Age is one of the most important prognostic factors associated to lethality in SARS-CoV-2 infection. In multivariate analysis, advanced age was an independent risk factor for death. Recent studies ...suggest a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome activation in lung inflammation and fibrosis in SARS-CoV and SARS-CoV-2 infections. Increased NLRP3/apoptosis-associated speck-like protein (ASC) mRNA expression and increased caspase-1 activity, have been observed in aged lung, provoking increased and heightened expression levels of mature Interleukin (IL)-1beta and IL-18 in aged individuals. Aged individuals have a basal predisposition to over-react to infection, displaying an increased hyper-inflammatory cascade, that seems not to be fully physiologically controlled. NLRP3 inflammasome is over-activated in aged individuals, through deficient mitochondrial functioning, increased mitochondrial Reactive Oxigen Species (mtROS) and/or mitochondrial (mt)DNA, leading to a hyper-response of classically activated macrophages and subsequent increases in IL-1 beta. This NLRP3 over-activated status in elderly individuals, is also observed in telomere dysfunctional mice models. In our opinion, the NLRP3 inflammasome plays a central role in the increased lethality observed in elderly patients infected by COVID-19. Strategies blocking inflammasome would deserve to be studied. Key words: NLRP3, inflammasome, age, COVID-19, pneumonia
•SARS-CoV-2 pneumonia severely ill patients, develop a systemic inflammatory response characterized by a sudden increase in several pro-inflammatory cytokines, mainly IL-1, IL-6 and TNF-alfa by ...activated M1 macrophages.•COVID-19 patients, develop a systemic cytokine inflammatory response Drug blockade of IL-6/IL-1 and respirator equipment is not offered to all patients.•Low dose radiotherapy (0,5 Gy), is an evidence-based anti-inflammatory treatment LDRT that could modify the immune landscape in the affected lung.•LDRT is a cost-effective non-toxic treatment available in most general hospitals.
The COVID-19 pandemia is affecting people worldwide. Most of the patients suffered of a respiratory disease that will progress to an acute respiratory distress syndrome (ARDS). SARS-CoV-2 pneumonia severely ill patients, develop a systemic inflammatory response with a Cytokine Release Syndrome (CRS), that is characterized by a sudden increase in several pro-inflammatory cytokines, mainly IL-1, IL-6 and TNF-alfa by activated macrophages (M1 phenotype). Blocking IL-6 with tocilizumab and using respirator equipment seems to be a very important issue in this (SARS-CoV-2) pneumonia, but not all patients are referred to such treatments.
Low dose radiotherapy (0,5 Gy), is an evidence-based anti-inflammatory treatment, that could modify the immune landscape in the lung affected of SARS-CoV-2 pneumonia, through macrophages polarization to alternatively activated Macrophages (M2 phenotype). Radiation-induced cancer risk could be assumed due to the very low dose used, the advanced age of the patients and the life-threatening condition of SARS-Cov2 pneumonia.
LDRT is a cost-effective non-toxic treatment already available in most general hospitals. This fact allows that it would be used for the large number of patients that will suffer this disease, and that would not receive specific anti-IL-6 treatments in ICUs in low and middle income countries.
Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition ...of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination.
MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review.
Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone.
The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.
•LDRT shows clinical response for COVID-19-induced pneumonia and ARDS via Nrf-2.•Nrf2-activation creates optimal redox environment for anti-inflammatory phenotype.•Nrf2-mediated response suppresses ...cytokine storm preventing COVID-19 deaths.•Activation of Nrf2 is highly dose dependent and conforms to a hormetic response.•LDRT can be regarded as safe and effective for use at any stage of COVID-19.
Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5–1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose–response. At the cellular and subcellular levels, hormetic doses of <1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations—and the historical clinical success of LDRT early in the 20th century—we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.
The percentage of patients with metastatic non-small cell lung cancer (NSCLC) and melanoma who benefit from anti-programmed cell death protein 1 (anti-PD-1) is low owing to resistance mechanisms. ...SABR has a role in oligoprogressive disease and can improve responses to anti-PD-1. This multicenter prospective observational study aimed to determine whether concomitant anti-PD-1 and SABR to oligoprogressive sites enhance tumor response in metastatic NSCLC and melanoma.
Patients with metastatic NSCLC or melanoma in progression to anti-PD-1 but continuing the same line owing to clinical benefit were referred for palliative SABR. All patients received concomitant pembrolizumab or nivolumab and SABR to 1 to 5 lesions, maintaining anti-PD-1 until further progression, unacceptable toxicity, or medical/patient decision. Objective response rate-complete responses and partial responses-was evaluated during all follow-up according to Response Evaluation Criteria in Solid Tumors 1.1. The abscopal response was evaluated 8 weeks after SABR as a ≥30% reduction in 1 to 2 predefined nonirradiated lesions.
Of the 61 patients enrolled, 50 could be analyzed. With a median follow-up of 32.8 months, objective response rate was 42% (30% complete responses and 12% partial responses). Median progression-free survival was 14.2 months (95% confidence interval, 6.9-29 months). Median overall survival since SABR was 37.4 months (95% confidence interval, 22.9 months-not reached). Abscopal response was 65%, evaluated in 40 patients who fulfilled the criteria.
