PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC).

BACKGROUND: Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy. MATERIAL AND METHODS: Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68 Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons. RESULTS: A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered. CONCLUSIONS: PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies.

SARS-CoV-2 S Protein Reduces Cytoprotective Defenses and Promotes Human Endothelial Cell Senescence.

Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-ß galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.

A Phase II Trial of Stereotactic Body Radiation Therapy and Androgen Deprivation for Oligometastases in Prostate Cancer (SBRT-SG 05).

PURPOSE: SBRT-Spanish Group-05 (ClinicalTrials.gov.Identifier: NCT02192788) is a collaborative (SBRT-SG, Grupo de Investigación Clínica en Oncología Radioterápica, and Sociedad Española de Oncología Radioterápica) prospective multicenter phase II trial testing stereotactic body radiation therapy (SBRT) and androgen deprivation therapy (ADT) in patients with oligorecurrent prostate cancer. METHODS AND MATERIALS: Two cohorts of patients with prostate cancer in an oligorecurrent stage (hormone-sensitive in the principal cohort and castration-resistant in the exploratory cohort) were assigned to receive ADT and SBRT for at least 24 months from the time of the enrollment. Concomitant treatment with chemotherapy, abiraterone, or enzalutamide was not allowed. Oncologic outcomes were assessed in both cohorts. Toxicity was prospectively analyzed. RESULTS: From 2014 to 2019, 81 patients with a total of 126 lesions from 14 centers met the inclusion criteria, 14 of whom were castration-resistant. With a median follow-up of 40 months (12-58 months), 3-year local recurrence-free survival was 92.5% (95% CI, 79.9%-96.3%) and 85.7% (95% CI, 48.2%-95.6%) in the principal and exploratory cohorts, respectively. In the principal cohort, biochemical relapse-free survival and metastasis progression-free survival at 1, 2, and 3 years were 91% (95% CI, 81%-95.8%), 73.7% (95% CI, 61.1%-82.8%), 50.6% (95% CI, 36.2%-63.3%), and 92% (95% CI, 83%-97%), 81% (95% CI, 70%-89%), and 67% (95% CI, 53%-77%), respectively. In the exploratory cohort, metastasis progression-free survival at 1, 2, and 3 years was 64% (95% CI, 34%-83%), 43% (95% CI, 18%-66%), and 26% (95% CI, 7%-51%), respectively. None of the patients developed grade III or higher toxicity or symptoms related to local progression, and only 2 (2.4%) patients developed grade II toxicity. CONCLUSIONS: The combination of SBRT and ADT is safe and shows favorable clinical outcomes in patients with hormone-sensitive and castration-resistant prostate cancer. Validation studies are needed in patients with castration-resistant prostate cancer.

Technical recommendations for implementation of Volumetric Modulated Arc Therapy and Helical Tomotherapy Total Body Irradiation.

As a component of myeloablative conditioning before allogeneic hematopoietic stem cell transplantation (HSCT), Total Body Irradiation (TBI) is employed in radiotherapy centers all over the world. In recent and coming years, many centers are changing their technical setup from a conventional TBI technique to multi-isocenter conformal arc therapy techniques such as Volumetric Modulated Arc Therapy (VMAT) or Helical Tomotherapy (HT). These techniques allow better homogeneity and control of the target prescription dose, and provide more freedom for individualized organ-at-risk sparing. The technical design of multi-isocenter/multi-plan conformal TBI is complex and should be developed carefully. A group of early adopters with conformal TBI experience using different treatment machines and treatment planning systems came together to develop technical recommendations and share experiences, in order to assist departments wishing to implement conformal TBI, and to provide ideas for standardization of practices.

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus.

Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.

