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A new ring gantry-based Linac with a dual-layer multi-leaf collimator offers fast imaging and delivery, and adaptive radiotherapy capability. We aimed to perform pre-clinical evaluation of treatment planning and delivery workflow for total marrow and lymphoid irradiation (TMLI) and total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) fields on this Linac. We retrospectively retrieved four pediatric/adolescent patients (age: 7 – 11) who previously received intensity modulated TBI at our institution. In-house developed software (TXIHelper, publicly available in online Github repository) concatenated upper body and lower extremity CT scans into one CT image set. In the TMLI plans, a prescription dose of 12 Gy in 8 fractions was prescribed to the skeletal bones, spleen, spinal canal, and lymphoid volume. In the TBI plans, the prescribed dose was 12 Gy in 8 fractions for the body volume excluding the lungs. Each VMAT field has a field size of 28 cm × 28 cm with the collimator at 90° and a full gantry rotation. Isocenters were placed with equal spacing of 14 cm along the patient's longitudinal direction. Two VMAT fields were placed at each isocenter for the upper body up to mid-thigh, while one VMAT field was placed at each isocenter for the lower extremities. In-house software rotated lower extremity fields for feet-in delivery. The nominal dose rate was 800 MU/minute, and the maximum gantry rotation speed was 24°/sec. Institutional dosimetric constraints were used for optimization. Treatment plans were delivered on an anthropomorphic phantom on the machine. The average body length in the concatenated CT scans was 137.3 cm (range: 126.0 – 152.3 cm). Five isocenters were used for the upper body from the top of skull to mid-thigh, while four isocenters were used for the lower extremities for all patients. In the VMAT TBI plans, the average mean lung dose (MLD) was 6.3±0.3 Gy (range: 5.9 – 6.5 Gy); while in the VMAT TMLI plans, it was 6.1±0.5 Gy (range: 5.8 – 6.9 Gy). The average OAR dose in the TMLI plans ranged from 15.8% to 78.4% relative to the prescription dose. The average net beam-on time in the TMLI plans was 254.8±12.1 sec (range: 239.6 – 269.1 sec), while it was 222.5±2.8 sec (range: 218.4 – 224.3 sec) in the TBI plans. The average dose gradient was 1.1 Gy/cm in the longitudinal direction in field overlapping regions. At each isocenter, the CBCT scan plus image registration took less than 60 seconds, while up to 2 minutes were needed to set up the patient from one isocenter to another as the couch position had to be changed inside the Linac vault. Arrangement of VMAT fields in this study allowed simple clinical setup and adequate plan robustness against setup uncertainty in TBI and TMLI treatments. The CBCT-based image setup time and net beam-on time in the TMLI and TBI plans were significantly shorter compared to other Linac models. However, overhead time cannot be ignored as the current system mandates entering the Linac vault for each couch movement. [ABSTRACT FROM AUTHOR]

The SCINTIX treatment technique on the medical technology company machine became clinically available in 2023. With an integrated positron emission tomography (PET) imaging system, the X1 uses real-time positron emission signals from the fludeoxyglucose F-18 (FDG)-avid tumor as a bio-guide for accurate radiation delivery. This study reviews our institutional experience in patient selection and treatment planning in the early phase of initiating clinical SCINTIX treatments with the aim of facilitating other institutions in implementing this technology. After commissioning SCINTIX hardware and software modules on the machine at our institution in the middle of 2023, we implemented a process of prospective patient screening for SCINTIX treatment eligibility. Potentially eligible patients were then further evaluated with quantitative measures by the physics team. Eligibility criteria included availability of recent diagnostic PET/CT scans, PET-avid tumor size of 1 to 5 cm, tumor location (in the lung or as bony metastases), tumor standardized update value (SUV) thresholds relative to tumor size, PET activity around the tumor, and patient tolerance to estimated treatment time. Diagnostic