National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes.

Inter-agency perspective: Translating advances in biomarker discovery and medical countermeasures development between terrestrial and space radiation environments.

Over the past 20+ years, the U.S. Government has made significant strides in establishing research funding and initiating a portfolio consisting of subject matter experts on radiation-induced biological effects in normal tissues.

Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.

Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients.

Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide.

Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities: Current Challenges and New Approaches: Report of the Symposium Held at the 63rd Annual Meeting of the Radiation Research Society, 15-18 October 2017; Cancun, Mexico.

The National Cancer Institute's (NCI) Radiation Research Program (RRP) is endeavoring to increase the relevance of preclinical research to improve outcomes of radiation therapy for cancer patients. These efforts include conducting symposia, workshops and educational sessions at annual meetings of professional societies, including the American Association of Physicists in Medicine, American Society of Radiation Oncology, Radiation Research Society (RRS), Radiosurgery Society, Society of Nuclear Medicine and Molecular Imaging, Society for Immunotherapy of Cancer and the American Association of Immunology. A symposium entitled "Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities" was conducted by the NCI's RRP during the 63rd Annual Meeting of the RRS on October 16, 2017 in Cancun, Mexico.

UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES BIODOSIMETRY AND RADIOLOGICAL/NUCLEAR MEDICAL COUNTERMEASURE PROGRAMS.

The United States Department of Health and Human Services (HHS) is fully committed to the development of medical countermeasures to address national security threats from chemical, biological, radiological, and nuclear agents. Through the Public Health Emergency Medical Countermeasures Enterprise, HHS has launched and managed a multi-agency, comprehensive effort to develop and operationalize medical countermeasures. Within HHS, development of medical countermeasures includes the National Institutes of Health (NIH), (led by the National Institute of Allergy and Infectious Diseases), the Office of the Assistant Secretary of Preparedness and Response/Biomedical Advanced Research and Development Authority (BARDA); with the Division of Medical Countermeasure Strategy and Requirements, the Centers for Disease Control and Prevention, and the Food and Drug Administration as primary partners in this endeavor.

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models.

High-throughput sample processing and sample management; the functional evolution of classical cytogenetic assay towards automation.

High-throughput individual diagnostic dose assessment is essential for medical management of radiation-exposed subjects after a mass casualty. Cytogenetic assays such as the Dicentric Chromosome Assay (DCA) are recognized as the gold standard by international regulatory authorities. DCA is a multi-step and multi-day bioassay.

Radioprotectors and Radiomitigators for Improving Radiation Therapy: The Small Business Innovation Research (SBIR) Gateway for Accelerating Clinical Translation.

Although radiation therapy is an important cancer treatment modality, patients may experience adverse effects. The use of a radiation-effect modulator may help improve the outcome and health-related quality of life (HRQOL) of patients undergoing radiation therapy either by enhancing tumor cell killing or by protecting normal tissues. Historically, the successful translation of radiation-effect modulators to the clinic has been hindered due to the lack of focused collaboration between academia, pharmaceutical companies and the clinic, along with limited availability of support for such ventures.

Response of human lymphocytes to proton radiation of 60 MeV compared to 250 kV X-rays by the cytokinesis-block micronucleus assay.

Particle radiotherapy such as protons provides a new promising treatment modality to cancer. However, studies on its efficacy and risks are relatively sparse. Using the cytokinesis-blocked micronucleus assay, we characterized response of human peripheral blood lymphocytes, obtained from health donors irradiated in vitro in the dose range: 0-4.

Radiation-induced brain damage, impact of Michael Robbins' work and the need for predictive biomarkers.

Purpose: To review the literature on radiation-induced normal tissue injury in the context of treatment of primary and metastatic brain tumors with a focus on Michael Robbins' work on mechanisms of injury and approaches to mitigation, and also to identify other potential opportunities to improve treatment outcome and quality of life (QOL).

Background: Brain tumors remain a significant challenge for patients, their families, the physicians treating them, and researchers seeking more effective treatments. Current treatment of brain tumors involves combinations of radiotherapy with surgery, chemotherapy, and molecularly targeted agents.

Mitigating the risk of radiation-induced cancers: limitations and paradigms in drug development.

The United States radiation medical countermeasures (MCM) programme for radiological and nuclear incidents has been focusing on developing mitigators for the acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE), and biodosimetry technologies to provide radiation dose assessments for guiding treatment. Because a nuclear accident or terrorist incident could potentially expose a large number of people to low to moderate doses of ionising radiation, and thus increase their excess lifetime cancer risk, there is an interest in developing mitigators for this purpose. This article discusses the current status, issues, and challenges regarding development of mitigators against radiation-induced cancers.

Premature chromosome condensation in human resting peripheral blood lymphocytes without mitogen stimulation for chromosome aberration analysis using specific whole chromosome DNA hybridization probes.