Intervenciones educativas en asma infantil: Una revisión sistemática / Educational interventions in childhood asthma: A systematic review

Objetivo: Analizar intervenciones educativas en pacientes pediátricos asmáticos para conseguir una técnica adecuada de inhalación y mejorar su automanejo. Diseño: Revisión sistemática basándose en las recomendaciones PRISMA. Fuentes de datos: Se revisaron las bases de datos PubMed, Scopus, Cuiden, Web of Science y Google académico. Selección de estudios: Se incluyeron 16 artículos publicados entre 2014-2021, con acceso a texto completo, idiomas: inglés, francés y español y población pediátrica: 0-18 años. Extracción de datos: Participaron 2.313 niños/as. Las variables analizadas fueron: nivel asistencial, tipo de intervención, realización correcta de la técnica de inhalación, seguimiento de la técnica, entrega de recomendaciones por escrito, categoría profesional-educador, variables relacionadas con la patología respiratoria, absentismo escolar, calidad de vida y costes económicos. Resultados: El nivel de atención sanitaria fue atención primaria, hospitalaria y comunitaria, donde destacaron como educadores: médicos especialistas, enfermeras y farmacéuticos. Las intervenciones educativas más prevalentes son demostración in situ y entrega de recomendaciones o intervenciones multimedia. Varios artículos reportan que no se realiza correctamente la educación en asma, otros enuncian que su técnica mejora tras la intervención, pero la mayoría de ellos resalta la importancia de una revisión periódica de la técnica. Conclusiones: Los autores refieren mejoría de la técnica de inhalación en todas ellas, así como un mayor automanejo de la enfermedad y adherencia al tratamiento. Es necesario intensificar la educación a los pacientes en el correcto manejo de los dispositivos, y el seguimiento y revisión posterior para optimizar el control de la enfermedad.(AU)

Objective: To analyze educational interventions in pediatric asthmatic patients to achieve an adequate inhalation technique and improve their self-management. Design: Systematic review based on the PRISMA recommendations. Data sources: Pubmed, Scopus, Cuiden, Web of Science and Google Scholar databases were reviewed. Study selection: Sixteen articles published between 2014 and 2021 were included, with access to full text, languages: English, French and Spanish and pediatric population: 0–18 years. Data extraction: Two thousand three hundred and thirteen children were participated. The variables analyzed were: level of care, type of intervention, correct performance of the inhalation technique, follow-up of the technique, delivery of written recommendations, professional-educator category, variables related to respiratory pathology, school absenteeism, quality of life and economic costs. Results: The health care level was primary, hospital and community care, where specialist doctors, nurses and pharmacists stood out as educators. The most prevalent educational interventions are on-site demonstration and delivery of recommendations or multimedia interventions. Several articles report that asthma education is not carried out correctly, others state that their technique improves after the intervention, but most of them highlight the importance of periodic review of the technique. Conclusions: The authors report improvement in the inhalation technique in all of them, as well as greater self-management of the disease and adherence to treatment. It is necessary to intensify the education of patients in the correct handling of the devices, and the follow-up and subsequent review to optimize the control of the disease.(AU)

SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.

BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.

[Educational interventions in childhood asthma: A systematic review]. / Intervenciones educativas en asma infantil: Una revisión sistemática.

OBJECTIVE: To analyze educational interventions in pediatric asthmatic patients to achieve an adequate inhalation technique and improve their self-management. DESIGN: Systematic review based on the PRISMA recommendations. DATA SOURCES: Pubmed, Scopus, Cuiden, Web of Science and Google Scholar databases were reviewed. STUDY SELECTION: Sixteen articles published between 2014 and 2021 were included, with access to full text, languages: English, French and Spanish and pediatric population: 0-18 years. DATA EXTRACTION: Two thousand three hundred and thirteen children were participated. The variables analyzed were: level of care, type of intervention, correct performance of the inhalation technique, follow-up of the technique, delivery of written recommendations, professional-educator category, variables related to respiratory pathology, school absenteeism, quality of life and economic costs. RESULTS: The health care level was primary, hospital and community care, where specialist doctors, nurses and pharmacists stood out as educators. The most prevalent educational interventions are on-site demonstration and delivery of recommendations or multimedia interventions. Several articles report that asthma education is not carried out correctly, others state that their technique improves after the intervention, but most of them highlight the importance of periodic review of the technique. CONCLUSIONS: The authors report improvement in the inhalation technique in all of them, as well as greater self-management of the disease and adherence to treatment. It is necessary to intensify the education of patients in the correct handling of the devices, and the follow-up and subsequent review to optimize the control of the disease.