PET/CT images for candidate patients were converted to simulate expected PET images on the X1 machine to calculate activity concentration (AC) and normalized target signal (NTS). If both AC and NTS were above eligibility thresholds, a PET scan was performed on the X1 machine to further evaluate SCINTIX treatment eligibility. In the few months leading to the first clinical SCINTIX treatment, simulated SCINTIX treatment planning were performed for six candidate patients among all patients evaluated. Two patients were found ineligible as simulated PET images showed low PET activity for the tumor and another patient was not eligible as the prescription dose did not meet SCINTIX treatment criteria. Three candidate patients received PET scans on the X1 machine. One of the patients was found to be not suitable due to low PET activity in the X1 scan, while another patient did not receive SCINTIX treatment due to target location and plan dose conformity. The remaining patient had a left femur bony lesion with maximum SUV of 9.4 and tumor size of around 2 cm. The SCINTIX treatment plan based on the X1 PET scan was generated with a prescription dose of 10 Gy in one fraction and the target volume was found to have an AC of 5.02 kBq/ml and NTS of 4.5. This patient was treated successfully on the X1 machine with a beam-on time of 19 minutes, as the third patient in the United States that received SCINTIX treatments and the first patient that received a single-fraction treatment. A comprehensive set of screening criteria was used for efficient screening of patients for SCINTIX treatment. Introduction of novel treatment modalities including the SCINTIX technique requires close collaboration among radiation oncologists and medical physicists for successful initiation of a clinical program. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM, WHO Grade 4) is associated with a low 5-year survival rate and a highly aggressive phenotype. PTEN is a tumor suppressor gene that is known to act as an inhibitor of the PI3K-Akt pathway. It is mutated in about 36-44% of GBM patients and its deficiency positively correlates with poor survival. We have previously shown that TRIB1 activates the Akt and ERK pathways in GBM providing survival advantage to GBM cells in response to radiation and chemotherapy treatments. Previous studies in prostate cancer have shown that TRIB1 mRNA expression is inversely correlated with PTEN gene expression. In this study we evaluated the relationship between TRIB1 and PTEN in the context of GBM. The publicly available TCGA GBM cohort was analyzed for TRIB1 gene expression in PTEN wildtype (WT) and mutant patients. Furthermore, correlative analysis was done between TRIB1 and PTEN gene expression in TCGA GBM and CGGA cohorts. Transient transfection was used to overexpress PTEN. Patient derived xenograft (PDX) cell lines stably overexpressing TRIB1 were created by antibiotic selection. Protein levels were detected by western blotting. CGGA cohorts (Table 1). Western blot data revealed that after overexpression of TRIB1, PTEN protein levels were decreased in the T08-387 PDX cell line (50% PTEN allelic loss) and LN18 cells (PTEN WT). We then overexpressed PTEN in U87 cells (PTEN null) overexpressing TRIB1 transgene and observed the same effect on PTEN protein levels. However, the Akt and ERK phosphorylation were also reduced. Table 1: Correlation between TRIB1 and PTEN gene expression in various patient cohorts. TRIB1 and PTEN gene expression have a direct correlation in TCGA GBM database. Also, TRIB1 mRNA levels are not dictated by PTEN mutation status. TRIB1 affects PTEN protein levels in respective cell lines however the mechanism is not known. The reduction in Akt and ERK phosphorylation in U87 cells may be attributed to TP53 status of these cells and the fact that addition of WT PTEN over WT TP53 may enhance tumor suppression in these cells. In conclusion, further studies are needed to delineate the relationship between TRIB1 and PTEN, as the mutation status of PTEN (WT, heterozygous loss and complete loss) has differing tumor-initiation effects. [ABSTRACT FROM AUTHOR]

