S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells alleviate radiation-induced lung injury and long-term pulmonary fibrosis via suppression of ferroptosis (preprint)

Background Radiation-induced pulmonary fibrosis (RIPF) is a late-stage complication of therapeutic radiation, associated with poor prognosis and limited therapeutic options. Radiation-induced lung injury (RILI) is an early manifestation of RIPF, and intervention of RILI is an effective method for preventing long-term RIPF. Mesenchymal stem cell (MSC)-derived exosomes exhibit regenerative activity in injured lungs and are effective drug-delivery nanoparticles. SARS-CoV-2-S-RBD enables ACE2+ cell targeting of MSC extracellular vesicles. miR-486-5p is a multifunctional miRNA with angiogenic and anti-fibrotic activities and is enriched in MSC-derived exosomes. In this study, we investigated the therapeutic effects of miR-486-5p and SARS-COV-2-S-RBD-engineered MSC exosomes on RIPF in vitro and in vivo.Results Adenovirus-mediated gene modification led to the overexpression of miR-486-5p in umbilical cord MSCs (UC-MSCs), which further enriched miR-486-5p in UC-MSCs-derived exosomes. MiR-486-5p-engineered MSC exosomes (miR-486-MSC-Exo) promoted the proliferation and migration of irradiated MLE-12 cells in vitro and inhibited RILI in vivo. An in vitro assay revealed the occurrence of ferroptosis, a major form of cell death during radiation injury, indicated by the upregulated expression of fibrosis-related genes. miR-486-MSC-Exo effectively reversed these changes. MiR-486-MSC-Exo strongly reversed the upregulated expression of MLE-12 fibrosis-related genes induced by TGF in vitro and improved pathological fibrosis in the RIPF model in vivo. The distribution of RBD-VSVG-MSC exosomes labeled with DiR dye in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated that the fluorescence of RBD-VSVG exosomes remained in the lungs for a long time. miR-486-RBD-MSC-exosomes significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice. Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects through targeted inhibition of SMAD2 and activation of Akt phosphorylation.Conclusions Here, miR-486-MSC-Exo inhibited lung injury and alleviated fibrosis in vivo and in vitro. Surface modification with COVID-S-RBD conferred engineered exosomes with the ability to target the lungs of animal models. The therapeutic effects of miR-486-5p and COVID-S-RBD-engineered MSC exosomes on RIPF were significantly enhanced. MSC-derived exosomes modified with recombinant COVID-S-RBD enabled targeted delivery of miR-486-5p, which is an effective approach for the treatment of RIPF.

Additional Evidence for Commonalities between COVID-19 and Radiation Injury: Novel Insight into COVID-19 Candidate Drugs.

COVID-19 is a challenge to biosecurity and public health. The speed of vaccine development lags behind that of virus evolution and mutation. To date, no agent has been demonstrated to be fully effective against COVID-19. Therefore, it remains of great urgency to rapidly develop promising therapeutic and diagnostic candidates. Intriguingly, mounting evidence hints at parallel etiologies between SARS-CoV-2 infection and radiation injury. Herein, from the perspectives of immunogenic pathway activation and metabolic alterations, we provide novel evidence of commonalities between these two pathological conditions based on the most recent findings. Since numerous agents have been developed to prevent or reverse radiation injury in the past 70 years to ensure nuclear safety, we also advocate investigating the promising function of radioprotectors and radiomitigators against COVID-19 in clinical settings.

Ultra-Hypofractionated vs. Moderate Fractionated Whole Breast Three Dimensional Conformal Radiotherapy during the COVID-19 Pandemic.

Background and Objectives: Reducing time of treatment during COVID-19 outbreaks has been recommended by the leading Radiation Oncology societies. Still minimizing radiation induced tissue toxicity is one of the most important issues in breast cancer patients. The study aimed to investigate compliance, clinical and dosimetry normal tissue toxicity, and cosmetic results between moderated and ultra-fractionated regimes for breast cancer patients during COVID-19 pandemic. Materials and Methods: This pilot prospective randomized study included 60 patients with early breast cancer after preserving surgery, 27 patients advocated to ultra-hypofractionated whole-breast three dimensional (3D) conformal radiotherapy of 26 Gy in 5 fractions over 1 week and 33 patients with moderate fractionated breast 3D conformal radiotherapy patients between March 2020 and July 2020, during the COVID pandemic outbreak. The compliance to treatment, dosimetric parameters, acute and late skin toxicity, subcutaneous tissue toxicity, cosmetic results and clinical follow up for 18 months for the two regimes were analyzed and compared. Results: When two regimes were compared 5 fraction group had significantly lower prevalence of newly infected cases of SARS-CoV-2 and thus delayed/interrupted treatment (p = 0.05), comparable grade 1 CTCAE v5, acute skin toxicity (p = 0.18), Grade 1 Radiation Morbidity Scoring Scheme (RESS) subcutaneous tissue toxicity (p = 0.18), Grade 1 RESS late skin toxicity (p = 0.88) and cosmetic results (p = 0.46). Dosimetric results reveled that patients in 5 fraction group received significantly lower median ipsilateral lung doses (p < 0.01) in addition to left breast cancer patients that received significantly lower median heart dose (p < 0.01) and median left anterior descending artery (LAD) dose (p < 0.01). Conclusion: Ultra-hypofractionated radiotherapy for breast cancer is comparable to moderate hypofractionation regimen regarding grade 1 acute skin toxicity, grade 1 subcutaneous tissue toxicity, late skin toxicity and cosmetic results. Application of ultra-hypofractionated radiotherapy with significantly lower radiation doses for lung and heart could be crucial in reducing the risk of acute/late pulmonary and heart radiation-induced toxicity.