Does choice change preferences? An incentivized test of the mere choice effect.

Widespread evidence from psychology and neuroscience documents that previous choices unconditionally increase the later desirability of chosen objects, even if those choices were uninformative. This is problematic for economists who use choice data to estimate latent preferences, demand functions, and social welfare. The evidence on this mere choice effect, however, exhibits serious shortcomings which prevent evaluating its possible relevance for economics. In this paper, we present a novel, parsimonious experimental design to test for the economic validity of the mere choice effect addressing these shortcomings. Our design uses well-defined, monetary lotteries, all decisions are incentivized, and we effectively randomize participants' initial choices without relying on deception. Results from a large, pre-registered online experiment find no support for the mere choice effect. Our results challenge conventional wisdom outside economics. The mere choice effect does not seem to be a concern for economics, at least in the domain of decision making under risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s10683-021-09728-5.

Ageism and nursing students, past or reality?: A systematic review.

OBJECTIVE: This systematic review aimed to summarise and update existing knowledge about ageism among nursing students through the following research question: what is the perception and attitudes of ageism among student nurses? DESIGN: A systematic review of longitudinal and cross-sectional studies of ageism in nursing students was carried out. DATA SOURCES: The literature search was conducted in the scientific databases Pubmed and Scopus in February 2021. REVIEW METHODS: After the screening process, 22 studies meeting the selection criteria were selected; 8 more were identified after manually searching the selected paper' reference lists. A total of 30 studies were included in the review. The JBI Critical Appraisal Checklists for Analytical Cross-Sectional studies and for Cohort Studies were used to appraise the articles' quality. RESULTS: There was large variability in the manifestation of ageism among student nurses, as well as in the instruments used for assessment. Most of the articles analysed attitudes towards old age, the majority of which were positive. Being a female student, being on the final year of study and having regular contact or cohabitation with an older adult were three of the main determinants in the expression of positive attitudes towards the elderly. CONCLUSIONS: Our findings suggest that student nurses generally have positive attitudes towards old age, although ageist beliefs and discriminatory behaviours were identified and should be studied in greater depth. Training programs for future care professionals have a responsibility to educate from a non-stereotypical perspective based on current societal needs.

Translation, Cultural Adaptation and Validation of the Nurses Self-Concept Instrument (NSCI) to Spanish.

Professional self-concept in nurses is understood as the way nurses think and feel about themselves in their nursing role and is both a predictor of quality of care and a protective factor against burnout. The aim of this study was to translate, culturally adapt and validate the Spanish version of the Nurses Self-Concept Instrument in a sample of 483 Spanish registered nurses. In addition, we analyzed gender differences in its dimensions in the same sample. Internal reliability was evaluated using Cronbach's Alpha, while construct validity was assessed using both exploratory and confirmatory factor analysis. The differences between groups were analyzed using the Mann-Whitney U test. Factor distribution was different from the original model. A gender gap was observed in the Nurse Thinking and Perception of Capabilities dimensions with higher values in the women group, while in the Leadership dimension, higher values were observed in the men group. While the Spanish version of the Nurses Self-Concept Instrument is a valid and reliable tool to measure this construct, the differences in its dimensions lead to a deeper understanding of the cultural differences in the construction of professional self-concept.

Dosimetric characterization of a novel commercial plastic scintillation detector with an MR-Linac.