We have previously described a unique, simple, and rapid method for inducing premature chromosome condensation (PCC) in "resting" human peripheral blood lymphocytes (HPBLs) without mitogen stimulation and an approach for studying numerical changes and/or structural aberrations involving a specific pair of human chromosomes. The current protocol incorporates improvements that provide better PCC, incorporates a high-throughput automated sample preparation unit and metaphase harvester to minimize manual labor and improve quality, and supports simultaneous painting of multiple sets of human autosomes in interphase nuclei. To induce PCC, isolated HPBLs are incubated at 37 °C in cell culture medium supplemented with a phosphatase inhibitor (okadaic acid or calyculin A), adenosine triphosphate, and p34(cdc2)/cyclin B kinase (an essential component of mitosis-promoting factor) for a short period of time.

Assessment of biodosimetry methods for a mass-casualty radiological incident: medical response and management considerations.

Following a mass-casualty nuclear disaster, effective medical triage has the potential to save tens of thousands of lives. In order to best use the available scarce resources, there is an urgent need for biodosimetry tools to determine an individual's radiation dose. Initial triage for radiation exposure will include location during the incident, symptoms, and physical examination.

Normal tissue protection for improving radiotherapy: Where are the Gaps?

Any tumor could be controlled by radiation therapy if sufficient dose were delivered to all tumor cells. Although technological advances in physical treatment delivery have been developed to allow more radiation dose conformity, normal tissues are invariably included in any radiation field within the tumor volume and also as part of the exit and entrance doses relevant for particle therapy. Mechanisms of normal tissue injury and related biomarkers are now being investigated, facilitating the discovery and development of a next generation of radiation protectors and mitigators.

Biological Dosimetry by the Triage Dicentric Chromosome Assay - Further validation of International Networking.

Biological dosimetry is an essential tool for estimating radiation doses received to personnel when physical dosimetry is not available or inadequate. The current preferred biodosimetry method is based on the measurement of radiation-specific dicentric chromosomes in exposed individuals' peripheral blood lymphocytes. However, this method is labour-, time- and expertise-demanding.

Biological dosimetry by the triage dicentric chromosome assay: potential implications for treatment of acute radiation syndrome in radiological mass casualties.

Biological dosimetry is an essential tool for estimating radiation dose. The dicentric chromosome assay (DCA) is currently the tool of choice. Because the assay is labor-intensive and time-consuming, strategies are needed to increase throughput for use in radiation mass casualty incidents.

Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop.

Radiation exposures from accidents, nuclear detonations or terrorist incidents are unlikely to be homogeneous; however, current biodosimetric approaches are developed and validated primarily in whole-body irradiation models. A workshop was held at the Armed Forces Radiobiology Research Institute in May 2008 to draw attention to the need for partial-body biodosimetry, to discuss current knowledge, and to identify the gaps to be filled. A panel of international experts and the workshop attendees discussed the requirements and concepts for a path forward.

Triage dose assessment for partial-body exposure: dicentric analysis.

Partial-body biodosimetry is likely to be required after a radiological or nuclear exposure. Clinical signs and symptoms, distribution of dicentrics in circulating blood cells, organ-specific biomarkers, and physical signals in teeth and fingernails all can provide indications of non-homogeneous exposures. Organ specific biomarkers may provide early warning regarding physiological systems at risk after radiation injury.

Differential radio-sensitivities of human chromosomes 1 and 2 in one donor in interphase- and metaphase-spreads after 60Co gamma-irradiation.

Background: Radiation-induced chromosome aberrations lead to a plethora of detrimental effects at cellular level. Chromosome aberrations provide broad spectrum of information ranging from probability of malignant transformation to assessment of absorbed dose. Studies mapping differences in radiation sensitivities between human chromosomes are seldom undertaken.

Interlaboratory comparison of the dicentric chromosome assay for radiation biodosimetry in mass casualty events.

This interlaboratory comparison validates the dicentric chromosome assay for assessing radiation dose in mass casualty accidents and identifies the advantages and limitations of an international biodosimetry network. The assay's validity and accuracy were determined among five laboratories following the International Organization for Standardization guidelines. Blood samples irradiated at the Armed Forces Radiobiology Research Institute were shipped to all laboratories, which constructed individual radiation calibration curves and assessed the dose to dose-blinded samples.

Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism.

The effective medical management of a suspected acute radiation overexposure incident necessitates recording dynamic medical data, measuring appropriate radiation bioassays, and estimating dose from dosimeters and radioactivity assessments in order to provide diagnostic information to the treating physician and a dose assessment for personnel radiation protection records. The accepted generic multiparameter and early-response approach includes measuring radioactivity and monitoring the exposed individual; observing and recording prodromal signs/symptoms and erythema; obtaining complete blood counts with white blood cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the "gold standard" dicentric assay (translocation assay for long times after exposure) for dose assessment; bioassay sampling, if appropriate, to determine radioactivity contamination; and using other available dosimetry approaches. In the event of a radiological mass-casualty incident, current national resources need to be enhanced to provide suitable dose assessment and medical triage and diagnoses.