Pathways Related to NLRP3 Inflammasome Activation Induced by Gold Nanorods

Gold; Inflammation; NanorodOro; Inflamación; NanorodOr; Inflamació; NanorodThe widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to ENM through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. Recently, anisotropic ENM have become of increasing interest, but knowledge of their effects on the immune system is still limited. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC- or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres, and, thus, also different surface chemistries, to assess NLRP3 inflammasome activation. Next, the exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC- or NLRP3-deficient cells did not show this effect. Gene Set Enrichment Analysis revealed that gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. At the level of individual genes, downregulation of Paraoxonase-2, a protein that controls oxidative stress, was most notable. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation. Future studies should include particle uptake and intracellular localization.This research was funded by the EU FP7 project FutureNanoNeeds (GA N° 604602), RIVM, and VITO

The European Organisation for Research and Treatment of Cancer, State of Science in radiation oncology and priorities for clinical trials meeting report

Background: New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers. Methods: Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development. Conclusions: Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology. (C) 2020 The Authors. Published by Elsevier Ltd

ESA's Ice Sheets CCI: validation and inter-comparison of surface elevation changes derived from laser and radar altimetry over Jakobshavn Isbræ, Greenland – Round Robin results

In order to increase the understanding of the changing climate, the European Space Agency has launched the Climate Change Initiative (ESA CCI), a program which joins scientists and space agencies into 13 projects either affecting or affected by the concurrent changes. This work is part of the Ice Sheets CCI and four parameters are to be determined for the Greenland Ice Sheet (GrIS), each resulting in a dataset made available to the public: Surface Elevation Changes (SEC), surface velocities, grounding line locations, and calving front locations. All CCI projects have completed a so-called Round Robin exercise in which the scientific community was asked to provide their best estimate of the sought parameters as well as a feedback sheet describing their work. By inter-comparing and validating the results, obtained from research institutions world-wide, it is possible to develop the most optimal method for determining each parameter. This work describes the SEC Round Robin and the subsequent conclusions leading to the creation of a method for determining GrIS SEC values. The participants used either Envisat radar or ICESat laser altimetry over Jakobshavn Isbræ drainage basin, and the submissions led to inter-comparisons of radar vs. altimetry as well as cross-over vs. repeat-track analyses. Due to the high accuracy of the former and the high spatial resolution of the latter, a method, which combines the two techniques will provide the most accurate SEC estimates. The data supporting the final GrIS analysis stem from the radar altimeters on-board Envisat, ERS-1 and ERS-2. The accuracy of laser data exceeds that of radar altimetry; the Round Robin analysis has, however, proven the latter equally capable of dealing with surface topography thereby making such data applicable in SEC analyses extending all the way from the interior ice sheet to margin regions. This shows good potential for a~future inclusion of ESA CryoSat-2 and Sentinel-3 radar data in the analysis, and thus for obtaining reliable SEC estimates throughout the entire GrIS

Re-irradiation in clinical practice:Results of an international patterns of care survey within the framework of the ESTRO-EORTC E²-RADIatE platform

Background: Re-irradiation is an increasingly utilized treatment for recurrent, metastatic or new malignancies after previous radiotherapy. It is unclear how re-irradiation is applied in clinical practice. We aimed to investigate the patterns of care of re-irradiation internationally. Material/Methods: A cross-sectional survey conducted between March and September 2022. The survey was structured into six sections, each corresponding to a specific anatomical region. Participants were instructed to complete the sections of their clinical expertise. A total of 15 multiple-choice questions were included in each section, addressing various aspects of the re-irradiation process. The online survey targeted radiation and clinical oncologists and was endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC).Results: 371 physicians from 55 countries across six continents participated. Participants had a median professional experience of 16 years, and the majority (60%) were affiliated with an academic hospital. The brain region was the most common site for re-irradiation (77%), followed by the pelvis (65%) and head and neck (63%). Prolonging local control was the most common goal (90–96% across anatomical regions). The most common minimum interval between previous radiotherapy and re-irradiation was 6–12 months (45–55%). Persistent grade 3 or greater radiation-induced toxicity (77–80%) was the leading contraindication. Variability in organs at risk dose constraints for re-irradiation was observed. Advanced imaging modalities and conformal radiotherapy techniques were predominantly used. A scarcity of institutional guidelines for re-irradiation was reported (16–19%). Participants from European centers more frequently applied thoracic and abdominal re-irradiation. Indications did not differ between academic and non-academic hospitals. Conclusion: This study highlights the heterogeneity in re-irradiation practices across anatomical regions and emphasizes the need for high-quality evidence from prospective studies to guide treatment decisions and derive safe cumulative dose constraints.</p