Preparedness for a 'no-notice' mass-casualty incident: a nuclear detonation scenario.

PURPOSE: An effective response for a mass-casualty incident requires understanding the relevant basic science and physical impact; detailed preparedness among jurisdictions; and clear, sequential response planning, including formal operational exercises, logistics, interagency, and public-private coordination, rapid activation of resilience, and continual improvement from lessons learned and new knowledge. This ConRad 2021 meeting report describes steps for civilian medical and public health response planning for a nuclear detonation; the utility of this type of planning for broader application; and extension of this planning to the international community. CONCLUSION: A nuclear detonation requires a response within minutes to what will be a large-scale disaster complicated by radiation, including some elements that are similar to a broad range of incidents. The response could be further complicated if multiple incidents occur simultaneously. Required are detailed planning, preparedness and scripting for an immediate operational response, addressing clinical manifestations of evolving radiation illness, and flexibility to adapt to a rapidly changing situation. This need translates into the use of just-in-time information; effective, credible communication; situational awareness on a global scale; and a template upon which to apply capabilities in a multi-sector response. This effort is greatly facilitated using a 'playbook' approach, the basics of which are presented.

Safety, Efficacy, and Patterns of Failure After Single-Fraction Stereotactic Body Radiation Therapy (SBRT) for Oligometastases.

PURPOSE: Fewer attendances for radiation therapy results in increased efficiency and less foot traffic within a radiation therapy department. We investigated outcomes after single-fraction (SF) stereotactic body radiation therapy (SBRT) in patients with oligometastatic disease. METHODS AND MATERIALS: Between February 2010 and June 2019, patients who received SF SBRT to 1 to 5 sites of oligometastatic disease were included in this retrospective study. The primary objective was to describe patterns of first failure after SBRT. Secondary objectives included overall survival (OS), progression-free survival (PFS), high-grade treatment-related toxicity (Common Terminology Criteria for Adverse Events grade ≥3), and freedom from systemic therapy (FFST). RESULTS: In total, 371 patients with 494 extracranial oligometastases received SF SBRT ranging from 16 Gy to 28 Gy. The most common primary malignancies were prostate (n = 107), lung (n = 63), kidney (n = 52), gastrointestinal (n = 51), and breast cancers (n = 42). The median follow-up was 3.1 years. The 1-, 3-, and 5-year OS was 93%, 69%, and 55%, respectively; PFS was 48%, 19%, and 14%, respectively; and FFST was 70%, 43%, and 35%, respectively. Twelve patients (3%) developed grade 3 to 4 treatment-related toxicity, with no grade 5 toxicity. As the first site of failure, the cumulative incidence of local failure (irrespective of other failures) at 1, 3 and 5 years was 4%, 8%, and 8%, respectively; locoregional relapse at the primary was 10%, 18%, and 18%, respectively; and distant failure was 45%, 66%, and 70%, respectively. CONCLUSIONS: SF SBRT is safe and effective, and a significant proportion of patients remain FFST for several years after therapy. This approach could be considered in resource-constrained or bundled-payment environments. Locoregional failure of the primary site is the second most common pattern of failure, suggesting a role for optimization of primary control during metastasis-directed therapy.

Acute and late toxicities of patients infected with SARS-CoV-2 and treated for cancer with radiation therapy during the COVID-19 pandemic.

