Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck.

Purpose Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. Methods and Materials This prospective first-in-human, multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. Results Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. Conclusions Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings

TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non small cell lung cancer

Background Recent developments in abscopal effect strongly support the use of radiotherapy for the treatment of metastatic disease. However, deeper understanding of the molecular mechanisms underlying the abscopal effect are required to best benefit a larger proportion of patients with metastasis. Several groups including ours, reported the involvement of wild-type (wt) p53 in radiation-induced abscopal effects, however very little is known on the role of wtp53 dependent molecular mechanisms. Methods We investigated through in vivo and in vitro approaches how wtp53 orchestrates radiation-induced abscopal effects. Wtp53 bearing (A549) and p53-null (H1299) NSCLC lines were xenotransplanted in nude mice, and cultured in 2D monolayers and 3D tumor spheroids. Extracellular vesicles (EVs) were isolated from medium cell culture by ultracentrifugation protocol followed by Nanoparticle Tracking Analysis. Gene expression was evaluated by RT-Real Time, digital qRT-PCR, and dot blot technique. Protein levels were determined by immunohistochemistry, confocal anlysis, western blot techniques, and immunoassay. Results We demonstrated that single high-dose irradiation (20 Gy) induces significant tumor growth inhibition in contralateral non-irradiated (NIR) A549 xenograft tumors but not in NIR p53-null H1299 or p53-silenced A549 (A549sh/p53) xenografts. We further demonstrates that irradiation of A549 cells in vitro induces a senescence-associated secretory phenotype (SASP) producing extracellular vesicles (EVs) expressing CD63 and carrying DNA:RNA hybrids and LINE-1 retrotransposon. IR-A549 EVs also hamper the colony-forming capability of recipient NIR A549 cells, induce senescent phenotype, nuclear expression of DNA:RNA hybrids, and M1 macrophage polarization. Conclusions In our models, we demonstrate that high radiation dose in wtp53 tumors induce the onset of SASP and secretion of CD63+ EVs loaded with DNA:RNA hybrids and LINE-1 retrotransposons that convey senescence messages out of the irradiation field triggering abscopal effect in NIR tumors

Cauliflower Mosaic Virus TAV, a Plant Virus Protein That Functions like Ribonuclease H1 and is Cytotoxic to Glioma Cells

Recent comparisons between plant and animal viruses reveal many common principles that underlie how all viruses express their genetic material, amplify their genomes, and link virion assembly with replication. Cauliflower mosaic virus (CaMV) is not infectious for human beings. Here, we show that CaMV transactivator/viroplasmin protein (TAV) shares sequence similarity with and behaves like the human ribonuclease H1 (RNase H1) in reducing DNA/RNA hybrids detected with S9.6 antibody in HEK293T cells. We showed that TAV is clearly expressed in the cytosol and in the nuclei of transiently transfected human cells, similar to its distribution in plants. TAV also showed remarkable cytotoxic effects in U251 human glioma cells in vitro. *ese characteristics pave the way for future analysis on the use of the plant virus protein TAV, as an alternative to human RNAse H1 during gene therapy in human cells

The ImSURE phantoms: a digital dataset for radiomic software benchmarking and investigation

In radiology and oncology, radiomic models are increasingly employed to predict clinical outcomes, but their clinical deployment has been hampered by lack of standardisation. This hindrance has driven the international Image Biomarker Standardisation Initiative (IBSI) to define guidelines for image preprocessing, standardise the formulation and nomenclature of 169 radiomic features and share two benchmark digital phantoms for software calibration. However, to better assess the concordance of radiomic tools, more heterogeneous phantoms are needed. We created two digital phantoms, called ImSURE phantoms, having isotropic and anisotropic voxel size, respectively, and 90 regions of interest (ROIs) each. To use these phantoms, we designed a systematic feature extraction workflow including 919 different feature values (obtained from the 169 IBSI-standardised features considering all possible combinations of feature aggregation and intensity discretisation methods). The ImSURE phantoms will allow to assess the concordance of radiomic software depending on interpolation, discretisation and aggregation methods, as well as on ROI volume and shape. Eventually, we provide the feature values extracted from these phantoms using five open-source IBSI-compliant software

Efficiency and calibration factors for continuous monitoring systems of airborne radioactivity in ducts: Monte Carlo, analytical and experimental approaches compared

In this work a set of calibration constants to measure the 18F airborne activity in straight ducts with square section are computed by means of a Geant4 simulation and provided for different duct lengths. The calibration constants are compared with analytical calculations and experimental measurements. The simulated calibration constants provide a useful cross-check for the actual calibration of airborne monitoring systems in ducts, which is practically complex and can be affected by large uncertainties

Quantitative analysis of synchrotron radiation intravenous angiographic images.

