The Radiation Oncology-Biology Integration Network (ROBIN) initiative addresses critical gaps in radiation oncology by integrating advanced biological research, technologic innovation, and clinical practice. ROBIN leverages "omics" technologies, data science, and integrative analyses to elucidate the mechanisms governing tumor and normal tissue responses to radiotherapy (RT). Through five specialized centers-OligoMET, ImmunoRad, GenRad, METEOR, and KIDSROBIN-the network covers a broad spectrum of cancer and radiation biology research. Each center conducts translational programs linked to clinical trials, targeting key domains, including metastasis biology, RT-immune system interactions, and genomic determinants of treatment response. KIDSROBIN assures the invaluable inclusion of pediatric cancers to the consortium. By collecting clinically annotated human biospecimens and applying single-cell and spatially resolved omics, ROBIN enables mechanistic insights into radiation effects directly in patients. A central pillar of the initiative is its commitment to data standardization and sharing, using cloud-based platforms to generate accessible and interoperable datasets. ROBIN also prioritizes education and cross-disciplinary training to cultivate the next generation of scientists in radiation biology and oncology. This integrated approach positions ROBIN to drive transformative advances in radiation oncology and multimodal cancer therapy, informing personalized treatment strategies and improving patient outcomes. This review provides an overview of the ROBIN program and its key strategies, research activities, and contributions to advancing radiation biology and oncology. The vision and leadership of Dr. Norman Coleman have been foundational to the development of the ROBIN initiative, inspiring a collaborative ecosystem that bridges science and clinical practice to drive meaningful impact in patient care.

Combined microbubble-mediated focused ultrasound (μB-FUS) and radiation therapy (RT) have been used to treat solid tumors. We have observed that μB-FUS+RT also leads to incision-less, targeted ablation in healthy brain tissue. This novel neurosurgical approach may minimize radiation doses (20–70 Gy) needed for radiosurgery and improve the ability to tailor surgery compared to μB-FUS ablation. Here, we studied the effect of μB-FUS and RT on lesioning in healthy rats. The striatum was targeted with pulsed FUS (273 kHz; ∼5 × 5 mm2; Definity μBs, 20 μl/kg). Acoustic pressures were modulated using a μB emissions-based controller (max 183 kPa). T1- and T2-weighted 7T MRI were used to confirm FUS effects. ∼1 h after FUS, RT (3 × 3 mm2) was delivered to the target. Lesion progression was monitored using T2-w MRI. 7 treatment groups (n = 4 locations/group) were tested: (1) μB-FUS-only, (2–4) RT-only (8, 12, and 15 Gy), and (5–7) μB-FUS+RT. 72 h after μB-FUS+RT, lesions were seen at all targets for 12 and 15 Gy and 2/4 targets for 8 Gy. Lesions were well colocalized with the overlap of the two treatment modalities, measuring ∼3 × 3 mm2, and persisted until day 21. Edema in the μB-FUS-only group resolved within 7 days, and no T2 effects were observed in the RT-only groups. Preliminary analyses indicate that mild edema on T2-w MRI immediately following μB-FUS may be predictive of successful μB-FUS+RT treatment outcomes. Ongoing work is aimed at understanding the effect of μB-FUS parameters, and the mechanisms of cell death and lesion progression.

High atomic number metal-based nanoparticles (NPs) enhance radiotherapy efficacy by improving tumor multimodal imaging and intensifying radiation dosage. AGuIX-Bi represents a theranostic NP comprising gadolinium and bismuth chelates grafted on a polysiloxane core. We hypothesize that modulating the surface of AGuIX-Bi with targeted peptides will enhance the therapeutic responses of radiation therapy. The cyclic Arg-Gly-Asp (cRGD) peptide has a high affinity to RGD-binding integrins overexpressed on various tumor cells, including lung cancer. In the present study, we introduced cRGD peptides onto the surface of AGuIX-Bi NPs using a PEG spacer to form an amide bond with the free amino functions present at the surface of the NPs. In vitro, AGuIX-Bi-cRGD showed enhanced internalization of NPs via integrin binding and increased radiosensitization. In murine Lewis lung carcinoma (LLC) tumors, AGuIX-Bi-cRGD exhibited increased accumulation and retention in tumors without causing systemic toxicity. Combined with fractionated irradiation, AGuIX-Bi-cRGD converted a “cold” LLC tumor microenvironment (TME) into a “hot” one by inducing the overexpression of the immunogenic cell death marker HMGB1 and increasing the density of tumor-infiltrating CD3+ CD8+ cytotoxic T cells and thereby delaying tumor growth and improving mice survival. Therefore, these results suggest a potential strategy for using targeted AGuIX-Bi-cRGD NPs to sensitize lung tumors to radiation and immunotherapies.