PURPOSE: This study aimed to assess the risk of acute and late radiation-induced toxicity in patients with COVID-19. MATERIAL AND METHODS: All the patients irradiated in Institut Curie from March to July 2020 were included if the first symptoms related to COVID-19 occurred no more than two months before the start of radiation therapy (RT) or 15 days after the end of RT. RESULTS: Twenty-nine patients were included in this analysis. Twenty-five patients had no co-morbidities (86.2%), including morbid obesity. The diagnosis of COVID-19 infection was based on a positive SARS-CoV-2 RNA test for 18 patients (62.1%), a positive serology test for three patients (10.3%), and/or radiologic findings for 12 patients (41.4%). Three patients with symptoms highly suggestive of COVID-19 were included, although they had negative biologic tests and did not have a chest CT scan. Median time from the diagnosis of COVID-19 to the onset of RT was 5.5 days. Modification of RT course due to COVID-19 status was observed in 15 patients, including four for whom RT was definitively stopped. Six patients needed hospitalization for hypoxemic lung disease requiring intensive care. The majority of patients did not experience severe (> grade 2) acute toxicity. After a median follow-up of 6 months (IQR, 1-9 months), none of the patients had unusual clinical or radiological late toxicities. CONCLUSION: The observed acute and late toxicities were ultimately similar to those observed in a population not infected with COVID-19. These results do not prompt modification of standard RT protocols for irradiation of COVID-19 patients.

Acute and sub-acute toxicity profile of ultra-hypofractionated low-dose total skin electron beam with two 4 Gy fractions for cutaneous T cell lymphoma.

PURPOSE: Low-dose total skin electron beam therapy (TSEBT) over 3 weeks has proved to be a safe and effective treatment for cutaneous T cell lymphomas (CTCL). In this prospective trial, we examined the feasibility of ultra-hypofractionated low-dose TSEBT regimen in two fractions with 4 Gy combined with systemic therapy to minimize the number of visits to radiation centers. PATIENTS AND METHODS: Six patients with mycosis fungoides (MF) or Sézary syndrome (SS) received TSEBT with a total radiation dose of 8 Gy in two fractions between April 2020 and June 2020. Patient and treatment characteristics, tumor burden, the impact on the quality of life using Skindex-29 questionnaires, and acute toxicities were analyzed. RESULTS: During TSEBT, all patients developed grade 1 toxicities while two patients developed grade 2 toxicities. One patient experienced sepsis. The most common adverse effects were erythema and edema. All grade 2 toxicities regressed after 4 weeks following TSEBT. Based on the reported symptoms measured by Skindex-29, we detected a significant reduction in total Skindex-29 score after 8 weeks of radiation (P = 0.03), particularly in the symptoms (P = 0.01) and emotional domains (P = 0.04). CONCLUSION: Ultra-hypofractionated low-dose TSEBT followed by systemic therapy seems to be a safe and feasible alternative to conventional fractionated TSEBT for patients with MF/SS. The skin tumor burden and the health-related quality of life have been significantly improved within 8 weeks following radiotherapy.

Get Protected! Recommendations for Staff in IR.

PURPOSE: Evaluation and registration of patient and staff doses are mandatory under the current European legislation, and the occupational dose limits recommended by the ICRP have been adopted by most of the countries in the world. METHODS: Relevant documents and guidelines published by international organisations and interventional radiology societies are referred. Any potential reduction of patient and staff doses should be compatible with the clinical outcomes of the procedures. RESULTS: The review summarises the most common protective measures and the needed quality control for them, the criteria to select the appropriate protection devices, and how to avoid unnecessary occupational radiation exposures. Moreover, the current and future advancements in personnel radiation protection using medical simulation with virtual and augmented reality, robotics, and artificial intelligence (AI) are commented. A section on the personnel radiation protection in the era of COVID-19 is introduced, showing the expanding role of the interventional radiology during the pandemic. CONCLUSION: The review is completed with a summary of the main factors to be considered in the selection of the appropriate radiation protection tools and practical advices to improve the protection of the staff.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

Improper Use of the Germicidal Range Ultraviolet Lamp for Household Disinfection Leading to Phototoxicity in COVID-19 Suspects.

PURPOSE: To report the germicidal range ultraviolet (UV) irradiation-induced phototoxicity because of unprotected exposure to the UV lamps for presumed household disinfection of SARS-CoV-2 in a domestic setting. METHODS: We report on a family of 3 adults who experienced photophobia, intense eye pain, epiphora, blurred vision, and a burning sensation over the face and neck area after a short period of unprotected exposure to the UV germicidal lamps. RESULTS: An initial examination revealed erythema and tenderness over the face and neck area, reduced visual acuity of 6/12, and conjunctival injections bilaterally in all 3 patients. Further assessment at the ophthalmology department 3 days later revealed gradual improvement of visual acuity to 6/6 bilaterally. Slit-lamp examinations revealed few punctate epithelial erosions. Fundal examinations were normal without evidence of solar retinopathy. The patients were diagnosed with germicidal range UV irradiation-induced photokeratitis and epidermal phototoxicity. Lubricants and emollients were prescribed for symptom relief, and the patients were warned against using a UV germicidal lamp for disinfection purposes without appropriate protection. CONCLUSIONS: Although SARS-CoV-2 is structurally akin to SARS-CoV-1 and MERS-CoV, and previous studies demonstrated high levels of inactivation of beta-coronavirus with germicidal-range UV, evidence for its efficacy to inactivate SARS-CoV-2 is lacking. This case report serves to emphasize the potential consequences of phototoxicity from the improper use of UV germicidal lamps for household disinfection and to highlight the fact that UV germicidal lamps currently have no established role in household disinfection of SARS-CoV-2.

