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					Planning for Radiation Emergency




          Nelson Chao, MD
          Duke University
              Disclaimer
• I have no financial interest
• I am not part of the military/industrial
  complex
• I have no financial gains
                     Overview

• Radiation Basics
• Radiation Biology/Acute Radiation Syndrome
• Biodosimetry
• Describe the Radiation Injury Treatment Network
• Incident Response
• Treatment
• Available resources
Magnitude of the problem (internal)
• Lack of infrastructure
• Complacence on the threat
• Restricted human “disease” (restricted
  to total body irradiation for
  hematological diseases and fortunately
  rare radiation accidents)
• Complexity of exposure in a terrorist
  act and type of radiation and blast
  trauma
    Radiation Basics




5
    Types of Ionizing Radiation




6
    Radioactive Contamination
• Internal contamination requires medical
  decorporation
• 90% of external contamination can be
  cleansed by removing clothing and washing
  exposed body parts




7
Reducing Radiation Exposure

    3 steps for protection:
    1) Keep your DISTANCE
    2) Limit your TIME
      exposed
    3) SHIELD yourself from
      exposure




8
    Acute Radiation Syndrome




9
     Acute Radiation Syndrome
                                             Weeks After Exposure
                               0       1       2      3      4     5      6      7      8
                           0         Prodromal
                                                        Onset of signs of     Approximate
     Radiation dose (Gy)

                                   nausea/vomiting
                                                       hematopoietic injury   time of death
                           2




                                                                                                  Mortality
                                       GI                                                   0%
                                    symptoms
                           4
                                                                                            50%

                           6
                                                                                            100%
                                                                  100% mortality
                           8
                                                                 (may be higher
                                                                 dose with HSCT)
                       10

                                           CNS injury (100% mortality within days)
       >100


10
 Toxicity is Proportional to Dose
 • LD50 for humans: LD50 is the level of exposure that is
   lethal to 50% of people exposed to that dose
    – 3.5 to 4 Gy
       • Without supportive care
       • However the use of antibiotics and transfusions
         may decrease the chance of morbidity
    – 4.5 to 7 Gy
       • With antibiotics, transfusions and other
         supportive care
    – Greater than 10 Gy
       • With HSCT
 • In a radiation incident, shielding will result in
   heterogenous body dosing
11
     Acute Radiation Syndrome -
          Combined Injury
 • Most victims with significant injury will have
   multi-organ dysfunction
     –   Trauma/wounds/burns
     –   Gastrointestinal
     –   Hematologic
     –   Neurologic
     –   Psychiatric




12
        Acute Radiation Syndrome -
             Gastrointestinal
     Symptoms                Degree of severity 1 to 4
     Diarrhea - frequency    Twice/day >10 times/day
     Stool - consistency     Bulky to watery
     Blood in stools         Occult to gross hemorrhage
     Abdominal pain/cramps   Minimal to excruciating
     Nausea                  Mild to excruciating
     Vomiting                1 per day to >10 times per day




13
        Acute Radiation Syndrome -
                Cutaneous
     Symptoms            Degree of severity 1 to 4
     Erythema            Minimal to severe
     Altered             Pruritis to severe
     sensation/Itching
     Edema               Asymptomatic to total dysfunction
     Blistering          Rare to bullae with hemorrhage
     Desquamation        Absent to confluent
     Ulcer/necrosis      Epidermal only to muscle/bone

     Hair loss           Thinning to complete

     Onycholysis         Absent to complete

14
Cutaneous Injuries from Open
          Sources
     Acute Radiation Syndrome -
           Hematopoietic




16
     Biodosimetry




17
            Biodosimetry Tools
• Definition
   – Biodosimetry is the use of biological markers to estimate dose
   – Dosing after radiological and nuclear events is complicated by a
     variety of factors, including shielding
• Standard approaches
   – Lymphocyte Depletion Kinetics
   – Dicentric Chromosomes in Peripheral Blood Lymphocytes
• Research approaches
   – Proteomics
   – Markers of DNA damage

• It is important to remember that in a true detonation, none of this
  will be all that useful, the clinical findings will drive therapy.



18
     ARS – Time to vomiting as a
           marker of dose




     From: CDC Radiological Terrorism
     Emergency Management Pocket Guide for
     Clinicians Pocket Guide:
     www.bt.cdc.gov/radiation/pocket.asp

19
     Acute Radiation Syndrome -
        Lymphocyte Kinetics




20
           Biodosimetry Tools
• AFRRI Biodosimetry Assessment Tool
  (BAT)
     – Downloadable software
• Radiation Event Medical Management
  (REMM) www.remm.nlm.gov
     – Web-based software
     – Provides suggested treatments based on
       estimated dose
     – Standardized admission and treatment
       order templates
21
22
              Response


1. Do nothing, definitely
easiest.

2. Plan in advance
RITN:
A U.S. Initiative
for Radiation
Preparedness
                 Agenda
• Who is RITN?

• What Needs Does RITN Fill?

• What Can RITN Offer?

• What is RITN Doing to Prepare?