BACKGROUND: Plastic scintillators have been used as radiation detectors for the past few years, as they are water-equivalent and independent of the dose, dose rate, and angle of incidence. In addition, they are also independent of the presence of a magnetic field and could be used for in vivo dosimetry in an MR-Linac. With the advent of a new commercial scintillation detector, Blue Physics Model 10, its characterization has been performed on an MR-Linac with a view to future applications. PURPOSE: To perform the dosimetric characterization and study potential applications of a novel commercial plastic scintillation detector in a MR-Linac. METHODS: Scintillation detector description, calibration procedure, short-term repeatability, dose-response linearity, dose-rate dependence, angular dependence, and temperature dependence have been studied. Percent-depth-dose (PDD) and beam profiles were measured for small fields and a standard field, as well as output factors, for comparison with other PTW detectors: a diamond diode and PinPoint and Semiflex 3D ionization chambers. The suitability of the plastic scintillator for in vivo dosimetry in a magnetic field has also been studied measuring the dose to a point in an anthropomorphic phantom while acquiring MR imaging. This measured dose was compared with that calculated with Monaco planning system and with that measured with a PTW Semiflex 3D chamber, the latter without acquiring MR images. RESULTS: Short-term repeatability presented negligible variations (<0.4%) for 100 and 20 MU. Similar results were obtained for dose-response linearity and dose-rate dependence. A small angular dependence was determined, while the scintillator resulted practically independent of the temperature. PDDs showed excellent agreement except in the build-up region, and calculated penumbras with the profiles given by the scintillator were between the ones obtained with the diamond detector and the PinPoint ionization chamber. Measured OF with the scintillator were the highest between all detectors, 1.26% higher than the value obtained with the microdiamond for the smallest field measured, 0.5 × 0.5 cm2 . Finally, the total dose to a point measured with the scintillator was 0.51% higher compared to that calculated by the planning system. CONCLUSION: The Blue Physics model 10 scintillation system showed excellent dosimetric characteristics. Its response independent of the temperature and the presence of a magnetic field make it suitable for in vivo dosimetry in an MR-Linac while acquiring MR images, which could solve the impossibility of performing a dosimetric QA for each adapted plan. Furthermore, its temporal resolution allows independent radiation pulses to be measured and visualized, which could be used in future applications.

Evolution of dosimetric treatment planning for pediatric total lymphoid irradiation (TLI): a single-institution experience.

Background: Total lymphoid irradiation (TLI) is a conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which may reduce long-term toxicities attributed to other techniques, such as total body irradiation (TBI). At our institution, TLI treatments were first planned with the three-dimensional conformal radiation therapy (3D-CRT) technique and later with volumetric modulated arc therapy (VMAT). With the recent availability of a basic helical tomotherapy (HT), the possible dosimetric gain of the latter for TLI is studied. Materials and methods: 22 pediatric patients were planned for VMAT and HT, prescribed to 8 Gy in 4 fractions. VMAT was planned with template based on a single cost function, using the Monaco treatment planning system (TPS). HT plans were planned using Accuray Precision TPS for a basic HT without the dynamic jaws feature or VOLO-Ultra algorithm. Plan quality was analyzed based on four quality indices, mean and maximum doses to planning target volume (PTV) and organs at risk (OARs), dose gradient and integral doses. Differences were analyzed with Wilcoxon signed-rank test. Results: HT plans resulted in improved conformity (CI) and homogeneity indices (HI) (p < 0.05) but less steep dose gradient (p = 0.181). VMAT plans created larger areas with high doses within the PTV, while comparable doses to OARs, except mainly for the spinal marrow, for which a reduction of 37.7% in D2% was obtained (p < 0.05). Integral dose for non-tumor tissue was 11.3% lower with the VMAT template (p < 0.05). Conclusion: HT achieves better conformity and homogeneity even without its more advanced features. Nevertheless, the VMAT template achieves dosimetric results close to those of HT, both with similar clinical outcome.

Ethical allocation of scarce vaccine doses: The Priority-Equality protocol.