Combined anti-PD-1 and SABR in oligoprogressive metastatic NSCLC or melanoma can achieve high rates of response and extend the clinical benefit of immunotherapy by delaying further progression and a new systemic therapy. This approach should be assessed in larger randomized trials.
Abstract
The terrestrial Antarctic Realm has recently been divided into 16 Antarctic Conservation Biogeographic Regions (ACBRs) based on environmental properties and the distribution of biota. ...Despite their prominent role in the primary production and nutrient cycling in Antarctic lakes, cyanobacteria were only poorly represented in the biological dataset used to delineate these ACBRs. Here, we provide a first high-throughput sequencing insight into the spatial distribution of benthic cyanobacterial communities in Antarctic lakes located in four distinct, geographically distant ACBRs and covering a range of limnological conditions. Cyanobacterial community structure differed between saline and freshwater lakes. No clear bioregionalization was observed, as clusters of community similarity encompassed lakes from distinct ACBRs. Most phylotypes (77.0%) were related to cyanobacterial lineages (defined at ≥99.0% 16S rRNA gene sequence similarity) restricted to the cold biosphere, including lineages potentially endemic to Antarctica (55.4%). The latter were generally rare and restricted to a small number of lakes, while more ubiquitous phylotypes were generally abundant and present in different ACBRs. These results point to a widespread distribution of some cosmopolitan cyanobacterial phylotypes across the different Antarctic ice-free regions, but also suggest the existence of dispersal barriers both within and between Antarctica and the other continents.
Benthic cyanobacterial communities in Antarctic lakes are mostly structured by lake conductivity.
Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad ...prognosis. These therapies are planned following the "maximum dose in minimum time" principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient's life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor's proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme.
We have reviewed a considerable amount of recent scientific papers relating inflammation caused by air pollution with chronic and severe medical conditions. Furthermore, there are evidences relating ...organ inflammation caused by not only outdoor long-term but also short-term inhaled radioisotopes contained in high polluted air or in household natural radioactive background aerosols, in addition to SARS-COV-2 attached to bioaerosols, which are related with a worst evolution of severe acute respiratory syndrome patients. Reactive oxygen species (ROS) production induced by the interaction with environmental ionizing radiation contained in pollution is pointed out as a critical mechanism that predispose mainly to elder population, but not excluding young subjects, presenting previous chronic conditions of lung inflammation or neuroinflammation, which can lead to the most serious consequences.
Global mortality from AIDS-related diseases has been declining since 2005, resulting primarily from the widespread use and early initiation of combination antiretroviral therapy. Despite the ...significant improvements, high rates of early mortality, usually defined as that occurring within the 1st year of entry to care, have been observed, especially in resource-limited settings. This analysis draws upon data from an observational cohort of people with HIV (PWH) followed at a reference center for HIV/AIDS care and research in the city of Rio de Janeiro, Brazil, to identify the pattern and factors associated with early mortality.
The study population includes PWH aged 18 or older followed at the National Institute of Infectious Diseases Evandro Chagas who were enrolled between 2004 and 2015. The primary outcome was early mortality, defined as deaths occurring within 1 year of inclusion in the cohort, considering two follow-up periods: 0 to 90 days (very early mortality) and 91 to 365 days (early mortality). Cox proportional hazards models were used to identify the variables associated with the hazard of very early and early mortality.
Overall, 3879 participants contributed with 3616.4 person-years of follow-up. Of 220 deaths, 132 happened in the first 90 days and 88 between 91 and 365 days. Very early mortality rate ratios (MRR) show no statistically significant temporal differences between the periods 2004-2006 to 2013-2015. In contrast, for early mortality, a statistically significant decreasing trend was observed: mortality rates in the periods 2004-2006 (MR = 5.5; 95% CI 3.9-7.8) and 2007-2009 (MR = 3.9; 95% CI 2.7-5.7) were approximately four and three-fold higher when compared to 2013-2015 (MR = 1.4; 95% CI 0.7-2.7). Low CD4 count and prior AIDS-defining illness were strongly associated with higher hazard ratios of death, especially when considering very early mortality.
The present study shows an excess of mortality in the 1st year of follow-up with no changes in the mortality rates within 90 days among PWH from Rio de Janeiro. We note the significant impact of initiating treatment with immunosuppression, as evidenced by the increased risk of death among those with low CD4 cell count and with AIDS-defining illnesses.
The European population is strongly affected by cancer. Radiotherapy is roughly used in 50% of cancer patients in European countries. The increased cancer burden demands a new generation of ...radiation/clinical oncologist (RO/CO) that, besides a strong evidence-based oncological knowledge, will be ready for leadership in cancer care. The mutual recognition of professional qualifications of Radiation/Clinical Oncology in the EU needs training harmonization. The European Society of Radiotherapy and Oncology (ESTRO) and the European Union for Medical Specialties (UEMS) made important efforts toward a European Common Curriculum for RO/CO leadership in cancer care. If qualifications are mutually recognized, the training supporting these qualifications should be also harmonized. Since 1991, ESTRO produced several editions of the Core Curriculum in Radiation Oncology (1991, 2004, 2012, 2019). These Core Curricula were endorsed as European Training Requirements by the UEMS in 2004, 2013, and 2019. A core curriculum for clinical oncology was also produced to provide this harmonization tool to countries where radiation oncology is practiced inside the broader specialty of clinical oncology. New initiatives are in place to continuously adapt the training programs to the rapidly evolving cancer care organization.
PDF