BACKGROUND:With the ever-increasing dependence on cone-beam CT (CBCT) for clinical decision-making, faster and more accurate CBCT simulation tools are necessary to develop the next generation of CBCT techniques and algorithms. PURPOSE:GECCO, a hybrid GPU-Monte Carlo (MC) software toolkit was built for the dual purpose of increasing both speed and accuracy in CBCT simulation. GECCO contains two applications: The GECCO application, a rapid converter of CT to CBCT, and the real-time image simulation (RTIS) application, a purely analytical approach that updates CBCT images in real-time according to acquisition technique. METHOD:The GECCO application calculates primary projections analytically and scatter with GPU-MC. The analytical model is a faster, less memory-intensive update to the Fastcat simulation toolkit, combining mono-energetic projections into a polyenergetic projection. Scatter is calculated using a modified version of GGEMs GPU-MC, denoised, and interpolated to reduce the number of MC histories needed for a full simulation. Conversely, the RTIS application is solely analytical and maximizes speed, only simulating a single CT slice and storing partial results to enable dynamic updating of the simulation. Validation compared GECCO simulations of an XCAT phantom, a virtual Catphan phantom, and an elementally decomposed planning CT of a central nervous system (CNS) patient to GGEMs MC projections, TrueBeam CBCT of a Catphan, and a registered CNS patient CBCT, respectively. RESULTS:The GECCO application took 63 min to simulate 915 full-resolution projection CNS patient CBCT on an NVIDIA 4090 GPU. The virtual Catphan sensitometry module showed an RMSE of 5.7 HU compared to the TrueBeam on-board imager (OBI). Likewise, RTIS had an initialization time of 917 ms and an update time of 36 ms, three orders of magnitude faster than any other simulation application. Profiles through the CNS patient showed 14 and 16 HU RMSE as compared to OBI for GECCO and RTIS, respectively. CONCLUSION:We introduce the GECCO software toolkit, containing the GECCO application for producing high-quality machine learning datasets and the RTIS application for real-time selection of imaging techniques for radiation therapists.

PURPOSE:AGuIX nanoparticles consisting of Gd atoms chelated to a polysiloxane matrix are under clinical evaluation as radiopharmaceuticals agents with radiation therapy (RT). A new generation, AGuIX-Bi, replaces 70% of the Gd atoms in AGuIX with Bi atoms, improving radiation dose amplification while maintaining magnetic resonance imaging (MRI) contrast. The therapeutic efficacy of AGuIX-Bi was investigated under clinical megavoltage and MRI conditions in 2 non-small cell lung cancer (NSCLC) models. METHODS AND MATERIALS:Murine (LLC) and human (A549) NSCLC were studied in mice, with animals inoculated and divided into cohorts for control (saline, AGuIX, and AGuIX-Bi) and irradiation (saline + RT, AGuIX + RT, and AGuIX-Bi + RT). Nanoparticle cohorts were injected 24 hours before delivering 10 Gy of irradiation using a 6 MV flattening-filter-free beam. Tumors were measured until euthanasia was necessary, taken as time-to-tumor doubling. Additionally, AGuIX and AGuIX-Bi phantoms were constructed with T1-weighted images and maps taken using a 3T clinical MRI scanner. T1-images of A549 inoculated mice were obtained on the same scanner with injection of AGuIX or AGuIX-Bi 2- and 24 hours before imaging. RESULTS:No toxicity was observed because of nanoparticle injection, anesthesia, or irradiation. In both LLC and A549 models, AGuIX-Bi + RT significantly outperformed both saline + RT and AGuIX + RT in reducing tumor growth (P < .05). Median time-to-tumor doubling for AGuIX-Bi + RT compared with AGuIX + RT groups was increased by 160% for A549, and by 60% for LLC models (P < .05). Longitudinal relaxivity constants (r1) derived from phantom T1-mapping were 6.9/mM/s for AGuIX and 8.4/mM/s for AGuIX-Bi. Additionally, T1-weighted mouse tumor imaging showed contrast-to-noise of AGuIX-Bi to be roughly half that of AGuIX. CONCLUSIONS:AGuIX-Bi nanoparticles proved more effective than AGuIX at delaying tumor growth for both NSCLC models while maintaining sufficient MRI contrast at 3T. Replacing some Gd atoms with bismuth improves the efficacy of AGuIX nanoparticles under clinical megavoltage energies without compromising imaging.