Background: Whenever vaccines for a new pandemic or widespread epidemic are developed, demand greatly exceeds the available supply of vaccine doses in the crucial, initial phases of vaccination. Rationing protocols must then fulfill a number of ethical principles balancing equal treatment of individuals and prioritization of at-risk and instrumental subpopulations. For COVID-19, actual rationing methods used a territory-based first allocation stage based on proportionality to population size, followed by locally-implemented prioritization rules. The results of this procedure have been argued to be ethically problematic. Methods: We use a formal-analytical approach arising from the mathematical social sciences which allows to investigate whether any allocation methods (known or unknown) fulfill a combination of (ethical) desiderata and, if so, how they are formulated algorithmically. Results: Strikingly, we find that there exists one and only one method that allows to treat people equally while giving priority to those who are worse off. We identify this method down to the algorithmic level and show that it is easily implementable and it exhibits additional, desirable properties. In contrast, we show that the procedures used during the COVID-19 pandemic violate both principles. Conclusions: Our research delivers an actual algorithm that is readily applicable and improves upon previous ones. Since our axiomatic approach shows that any other algorithm would either fail to treat people equally or fail to prioritize those who are worse off, we conclude that ethical principles dictate the adoption of this algorithm as a standard for the COVID-19 or any other comparable vaccination campaigns.

Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies.

INTRODUCTION: The clinical practice and outcome results of intraoperative electron radiation therapy (IOeRT) in cancer patients have been extensively reported over 4 decades. Electron beams can be delivered in the promising FLASH dose rate. METHODS AND MATERIALS: Several cancer models were approached by two alternative radiobiological strategies to optimize local cancer control: boost versus exclusive IOeRT. Clinical outcomes are revisited via a bibliometric search performed for the elaboration of ESTRO/ACROP IORT guidelines. RESULTS: In the period 1982 to 2020, a total of 19,148 patients were registered in 116 publications concerning soft tissue sarcomas (9% of patients), unresected and borderline-resected pancreatic cancer (22%), locally recurrent and locally advanced rectal cancer (22%), and breast cancer (45%). Clinical outcomes following IOeRT doses in the range of 10 to 25 Gy (with or without external beam fractionated radiation therapy) show a wide range of local control from 40 to 100% depending upon cancer site, histology, stage, and treatment intensity. Constraints for normal tissue tolerance are important to maintain tumor control combined with acceptable levels of side effects. CONCLUSIONS: IOeRT represents an evidence-based approach for several tumor types. A specific risk analysis for local recurrences supports the identification of cancer models that are candidates for FLASH studies.

Resolvin E1 attenuates doxorubicin-induced cardiac fibroblast senescence: A key role for IL-1ß.

Cardiac fibroblasts (CFs) undergo senescence in reaction to different stressors, leading to a poor prognosis of cardiac disease. Doxorubicin (Doxo) is an antineoplastic drug with strong cardiotoxic effects, which induces IL-1ß secretion and thus, triggers a potent pro-inflammatory response. Doxo induces CFs senescence; however, the mechanisms are not fully understood. Different pharmacological strategies have been used to eliminate senescent cells by inducing their apoptosis or modifying their secretome. However, Resolvin E1 (RvE1), a lipid derivative resolutive mediator with potent anti-inflammatory effects has not been used before to prevent CFs senescence. CFs were isolated from adult male C57BL/6J mice and subsequently stimulated with Doxo, in the presence or absence of RvE1. Senescence-associated ß-galactosidase activity (SA-ß-gal), γ-H2A.X, p53, p21, and senescence-associated secretory phenotype (SASP) were evaluated. The involvement of the NLRP3 inflammasome/interleukin-1 receptor (IL-1R) signaling pathway on CFs senescence was studied using an NLRP3 inhibitor (MCC950) and an endogenous IL-1R antagonist (IR1A). Doxo is able to trigger CFs senescence, as evidenced by an increase of γ-H2A.X, p53, p21, and SA-ß-gal, and changes in the SASP profile. These Doxo effects were prevented by RvE1. Doxo triggers IL-1ß secretion, which was dependent on NLRP3 activation. Doxo-induced CFs senescence was partially blocked by MCC950 and IR1A. In addition, IL-1ß also triggered CFs senescence, as evidenced by the increase of γ-H2A.X, p53, p21, SA-ß-gal activity, and SASP. All these effects were also prevented by RvE1 treatment. CONCLUSION: These data show the anti-senescent role of RvE1 in Doxo-induced CFs senescence, which could be mediated by reducing IL-1ß secretion.