The Reflexion Biology Guided Radiation Therapy (BGRT) (Reflexion Medical Systems, Hayward CA) system incorporates Positron Emission Tomography (PET) in treatment planning and delivery. This work details our institutional commissioning of the system for patient treatment. The manufacturer provided custom insert phantoms for the check device) including a hollow 2-cm sphere fillable with Fludeoxyglucose F18 (FDG) with a film plane and a point geometry Na-22 source. We constructed custom phantoms composed of solid water, cork to represent lung density, and PET sources including a Ge-68 bar source various cylindrical plastic inserts for FDG filling (diameters 2.2 cm, 3.5 cm, and 5.5 cm). Computed Tomography (CT) and PET Images of the phantoms were acquired on diagnostic PET/CT and on the system on a motion platform capable of simulating respiratory motion and intra-fraction gross anatomic shifts. Treatment plans were generated including varying PTV size for fixed PET-source geometry (range = 17-230 cc), varying doses from 7-12 Gy / fraction, and varying geometry of proximal PET active regions and background activity. We evaluated the delivery system response in planning conditions, and the system response to perturbations from the planning conditions including varying PET activity and geometric shifts including simulation of respiratory and gross intra-fraction motion. Varying PTV size and geometry for fixed PET-sources did not affect accurate planning and delivery in planning conditions, confirming BgRT can safely deliver non-uniform margin expansions of PET-active volumes (as is customary in PTV definition). In delivery matching the planning conditions, planned vs. measured dosimetry routinely exceed 90% 3mm/3% Gamma with ion chamber and film readings generally within 3%. Varying PET activity from 30-105% of the planned kBq/ml resulted in no dose variations, indicating the system delivery is robust to injection and uptake variations which may be observed clinically. Geometric variations including varying breathing motion did show interplay effects in large targets reducing Gamma passing rates, but the clinical significance of these variations may be averaged out over several fractions. Intra-fraction geometric shifts of 5-10mm revealed the system has the ability to perform real-time plan adaptation and avoid major dosimetric errors. The BGRT system was validated as a robust treatment modality for multiple PET sources of varying activity, active volume, and PTVs. When varying delivery parameters, the system was robust against large variations in absolute PET activity and real-time adaptation was possible when gross motion occurred. Further studies are needed to understand the interplay effect in large targets. [ABSTRACT FROM AUTHOR]

The RefleXion® X1 system is a biology-guided radiotherapy (BgRT) machine with SCINTIX® treatment capability, which uses real-time positron emission signals from the tumor to guide radiation delivery. This study aims to evaluate the feasibility of using the Gallium-68 (Ga-68) prostate-specific membrane antigen (PSMA)-11 radiotracer as a bio-guide for SCINTIX® treatment on the X1 machine in the future for bony metastases in prostate cancer patients. A retrospective review was performed on patients who underwent recent diagnostic Ga-68 PSMA-11 PET/CT scans at our institution. Five patients with PET-avid bone metastases identified in the scans were included. A gross tumor volume (GTV) was drawn for a PET-avid bone lesion for each patient. The PTV was created by adding a 5 mm margin to the GTV, and a biology tracking zone (BTZ) was created to encompass the potentially full range of motion of the tumor plus margin. To create SCINTIX treatment plans on the X1 machine, the diagnostic PET images were first converted to simulated treatment planning PET images on the X1 machine to account for differences in PET detector size and reconstruction algorithms. Then the activity concentration (AC) and normalized target signal (NTS) were calculated. The SCINTIX plans used a jaw width of 2 cm and a prescription dose of 27 Gy in 3 fractions given to the PTV using four couch passes. A 64-leaf binary MLC was used to modulate a 6-MV flattening filter-free photon beam on a ring gantry that rotates around the patient at 60 RPM. Patients received an average Ga-68 injection dose of 4.86 ± 0.73 mCi (range = 4.1 – 5.6 mCi) prior to PET/CT scans. In the diagnostic