This article presents bioconjugates combining nanoparticles (AGuIX) with nanobodies (VHH) targeting Programmed Death-Ligand 1 (PD-L1, A12 VHH) and Cluster of Differentiation 47 (CD47, A4 VHH) for active tumor targeting. AGuIX nanoparticles offer theranostic capabilities and an efficient biodistribution/pharmacokinetic profile (BD/PK), while VHH's reduced size (15 kDa) allows efficient tumor penetration. Site-selective sortagging and click chemistry were compared for bioconjugation. While both methods yielded bioconjugates with similar functionality, click chemistry demonstrated higher yield and could be used for the conjugation of various VHH. The specific targeting of AGuIX@VHH has been demonstrated in both in vitro and ex vivo settings, paving the way for combined targeted immunotherapies, radiotherapy, and cancer imaging.

To mitigate the risk of radioactive isotope dissemination, the development of preventative and curative measures is of particular interest. For mass treatment, the developed solution must be easily administered, preferably orally, with effective, nontoxic decorporating properties against a wide range of radioactive isotopes. Currently, most orally administered chelation therapy products are quickly absorbed into the blood circulation, where chelation of the radioactive isotope is a race against time due to the short circulation half-life of the therapeutic. This report presents an alternative therapeutic approach by using a functionalized chitosan (chitosan@DOTAGA) with chelating properties that remains within the gastrointestinal tract and is eliminated in feces, that can protect against ingested radioactive isotopes. The polymer shows important in vitro chelation properties towards different metallic cations of importance, including (Cs(I), Ir(III), Th(IV), Tl(I), Sr(II), U(VI) and Co(II)), at different pH (from 1 to 7) representing the different environments in the gastrointestinal tract. An in vivo proof of concept is presented on a rodent model of uranium contamination following an oral administration of Chitosan@DOTAGA. The polymer partially prevents the accumulation of uranium within the kidneys (providing a protective effect) and completely prevents its uptake by the spleen.

Focused Ultrasound (FUS) has been shown to sensitize tumors outside the brain to Radiotherapy (RT) through increased ceramide-mediated apoptosis. This study investigated the effects of FUS + RT in healthy rodent brains and F98 gliomas. Tumors, or striata in healthy rats, were targeted with microbubble-mediated, pulsed FUS (220 kHz, 102–444 kPa), followed by RT (4, 8, 15 Gy). FUS + RT (8, 15 Gy) resulted in ablative lesions, not observed with FUS or RT only, in healthy tissue. Lesions were visible using Magnetic Resonance Imaging (MRI) within 72 h and persisted until 21 days post-treatment, indicating potential applications in ablative neurosurgery. In F98 tumors, at 8 and 15 Gy, where RT only had significant effects, FUS + RT offered limited improvements. At 4 Gy, where RT had limited effects compared with untreated controls, FUS + RT reduced tumor volumes observed on MRI by 45–57%. However, survival benefits were minimal (controls: 27 days, RT: 27 days, FUS + RT: 28 days). Histological analyses of tumors 72 h after FUS + RT (4 Gy) showed 93% and 396% increases in apoptosis, and 320% and 336% increases in vessel-associated ceramide, compared to FUS and RT only. Preliminary evidence shows that FUS + RT may improve treatment of glioma, but additional studies are required to optimize effect size.