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer:Two externally validated nomograms

Introduction Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. Methods 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n = 214, patients treated in one hospital) and an external validation cohort n = 281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3 months) and long-term survival (>12 months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. Results Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p < 0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC = 0.70 versus range AUCs = 0.51–0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1 year survival statistically significantly better (p < 0.05) than the favorable groups of four models (range AUCs = 0.57–0.61), except for the SIR (AUC = 0.64, p = 0.34). The models are available on www.predictcancer.org. Conclusion The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice

Dosimetric consequences of the shift towards computed tomography guided target definition and planning for breast conserving radiotherapy

Background: The shift from conventional two-dimensional (2D) to three-dimensional (3D)conformal target definition and dose-planning seems to have introduced volumetric as well as geometric changes. The purpose of this study was to compare coverage of computed tomography (CT)-based breast and boost planning target volumes (PTV), absolute volumes irradiated, and dose delivered to the organs at risk with conventional 2D and 3D-conformal breast conserving radiotherapy. Methods: Twenty-five patients with left-sided breast cancer were subject of CT-guided target definition and 3D-conformal dose-planning, and conventionally defined target volumes and treatment plans were reconstructed on the planning CT. Accumulated dose-distributions were calculated for the conventional and 3D-conformal dose-plans, taking into account a prescribed dose of 50 Gy for the breast plans and 16 Gy for the boost plans. Results: With conventional treatment plans, CT-based breast and boost PTVs received the intended dose in 78% and 32% of the patients, respectively, and smaller volumes received the prescribed breast and boost doses compared with 3D-conformal dose-planning. The mean lung dose, the volume of the lungs receiving > 20 Gy, the mean heart dose, and volume of the heart receiving > 30 Gy were significantly less with conventional treatment plans. Specific areas within the breast and boost PTVs systematically received a lower than intended dose with conventional treatment plans. Conclusion: The shift towards CT-guided target definition and planning as the golden standard for breast conserving radiotherapy has resulted in improved target coverage at the cost of larger irradiated volumes and an increased dose delivered to organs at risk. Tissue is now included into the breast and boost target volumes that was never explicitly defined or included with conventional treatment. Therefore, a coherent definition of the breast and boost target volumes is needed, based on clinical data confirming tumour control probability and normal tissue complication probability with the use of 3D-conformal radiotherapy

Myocardial perfusion imaging with 99 mTc - tetrofosmin SPECT in breast cancer patients that received postoperative radiotherapy: a case-control study

<p>Abstract</p> <p>Purpose</p> <p>To evaluate the cardiac toxicity of radiotherapy (RT) in breast cancer (BC) patients employing myocardial perfusion imaging (MPI) with Tc-99 m Tetrofosmin - single photon emission computer tomography (T-SPECT).</p> <p>Materials and methods</p> <p>We studied 46 BC female patients (28 patients with left and 18 patients with right BC) treated with postoperative RT compared to a control group of 85 age-matched females. The median time of RT to SPECT was 40 months (6-263).</p> <p>Results</p> <p>Abnormalities in the summed stress score (SSS) were found in 54% of left BC patients, 44.4% of right BC patients, and 32.9% of controls. In left BC patients there were significantly more SSS abnormalities compared to controls (4.0 ± 3.5 vs 2.6 ± 2.0, p = 0.05) and possible trend of increased abnormalities of right BC patients (3.7 ± 3.0 vs 2.6 ± 2.0, p = 0.14). Multiple regression analysis showed more abnormalities in the MPI of left BC patients compared to controls (SSS, p = 0.0001); Marginal toxicity was also noted in right BC patients (SSS, p = 0.045). No additional toxicity was found in patients that received adjuvant cardiotoxic chemotherapy. All T-SPECT abnormalities were clinically silent.</p> <p>Conclusion</p> <p>The study suggests that radiation therapy to BC patients result in MPI abnormalities but without apparent clinical consequences.</p

Sentinel Node Identification Rate and Nodal Involvement in the EORTC 10981-22023 AMAROS Trial

Background The randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement. Methods The first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed. Results In 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively. Conclusions With a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar—both were 18%