Commissioning and validation of a single photon beam model in RayStation for multiple matched Elekta Linacs.

PURPOSE: A single treatment planning system (TPS) model for matched linacs provides flexible clinical workflows from patient treatment to intensity-modulated radiation therapy (IMRT) quality assurance (QA) measurement. Since general guidelines for building a single TPS model and its validation for matched linacs are not well established, we present our RayStation photon TPS modeling strategy for matched Elekta VersaHD linacs. METHOD: The four linacs installed from 2013 to 2020 were matched in terms of Percent Depth Dose (PDD), profile, output factor and wedge factors for 6-MV, 10-MV, 15-MV, and 6-MV-FFF, and maintained following TG-142 recommendations until RayStation commissioning. The RayStation single model was built to represent all four linacs within the tolerance limits recommended by MPPG-5.a. The comprehensive validation tests were performed for one linac following MPPG-5.a and TG-119 guidelines, and spot checks for the other three. Our TPS modeling/validation method was evaluated by re-analyzing the previous 103 patient-specific IMRT/volumetric modulated arc therapy (VMAT) QA measurements with the calculated planar doses by the single model in comparison with the analysis results using four individual Pinnacle TPS models. RESULTS: For all energies, our single model PDDs were within 1% agreement of the four-linac commissioning measurements. The MPPG-5.a validation tests from 5.1 through 7.5 and all TG-119 measurements passed within the recommended tolerance limits. The IMRT QA results (mean ± standard deviation) for RayStation single model versus Pinnacle individual models were 98.9% ± 1.3% and 98.0% ± 1.4% for 6-MV, 99.9% ± 0.1% and 99.1% ± 1.9% for 10-MV, and 98.2% ± 1.3% and 97.9% ± 1.8% for 6-MV-FFF, respectively. CONCLUSION: We successfully built and validated a single photon beam model in RayStation for four Elekta Linacs. The proposed new validation methods were proven to be both efficient and effective.

Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models.

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90 Y, 177 Lu, and 225 Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225 Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 + /Treg ratios increased in tumors 7 days after 90 Y- and 177 Lu-NM600 and day 21 after 225 Ac-NM600. 225 Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. Teaser: This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

Statistical analysis plan for the PRO B study: open-label, superiority randomised controlled trial of alarm-based patient-reported outcome monitoring in patients with metastatic breast cancer.

BACKGROUND: With an increasing collection of patient-reported outcomes (PROs) to measure health-related quality of life (HRQoL) in oncological patients, there is still a lack of standardised strategies on how to interpret and use these data in patient care. Prior research has shown support for the use of digital PRO monitoring together with alarm systems to notify clinicians when the PRO values are deteriorating. This system has demonstrated advantages in improving HRQoL and increasing survival rates among oncology patients. Hence, we designed the PRO B study, a superiority multi-centre randomised controlled trial, to investigate the effects of alarm-based monitoring in metastatic breast cancer patients in Germany. The study protocol for the PRO B study was published in September 2021, and this manuscript describes a formal statistical analysis plan (SAP) for the PRO B study to improve the transparency and quality of this trial. METHODS AND DESIGN: The trial aimed to recruit 1000 patients with metastatic breast cancer. However, as of the completion of recruitment on June 15, 2023, we have successfully enrolled 924 patients from 52 breast cancer centres. Patients were 1:1 stratified randomised to the intervention and control groups. App-based PRO questionnaires are sent weekly to the intervention group and every 3 months to the control group. Only patients in the intervention group trigger an alarm if their PRO scores deteriorate, and they are subsequently contacted by the local care team within 48 h. The primary outcome is the fatigue score at 6 months, and secondary outcomes are other HRQoL and overall survival. Evaluation of the superiority of the intervention will be done using a linear mixed model with random intercepts for study centres. CONCLUSION: This detailed SAP defines the main components of the statistical analysis for the PRO B study to assist the statistician and prevent bias in selecting analysis and reporting findings. Version 1 of the SAP was finalised on January 18, 2024. TRIAL REGISTRATION: DRKS (German Clinical Trials Register) DRKS00024015 . Registered on February 15, 2021.

Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Voxel-Level Dosimetry for Combined Iodine 131 Radiopharmaceutical Therapy and External Beam Radiation Therapy Treatment Paradigms for Head and Neck Cancer.

PURPOSE: Targeted radiopharmaceutical therapy (RPT) in combination with external beam radiation therapy (EBRT) shows promise as a method to increase tumor control and mitigate potential high-grade toxicities associated with re-treatment for patients with recurrent head and neck cancer. This work establishes a patient-specific dosimetry framework that combines Monte Carlo-based dosimetry from the 2 radiation modalities at the voxel level using deformable image registration (DIR) and radiobiological constructs for patients enrolled in a phase 1 clinical trial combining EBRT and RPT. METHODS AND MATERIALS: Serial single-photon emission computed tomography (SPECT)/computed tomography (CT) patient scans were performed at approximately 24, 48, 72, and 168 hours postinjection of 577.2 MBq/m2 (15.6 mCi/m2) CLR 131, an iodine 131-containing RPT agent. Using RayStation, clinical EBRT treatment plans were created with a treatment planning CT (TPCT). SPECT/CT images were deformably registered to the TPCT using the Elastix DIR module in 3D Slicer software and assessed by measuring mean activity concentrations and absorbed doses. Monte Carlo EBRT dosimetry was computed using EGSnrc. RPT dosimetry was conducted using RAPID, a GEANT4-based RPT dosimetry platform. Radiobiological metrics (biologically effective dose and equivalent dose in 2-Gy fractions) were used to combine the 2 radiation modalities. RESULTS: The DIR method provided good agreement for the activity concentrations and calculated absorbed dose in the tumor volumes for the SPECT/CT and TPCT images, with a maximum mean absorbed dose difference of -11.2%. Based on the RPT absorbed dose calculations, 2 to 4 EBRT fractions were removed from patient EBRT treatments. For the combined treatment, the absorbed dose to target volumes ranged from 57.14 to 75.02 Gy. When partial volume corrections were included, the mean equivalent dose in 2-Gy fractions to the planning target volume from EBRT + RPT differed -3.11% to 1.40% compared with EBRT alone. CONCLUSIONS: This work demonstrates the clinical feasibility of performing combined EBRT + RPT dosimetry on TPCT scans. Dosimetry guides treatment decisions for EBRT, and this work provides a bridge for the same paradigm to be implemented within the rapidly emerging clinical RPT space.

Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides.

Bioactive peptides are key molecules in health and medicine. Deep learning holds a big promise for the discovery and design of bioactive peptides. Yet, suitable experimental approaches are required to validate candidates in high throughput and at low cost. Here, we established a cell-free protein synthesis (CFPS) pipeline for the rapid and inexpensive production of antimicrobial peptides (AMPs) directly from DNA templates. To validate our platform, we used deep learning to design thousands of AMPs de novo. Using computational methods, we prioritized 500 candidates that we produced and screened with our CFPS pipeline. We identified 30 functional AMPs, which we characterized further through molecular dynamics simulations, antimicrobial activity and toxicity. Notably, six de novo-AMPs feature broad-spectrum activity against multidrug-resistant pathogens and do not develop bacterial resistance. Our work demonstrates the potential of CFPS for high throughput and low-cost production and testing of bioactive peptides within less than 24 h.