BACKGROUND:MR-LINAC systems have been increasingly utilized for real-time imaging in adaptive treatments worldwide. Challenges in MR representation of air cavities and subsequent estimation of electron density maps impede planning efficiency and may lead to dose calculation uncertainties.PURPOSE:To demonstrate the generation of accurate electron density maps using the primary MV beam with a flat-panel imager.METHODS:The ViewRay MRIdian MR-LINAC system was modeled digitally for Monte Carlo simulations. Iron shimming, the magnetic field, and the proposed flat panel detector were included in the model. The effect of the magnetic field on the detector response was investigated. Acquisition of projections over 360 degrees was simulated for digital phantoms of the Catphan 505 phantom and a patient treated for Head and Neck cancer. Shim patterns on the projections were removed and detector noise linearity was assessed. Electron density maps were generated for the digital patient phantom using the flat-panel detector and compared with actual treatment planning CT generated electron density maps of the same patient.RESULTS:The effect of the magnetic field on the detector point-spread function (PSF) was found to be substantial for field strengths above 50 mT. Shims correction in the projection images using air normalization and in-painting effectively removed reconstruction artifacts without affecting noise linearity. The relative difference between reconstructed electron density maps from the proposed method and electron density maps generated from the treatment planning CT was 11% on average along all slices included in the iMREDe reconstruction.CONCLUSIONS:The proposed iMREDe technique demonstrated the feasibility of generating accurate electron densities for the ViewRay MRIdian MR-LINAC system with a flat-panel imager and the primary MV beam. This work is a step towards reducing the time and effort required for adaptive radiotherapy in the current ViewRay MR-LINAC systems.

AbstractAGuIX, a novel gadolinium-based nanoparticle, has been deployed in a pioneering double-blinded Phase II clinical trial aiming to assess its efficacy in enhancing radiotherapy for tumor treatment. This paper moves towards this goal by analyzing AGuIX uptake patterns in 23 patients. A phantom was designed to establish the relationship between AGuIX concentration and longitudinal ($${T}_{1}$$ T 1 ) relaxation. A 3T MRI and MP2RAGE sequence were used to generate patient $${T}_{1}$$ T 1 maps. AGuIX uptake in tumors was determined based on longitudinal relaxivity. AGuIX (or placebo) was administered to 23 patients intravenously at 100 mg/kg 1–5 hours pre-imaging. Each of 129 brain metastases across 23 patients were captured in $${T}_{1}$$ T 1 maps and examined for AGuIX uptake and distribution. Inferred AGuIX recipients had average tumor uptakes between 0.012 and 0.17 mg/ml, with a mean of 0.055 mg/ml. Suspected placebo recipients appeared to have no appreciable uptake. Tumors presented with varying spatial AGuIX uptake distributions, suspected to be related to differences in accumulation time and patient-specific bioaccumulation factors. This research demonstrates AGuIX's ability to accumulate in brain metastases, with quantifiable uptake via $${T}_{1}$$ T 1 mapping. Future analyses will extend these methods to complete clinical trial data (~ 134 patients) to evaluate the potential relationship between nanoparticle uptake and possible tumor response following radiotherapy.Clinical Trial Registration Number: NCT04899908.Clinical Trial Registration Date: 25/05/2021.