Ga-68 PSMA-11 PET images, the average maximum and mean PET activities in the GTVs were 25.2 ± 12.0 kBq/mL (range = 13.3 – 43.5 kBq/mL) and 16.44 ± 5.6 kBq/mL (range = 14.3 – 24.2 kBq/mL), respectively. The average AC and NTS values for targets in the simulated treatment planning PET images were 11.5 ± 5.2 kBq/mL (range = 6.2 - 18.9 kBq/mL) and 12.6 ± 5.5 (range = 8.7 - 22.2), respectively. With an average PTV volume of 15.7 ± 9.6 cc (range = 7.0 – 30.9 cc), the average treatment beam-on time was 1,678 ± 290 seconds (range = 1,416 – 2,120 seconds). Bounded dose-volume histograms (bDVH) were calculated to estimate the range of delivered dose due to PET signal and patient position uncertainties. The average PTV coverage, conformity index, and homogeneity index were 93.6 ± 1.9%, 1.14 ± 0.1, and 1.63 ± 0.1, respectively. This is one of the first studies on Ga-68 based tracers for SCINTIX planning as the current plan creation software was developed for F-18 based tracers. Metastatic bony lesions from prostate cancer could have sufficient positron emission strength for SCINTIX treatment when Ga-68 PSMA-11 radiotracer is used at diagnostic dose levels. This study demonstrated the feasibility of using Ga-68 PSA-11 radiotracer for future PET-guided SCINTIX treatments on the X1 machine. [ABSTRACT FROM AUTHOR]

There is interest in utilizing radiomics to monitor, and potentially act upon, treatment response in patients receiving radiation treatment. Historically, computed tomography (CT) imaging obtained for image-guided radiotherapy is of insufficient quality for use in radiomic analyses. A new linear accelerator that utilizes fan-beam kilovoltage CT (kVCT) has higher-quality imaging, creating opportunities for radiomic analysis. This study sought to evaluate the feasibility of using these scans to correlate radiomic feature changes with treatment response in patients undergoing definitive treatment for lung cancer. Patients were scanned using the novel fan-beam kVCT system throughout treatment. CT scans used standardized acquisition parameters for all treatments to minimize variation. Images were acquired using "Body/Medium Dose/Slow Couch" parameters. The primary tumor gross tumor volume (GTV) was contoured by a radiation oncologist on each scan, which were anonymized and put in random order to prevent bias. CTs and structure files were imported into an Image Biomarker Standardization Initiative compliant radiomic software package (LifeX) to extract radiomic features. 40 radiomic features that were identified to be stable in normal tissues during treatment were extracted from each scan with the volume-of-interest defined as the GTV. Pearson correlation coefficients were calculated between these features and relative change in GTV volume (1 - {GTV volume/GTV volume at time of 1st fraction [fx]}). Coefficients greater than 0.4, 0.7, and 0.9 were considered moderately, strongly, and very strongly correlated, respectively. All distributions are expressed as median [IQR] unless otherwise stated. 12 patients (9 male) with lung cancer (11 non-small cell lung cancer, 1 small cell lung cancer) treated with conventionally fractionated (60 Gy/30 fx [n = 8] or 66 Gy/33 fx [n = 3]) or hypofractionated (45 Gy/15 fx [n = 1]) radiation between 9/2021 and 10/2023 were analyzed. Median age was 64 (range: 42-84) years. During treatment, median decrease in GTV volume was 42.3% (8.9-62.5%). One radiomic feature was very strongly correlated with GTV response: GLZLM_GLNU (0.96 [0.91-0.97]). Two features were strongly correlated: NGLDM_Coarseness (0.83 [0.72-0.92]) and NGLDM_Busyness (0.72 [0.46-0.79]). Four other features were moderately correlated: DISCRETIZED_HUpeakSphere0.5mL, DISCRETIZED_HUQ1, NGLDM_Contrast, and CONVENTIONAL_HUQ1. Three radiomic features were at least strongly correlated with primary GTV volume changes when evaluated on images obtained by a fan-beam kVCT in patients treated definitively for lung cancer. These findings demonstrate potential feasibility to use these images for radiomic analysis during treatment to predict individual patient response. Once sufficient follow-up is available, future work will focus on whether these features also correlate with overall treatment response and disease control. [ABSTRACT FROM AUTHOR]