Low-dose radiotherapy (LD-RT) for COVID-19-induced pneumopathy: a worth considering approach.

PURPOSE: It seems that 2020 would be always remembered by the name of novel coronavirus (designated as SARS-CoV-2), which exerted its deteriorating effects on the health care, economy, education, and political relationships. In August 2020 more than eight hundred thousand patients lost their lives due to acute respiratory syndrome. In the limited list of therapeutic approaches, the effectiveness of low-dose radiation therapy (LD-RT) for curing inflammatory-related diseases have sparkled a light that probably this approach would bring promising advantages for COVID-19 patients. LD-RT owns its reputation from its ability to modulate the host inflammatory responses by blocking the production of pro-inflammatory cytokines and hampering the activity of leukocytes. Moreover, the cost-effective and availability of this method allow it to be applied to a large number of patients, especially those who could not receive anti-IL-6 treatments in low-income countries. But enthusiasm for applying LD-RT for the treatment of COVID-19 patients has been muted yet. CONCLUSION: In this review, we take a look at LD-RT mechanisms of action in the treatment of nonmalignant diseases, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if LD-RT might be a promising therapeutic approach in COVID-19 patients.

Prediction of evolution of the second wave of Covid-19 pandemic in Italy (preprint)

A relevant problem in the study of the Covid-19 pandemic is the study of its temporal evolution. Such evolution depends on a number of factors, among which the average rate of contacts between susceptible and infected individuals, the duration of infectiousness and the transmissibility, that is the probability of infection after a contact between susceptible and infected individuals. In a previous study, we analyzed the potentiality of a number of distributions to describe the evolution of the pandemic and the potentiality of each distribution to mathematically predict the evolution of the pandemic in Italy. Since the number of daily tests was changing and increasing with time, we used the ratio of the new daily cases per swab. We considered distributions of the type of Gauss (normal), Gamma, Beta, Weibull, Lognormal and in addition of the type of the Planck blackbody radiation law. The Planck law, describing the amount of energy of the electromagnetic radiation emitted by a black body at each wavelength or at each frequency, marked in 1900 the beginning of Quantum Mechanics. The result of our analysis was that, among the considered distributions, the Planck law has the best potentiality to mathematically predict the evolution of the pandemic and the best fitting capability. In this paper, we analyze the time evolution of this second wave of Covid-19 pandemic in Italy. In this study there is also an attempt to account for the effects of the governmental containment measures.

Pneumonia After Bacterial or Viral Infection Preceded or Followed by Radiation Exposure: A Reanalysis of Older Radiobiologic Data and Implications for Low-Dose Radiation Therapy for Coronavirus Disease 2019 Pneumonia.

PURPOSE: Currently, there are about 15 ongoing clinical studies on low dose radiation therapy for Coronavirus Disease 2019 pneumonia. One of the underlying assumptions is that irradiation of 0.5 to 1.5 Gy is effective at ameliorating viral pneumonia. We aimed to reanalyze all available experimental radiobiologic data to assess evidence for such amelioration. METHODS AND MATERIALS: With standard statistical survival models, and based on a systematic literature review, we reanalyzed 13 radiobiologic animal data sets published in 1937 to 1973 in which animals (guinea pigs/dogs/cats/rats/mice) received radiation before or after bacterial or viral inoculation, and assessing various health endpoints (mortality/pneumonia morbidity). In most data sets absorbed doses did not exceed 7 Gy. RESULTS: For 6 studies evaluating postinoculation radiation exposure (more relevant to low dose radiation therapy for Coronavirus Disease 2019 pneumonia) the results are heterogeneous, with one study showing a significant increase (P < .001) and another showing a significant decrease (P < .001) in mortality associated with radiation exposure. Among the remaining 4 studies, mortality risk was nonsignificantly increased in 2 studies and nonsignificantly decreased in 2 others (P > .05). For preinoculation exposure the results are also heterogeneous, with 6 (of 8) data sets showing a significant increase (P < .01) in mortality risk associated with radiation exposure and the other 2 showing a significant decrease (P < .05) in mortality or pneumonitis morbidity risk. CONCLUSIONS: These data do not provide support for reductions in morbidity or mortality associated with postinfection radiation exposure. For preinfection radiation exposure the inconsistency of direction of effect is difficult to interpret. One must be cautious about adducing evidence from such published reports of old animal data sets.