International audienceA medical research protocol on clinical intravenous coronary angiography has been completed at the European Synchrotron Radiation Facility (ESRF) biomedical beamline. The aim was to investigate the accuracy of intravenous coronary angiography based on the K-edge digital subtraction technique for the detection of in-stent restenosis. For each patient, diagnosis has been performed on the synchrotron radiation images and monitored with the conventional selective coronary angiography method taken as the golden standard. In this paper, the methods of image processing and the results of the quantitative analysis are described. Image processing includes beam harmonic contamination correction, spatial deconvolution and the extraction of a 'contrast' and a 'tissue' image from each couple of radiograms simultaneously acquired at energies bracketing the K-edge of iodine. Quantitative analysis includes the estimation of the vessel diameter, the calculation of the absolute iodine concentration profiles along the coronary arteries and the stenosis degree measurement

Quantitative analysis of synchrotron radiation intravenous angiographic images.

International audienceA medical research protocol on clinical intravenous coronary angiography has been completed at the European Synchrotron Radiation Facility (ESRF) biomedical beamline. The aim was to investigate the accuracy of intravenous coronary angiography based on the K-edge digital subtraction technique for the detection of in-stent restenosis. For each patient, diagnosis has been performed on the synchrotron radiation images and monitored with the conventional selective coronary angiography method taken as the golden standard. In this paper, the methods of image processing and the results of the quantitative analysis are described. Image processing includes beam harmonic contamination correction, spatial deconvolution and the extraction of a 'contrast' and a 'tissue' image from each couple of radiograms simultaneously acquired at energies bracketing the K-edge of iodine. Quantitative analysis includes the estimation of the vessel diameter, the calculation of the absolute iodine concentration profiles along the coronary arteries and the stenosis degree measurement

Alpha-Emitter Radiopharmaceuticals and External Beam Radiotherapy: A Radiobiological Model for the Combined Treatment

Previously published studies combined external beam radiotherapy (EBRT) treatments with different activities of 223Ra. The data of two-year overall survival (2y-OS) and neutropenia (TOX) incidence when combining EBRT and 223Ra are not homogeneous in literature. We adapted the linear–quadratic model (LQ) to 223Ra therapy using brachytherapy formalism for a mixture of radionuclides, considering the contribution of all daughter isotopes in the decay chain. A virtual cohort of patients undergoing 223Ra therapy was derived using data from the literature. The doses delivered using 223Ra and EBRT were converted into biologically equivalent doses. Fixed-effect logistic regression models were derived for both the 2y-OS and TOX and compared with available literature. Based on the literature search, four studies were identified to have reported the 223Ra injection activity levels varying from the placebo (0) to 80 kBq/kg, associated or not with EBRT. Logistic regression models revealed a dose-dependent increase in both the 2y-OS (intercept = −1.364; slope = 0.006; p-value ≤ 0.05) and TOX (−5.035; 0.018; ≤0.05) using the EBRT schedule of 8 Gy in 1 fr. Similar results were obtained for other schedules. Discrepancies between our TOX model and those derived for EBRT combined with chemotherapy are discussed. Radiobiological models allow us to estimate dose-dependent relationships, to predict the OS and TOX following combined 223Ra + EBRT treatment, which will guide future treatment optimization

Quantitative accuracy of177Lu SPECT imaging for molecular radiotherapy

The purpose of this study is to investigate the optimal reference geometry for gamma camera calibration. Yet another question of interest was to assess the influence of the number of 3D Ordered Subsets Expectation Maximization (3D-OSEM) updates on activity quantification for SPECT imaging with177Lu. The accuracy of177Lu activity quantification was assessed both in small and in large objects. Two different reference geometries, namely a cylindrical homogeneous phantom and a Jaszczak 16 ml sphere surrounded by cold water, were used to determine the gamma camera calibration factor of a commercial SPECT/CT system. Moreover, the noise level and the concentration recovery coefficient were evaluated as a function of the number of 3D-OSEM updates by using the SPECT/CT images of the reference geometry phantoms and those of a cold Jaszczak phantom with three hot spheres (16ml, 8ml and 4ml), respectively. The optimal choice of the number of 3D-OSEM updates was based on a compromise between the noise level achievable in the reconstructed SPECT images and the concentration recovery coefficients. The quantitative accuracy achievable was finally validated on a test phantom, where a spherical insert composed of two concentric spheres was used to simulate a lesion in a warm background. Our data confirm and extend previous observations. Using the calibration factor obtained with the cylindrical homogeneous phantom and the Jaszczak 16 ml sphere, the recovered activity in the test phantom was underestimated by -16.4% and -24.8%, respectively. Our work has led us to conclude that gamma camera calibration performed with large homogeneous phantom outperforms calibration executed with the Jaszczak 16ml sphere. Furthermore, the results obtained support the assumption that approximately 50 OSEM updates represent a good trade-off to reach convergence in small volumes, meanwhile minimizing the noise level