Sargramostim in acute radiation syndrome.

INTRODUCTION: Since 1944, nearly 400 radiologic accidents/incidents have exposed about 3,000 people to substantial doses of ionizing radiation, with more than 125 deaths. Known are the Chernobyl and Fukushima nuclear power facility accidents, but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, whole-body exposures to ionizing radiation includes transfusions, antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT). AREAS COVERED: We focus on approved therapies including recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim). Animal data indicate sargramostim accelerates marrow recovery and increases survival. In 2018, the United States Food and Drug Administration approved sargramostim for persons acutely exposed to myelosuppressive radiation doses based on two large nonhuman primate studies. In seven radiation accidents since 1986, 28 victims exposed to acute high-dose ionizing radiation received rhu GM-CSF alone or with other hematopoietic growth factors. Therapy appeared effective with few, if any, adverse events; 18 survived. EXPERT OPINION: This favorable benefit-to-risk ratio suggests giving sargramostim soon after exposure and is favored over HCT based on greater safety and fewer resource requirements, especially in the context of large-scale exposures which might occur after use of a tactical nuclear weapon or nuclear terrorism.

A New Smartphone Application to Predict Hematologic Acute Radiation Syndrome Based on Blood Cell Count Changes-The H-module App.

Treatment regimens for acute radiation syndrome have been improved over the past years. The application of appropriate therapy relies on rapid and high-throughput tests ideally conducted in the first 3 d after a radiation exposure event. We have examined the utility of blood cell counts (BCCs) 3 d post irradiation to predict clinical outcome for hematologic acute radiation syndrome (HARS). The BCCs and HARS severity information originated from data available in the System-for-Evaluation-and-Archiving-of-Radiation Accidents-based-on-Case-Histories (SEARCH). We found an almost complete discrimination of unexposed (HARS score H0) vs. irradiated individuals during model development and validation (negative predictive value > 94%) when using BCC data for all 3 d. We also found that BCC data increased the correct prediction of exposed individuals from day 1 to day 3. We developed spreadsheets to calculate the likelihood of correct diagnoses of the worried-well, requirement of hospitalization (HARS 2-4), or development of severe hematopoietic syndrome (HARS 3-4). In two table-top exercises, we found the spreadsheets were confusing and cumbersome, so we converted the spreadsheets into a smartphone application, named the H-module App, designed for ease of use, wider dissemination, and accommodation of co-morbidities in the HARS severity prediction algorithm.

Bilirubin augments radiation injury and leads to increased infection and mortality in mice: molecular mechanisms.

Our earlier results demonstrated that clinically relevant concentrations of unconjugated bilirubin (UCB) possessed immunotoxic effects. Whole-body irradiation (WBI) with 1 to 6 Gy leads to acute radiation syndrome, immunosuppression, and makes the host susceptible to infection. Since hyperbilirubinemia has been shown to be associated with several types of cancer, the present studies were undertaken to evaluate the radiomodifying effects of UCB in radiation-exposed mice having elevated levels of UCB. Pretreatment of splenic lymphocytes with UCB (1-50 µM at UCB/BSA ratio <1) augmented radiation-induced DNA strand breaks, MMP loss, calcium release, and apoptosis. Combination treatment of mice with UCB (50mg/kg bw) followed by WBI (2 Gy) 0.5h later, resulted in significantly increased splenic atrophy, bone marrow aplasia, decreased counts of peritoneal exudate cells, and different splenocyte subsets such as CD3+ T, CD4+ T, CD8+ T, CD19+ B, and CD14+ macrophages as compared to either UCB or WBI treatment. Hematological studies showed that WBI-induced lymphopenia, thrombocytopenia, and neutropenia were further aggravated in the combination treatment group. UCB pretreatment of mice potentiated WBI-induced apoptosis and decreased WBI-induced loss of functional response of various immune cells leading to augmentation of immunosuppression and infection susceptibility caused by WBI. In an acute bacterial peritonitis model, UCB pretreatment of mice significantly increased WBI-induced proinflammatory cytokines, nitric oxide, and peritoneal bacterial load resulting in increased infection and death. Studies using the pharmacological inhibitor of p38MAPK demonstrated the involvement of p38MAPK activation in the inflammatory cascade of peritonitis. These findings should prove useful in understanding the potential risk to hyperbilirubinemic patients during radiotherapy and victims of acute radiation exposure in the course of radiation accidents.