Stern W, Alaei P, Berbeco R, DeWerd LA, Kamen J, MacKenzie C, Moros EG, Poirier Y, Potter CA, Schaue D, Silvestre Patallo I, Abend M, Swarts S, Trompier F. Achieving Consistent Reporting of Radiation Dosimetry by Adoption of Compatibility in Irradiation Research Protocols Expert Roundtable (CIRPER) Recommendations. Radiat Res. 201, 267-269 (2024). (c) 2024 by Radiation Research Society

Objective . To demonstrate that complete cone beam CT (CBCT) scans from both MV-energy and kV-energy LINAC sources can reduce metal artifacts in radiotherapy guidance, while maintaining standard-of-care x-ray doses levels. Approach . MV-CBCT and kV-CBCT scans are acquired at half normal dose. The impact of lowered dose on MV-CBCT data quality is mitigated by the use of a 4-layer MV-imager prototype and reduced LINAC energy settings (2.5 MV) to improve photon capture. Additionally, the MV-CBCT is used to determine the 3D position and pose of metal implants, which in turn is used to guide model-based poly-energetic correction and interleaving of the kV-CBCT and MV-CBCT data. Certain edge-preserving regularization steps incorporated into the model-based correction algorithm further reduce MV data noise. Main results . The method was tested in digital phantoms and a real pelvis phantom with large 2.5″ spherical inserts, emulating hip replacements of different materials. The proposed method demonstrated an appealing compromise between the high contrast of kV-CBCT and low artifact content of MV-CBCT. Contrast-to-noise improved 3-fold compared to MV-CBCT with a clinical 1-layer architecture at matched dose (37 mGy) and edge blur levels. Visual delineation of the bladder and prostate improved noteably over kV- or MV-CBCT alone. Significance . The proposed method demonstrates that a full MV-CBCT scan can be combined with kV-CBCT to reduce metal artifacts without resorting to complicated beam collimation strategies to limit the MV-CBCT dose contribution. Additionally, significant improvements in CNR can be achieved as compared to metal artifact reduction through current clinical MV-CBCT practices.

Purpose/Objective(s) Dual-energy imaging confers potential advantages including reduced artifacts and material decomposition – e.g. allowing material enhancement for contrast or material suppression to view underlying anatomy better. Spectral separation may be achieved via a dual-layer detector, with beam hardening by the first layer providing the shift in spectra. This approach may offer unique advantages relative to other on-board spectral imaging concepts, in terms of dose savings, motion artifact elimination, and innate view registration. Materials/Methods The first layer of the on-board dual-layer imager (DLI) was designed to be identical to existing detector construction, with a CsI scintillator followed by an aSi TFT photodiode array. This enabled seamless clinical implementation, as standard onboard image guidance was maintained, using the top layer only. The bottom layer has a slightly thicker scintillator to aid in photon detection efficiency given the reduced fluence received after the top layer. The DLI prototype was constructed and underwent rigorous safety testing by a commercial partner prior to clinical integration. The DLI was installed on a clinical Linac with a novel imaging chain in which the top layer only is used for clinical tasks and both layers are read out to a research computer for retrospective analysis. Modulation transfer function (MTF), noise power spectrum, and detective quantum efficiency (DQE) were measured for the top, bottom, and combined layers. Detector imaging performance was further characterized by Leeds, Catphan, and anthropomorphic phantoms. To date, data collection has been performed for more than 20 patients of diverse disease sites. Results Clinical installation of the prototype DLI was completed successfully without any interruption to routine workflow. Phantom measurements confirmed that the top layer MTF and DQE were similar to the commercial single-layer imager which had been replaced. Spatial resolution for the combined-layer images were slightly lower than the top layer only but benefited from increased photon detection efficiency. The patients imaged so far include head & neck, pelvis, extremity, thorax, and CNS. All routine treatment imaging and delivery proceeded as usual without interference from the study. Virtual monoenergetic images were generated from the dual-layer CBCT data using a U-net convolutional neural network. In 2D imaging, log-weighted subtraction of two layers successfully removed bone and metal hardware from resulting images, enabling better tumor visualization. Conclusion A prototype kV DLI was constructed and clinically translated for study under protocol. Combining the layers yields a higher photon detection efficiency with a small loss in resolution. Preliminary clinical results show promise for spectral imaging applications, such as removing ribs to enable better lung tumor imaging. The dual-layer design may be an effective method for adding spectral imaging capabilities to a Linac.