Angiotensin II Triggers NLRP3 Inflammasome Activation by a Ca2+ Signaling-Dependent Pathway in Rat Cardiac Fibroblast Ang-II by a Ca2+-Dependent Mechanism Triggers NLRP3 Inflammasome in CF.

Angiotensin II (Ang-II) is a widely studied hypertensive, profibrotic, and pro-inflammatory peptide. In the heart, cardiac fibroblasts (CF) express type 1 angiotensin II receptors (AT1R), Toll-like receptor-4 (TLR4), and the NLRP3 inflammasome complex, which play important roles in pro-inflammatory processes. When activated, the NLRP3 inflammasome triggers proteolytic cleavage of pro-IL-1, resulting in its activation. However, in CF the mechanism by which Ang-II assembles and activates the NLRP3 inflammasome remains not fully known. To elucidate this important point, we stimulated TLR4 receptors in CF and evaluated the signaling pathways by which Ang-II triggers the assembly and activity. In cultured rat CF, pro-IL-1ß levels, NLRP3, ASC, and caspase-1 expression levels were determined by Western blot. NLRP3 inflammasome complex assembly was analyzed by immunocytochemistry, whereas by ELISA, we analyzed NLRP3 inflammasome activity and [Formula: see text] release. In CF, Ang-II triggered NLRP3 inflammasome assembly and caspase-1 activity; and in LPS-pretreated CF, Ang-II also triggered [Formula: see text] secretion. These effects were blocked by losartan (AT1R antagonist), U73221 (PLC inhibitor), 2-APB (IP3R antagonist), and BAPTA-AM (Ca2+ chelator) indicating that the AT1R/PLC/IP3R/Ca2+ pathway is involved. Finally, bafilomycin A1 prevented Ang-II-induced [Formula: see text] secretion, indicating that a non-classical protein secretion mechanism is involved. These findings suggest that in CF, Ang-II by a Ca2+-dependent mechanism triggers NLRP3 inflammasome assembly and activation leading to [Formula: see text] secretion through a non-conventional protein secretion mechanism.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children.

BACKGROUND AND PURPOSE: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Resolvin E1 attenuates doxorubicin-induced endothelial senescence by modulating NLRP3 inflammasome activation.

Endothelial cell senescence contributes to chronic inflammation and endothelial dysfunction, while favoring cardiovascular disorders and frailty. Senescent cells acquire a pro-inflammatory secretory phenotype that further propagates inflammation and senescence to neighboring cells. Cell senescence can be provoked by plethora of stressors, including inflammatory molecules and chemotherapeutic drugs. Doxorubicin (Doxo) is a powerful anthracycline anticancer drug whose clinical application is constrained by a dose-limiting cardiovascular toxicity. We here investigated whether cell senescence can contribute to the vascular damage elicited by Doxo. In human umbilical vein endothelial cells (HUVEC) cultures, Doxo (10-100 nM) increased the number of SA-ß-gal positive cells and the levels of γH2AX, p21 and p53, used as markers of senescence. Moreover, we identified Doxo-induced senescence to be mediated by the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, a key player of the immune innate system capable of releasing interleukin (IL)-1ß. In fact, IL-1ß itself mimicked the stimulatory action of Doxo on both NLRP3 activation and cellular senescence, while the pharmacological blockade of IL-1 receptors markedly attenuated the pro-senescence effects of Doxo. In search of additional pharmacological strategies to attenuate Doxo-induced endothelial senescence, we identified resolvin E1 (RvE1), an endogenous pro-resolving mediator, as capable of reducing cell senescence induced by both Doxo and IL-1ß by interfering with the increased expression of pP65, NLRP3, and pro-IL-1ß proteins and with the formation of active NLRP3 inflammasome complexes. Overall, RvE1 and the blockade of the NLRP3 inflammasome-IL-1ß axis may offer a novel therapeutic approach against Doxo-induced cardiovascular toxicity and subsequent sequelae.