lung stereotactic body radiation therapy. The method calculates the dose distribution for all control points from a dynamic treatment in all respiratory phases. The methodology includes some characteristics of a patient's irregular breathing patterns. It selects, for each control point, the phases with maximum and minimum mean dose over the tumor and their corresponding adjacent phases, whenever necessary. According to this selection, the dose matrices from each control point are summed up to obtain two dose distributions in each phase, which are accumulated in the reference phase subsequently by deformable image registration (DIR). D 95 and [Formula: see text] were calculated over those accumulated dose distributions for Gross Tumor Volume (GTV), Planning Target Volume-based on Internal Target Volume approach-and Evaluation Target Volume (ETV), a novel concept that applies to 4D dose accumulation. With the ETV, DIR and interplay uncertainties are separated. The methodology also evaluated how variations in the breathing rate and field size affects the mean dose received by the GTV. The method was applied retrospectively in five patients treated with intensity modulated radiotherapy-minimum area defined by the leaves configuration at any control point was at least 4 cm2. Uncertainties in tumor coverage were small (in most patients, changes on D 95 and [Formula: see text] were below 2% for GTV and ETV) but significant over- and under-dosages near ETV, which can be accentuated by highly irregular breathing. Uncertainties in mean dose for GTV tended to decrease exponentially with increasing field size and were reduced by an increase of breathing rate. The implementation of this method would be helpful to assess treatment quality in patients with irregular breathing. Furthermore, it could be used to study interplay uncertainties when small field sizes are used.

A novel concept to include uncertainties in the evaluation of stereotactic body radiation therapy after 4D dose accumulation using deformable image registration.

PURPOSE: To use four-dimensional (4D) dose accumulation based on deformable image registration (DIR) to assess dosimetric uncertainty in lung stereotactic body radiation therapy (SBRT) treatment planning. A novel concept, the Evaluation Target Volume (ETV), was introduced to achieve this goal. METHODS: The internal target volume (ITV) approach was used for treatment planning for 11 patients receiving lung SBRT. Retrospectively, 4D dose calculation was done in Pinnacle v9.10. Total dose was accumulated in the reference phase using DIR with MIM. DIR was validated using landmarks introduced by an expert radiation oncologist. The 4D and three-dimensional (3D) dose distributions were compared within the gross tumor volume (GTV) and the planning target volume (PTV) using the D95 and Dmin (calculated as Dmin,0.035cc ) metrics. For lung involvement, the mean dose and V20 , V10 , and V5 were used in the 3D to 4D dose comparison, and Dmax (D0.1cc ) was used for all other organs at risk (OAR). The new evaluation target volume (ETV) was calculated by expanding the GTV in the reference phase in order to include geometrical uncertainties of the DIR, interobserver variability in the definition of the tumor, and uncertainties of imaging and delivery systems. D95 and Dmin,0.035cc metrics were then calculated on the basis of the ETV for 4D accumulated dose distributions, and these metrics were compared with those calculated from the PTV for 3D planned dose distributions. RESULTS: The target registration error (TRE) per spatial component was below 0.5 ± 2.1mm for all our patients. For five patients, dose degradation above 2% (>4% in 2 patients) was found in the PTV after 4D accumulation and attributed to anatomical variations due to breathing. Comparison of D95 and Dmin,0.035cc metrics showed that the ETV (4D accumulated dose) estimated substantially lower coverage than the PTV (3D planning dose): in six out of the 11 cases, and for at least for one of the two metrics, coverage estimated by ETV was at least 5% lower than that estimated by PTV. Furthermore, the ETV approach revealed hot and cold spots within its boundaries. CONCLUSIONS: A workflow for 4D dose accumulation based on DIR has been devised. Dose degradation was attributed to respiratory motion. To overcome limitations in the PTV for the purposes of evaluating DIR-based 4D accumulated dose distributions, a new concept, the ETV, was proposed. This concept appears to facilitate more reliable dose evaluation and a better understanding of dosimetric uncertainties due to motion and deformation.