• Concerns

25
                  Charter
The Radiation Injury Treatment Network® (RITN)
 provides comprehensive evaluation and treatment
 for victims of radiation exposure or other marrow
toxic injuries. RITN develops treatment guidelines,
educates health care professionals, works to expand
  the network, and coordinates situation response.
    RITN is a cooperative effort of the National
 Marrow Donor Program (NMDP) and The American
   Society for Blood and Marrow Transplantation
                      (ASBMT).
 26
                   RITN Goals
1. Provide facilities and staff for
     intensive supportive care and treatment
     expertise in the aftermath of a marrow
     toxic incident resulting in mass
     casualties.
2. Educate hematologists, oncologists, and
     stem cell transplant practitioners about
27
     their potential involvement in the
     RITN Development Timeline
 1986 - Initiation of NMDP - Navy relationship
 ’86-’01 - Response network realized as an unfulfilled need
 2001 - NMDP begins organizing concept of core network
 2003 - NMDP transplant center physicians discuss options
 2004 - ASBMT joins initiative
 2005 - ASBMT increases emphasis
     NMDP solicits HSCT physician support
 2006 - NMDP initiates agreements with 13 transplant centers
     RITN steering committee finalizes materials
 2007 - Expansion of RITN to include donor centers and cord blood
   banks (52 total centers)
 Tomorrow…
28
Key Partners in the Development of RITN
 • American Society for Blood and Marrow Transplantation (ASBMT)
 • Department of Defense - Office of Naval Research (ONR)
 • Health Resources and Services Administration (HRSA)
 • Center for International Blood and Marrow Transplant Research
   (CIBMTR)
 • Radiation Emergency Assistance Center/Training Site (NNSA, DOE)
 • Dept. Health & Human Services - Asst. Secretary of Preparedness
   and Response (DHHS-ASPR)
 • National Library of Medicine - Radiological Event Medical
   Management (NLM-REMM) www.remm.nlm.gov
 • Leading hematopoietic stem cell transplantation physicians
  29
            Organization of RITN
                        Executive
                       Committee                     Steering
                       Co-Chaired by                Committee
                      NMDP & ASBMT
   RITN
Oversight and
Management                                  Original 13
                   ASBMT         NMDP         RITN               External
                                            Transplant           Advisors
                                             Center            (civilian and
                                             Medical          government)
                                            Directors




                               56 RITN
                               Centers

  RITN
 Network
Composition
                                                 7 NMDP &
                8 NMDP         41 NMDP
                                                   NCBI
                 Donor         Transplant
                                                 Cord Blood
                Centers         Centers
                                                   Banks
RITN Distribution Across USA




31
Possible Events Involving RITN

• Focus of preparations: Any incident resulting in
  mass casualties with a marrow toxic injury
• Examples of possible events:
     – Radiological
        •   Improvised Nuclear Device (IND)
        •   Military grade nuclear weapon
        •   Radiological exposure device (open source)
        •   Radiological Dispersal Device (RDD) a.k.a. dirty bomb
             – Less likely to overwhelm existing response resources
     – Chemical: Mustard gas
     – Unknown
33
    What Need Does RITN Fulfill?
•   Provide ready facilities with practicing
    specialists for intensive supportive care and
    treatment
   – Infrastructure and process for transplant if
       needed
• Increases transplant community awareness about
    potential need of their services in time of crisis
• Involves transplant community in emergency
    preparedness
• Most victims of a marrow toxic mass casualty
    incident will require intensive supportive care to
 34
    recover without a transplant
           RITN in Federal Response Planning:
              Improvised Nuclear Device Critical
                         AC                          MC
                                       RTR1
                                                                                     Ambulatory
                                    (collection)                         MC
                                                                                AC



                                                             RTR2
                                                            (plume)


                                                                       RTR2
                                                                      (plume)
                       RTR1
     RTR3             (blast)
                                                                                         Evacuation
  (collection)                                                                            centers
                                                                                MC

                                                              MC
    MC

                 AC                                                      AC



Modified from Weinstock et al. Blood 2008     RITN center
RITN centers are not
  first responders
 or a local response
        asset



RITN centers plan to
receive patients from
   impacted area
   RITN Centers are Cancer
         Specialists
• RITN centers are NOT first responders
  – Not HAZMAT (Hazardous Materials)
    technicians
  – Not victim triage experts
  – Not decontamination specialists
  – Not emergency medical specialists
  – Not trauma or burn specialists
• RITN staff are cancer treatment
37 experts
      RITN Centers are Cancer
            Specialists
• In the aftermath of a marrow toxic
  incident, RITN centers may be asked to:
     – Accept patient transfers to their institutions
     – Provide treatment expertise to practitioners
       caring for victims at other centers
     – Travel to other centers to provide medical
       expertise
     – Provide data on victims treated at their
       centers
38
     What RITN Offers to the Response?
•     Provide expert knowledge based on significant practical
      experience in treating patients with compromised
      immune-systems
•     Treatment facilities for victims
•     Regional dispersion other transplant physicians can talk
      to a peer in RITN
•     Available through RITN Website: www.RITN.net
     – RITN Acute Radiation Syndrome treatment
         guidelines
     – RITN center standard operating procedure
         templates
     – Donor selection criteria
     – NMDP data collection protocol
     – Training resources
     – Pertinent publications
39
     RITN Preparedness Efforts
•    Standard Operating Procedures
•    Standardized admission and treatment orders
•    Standardized data collection protocol
•    Training
     –   Basic Radiation Training (over 1800 trained since
         2006)
     –   Additional training resources on www.RITN.net
•    Coordination with international organizations
     –   EBMT and WHO - REMPAN
40
      RITN Preparedness Efforts
• Conduct readiness exercises
   – Annual tabletop exercise
   – Participate in national exercises (TOPOFF 4, Pinnacle
     07)
   – Participate in international exercises (IAEA ConEX
     2008)
• Emergency communications equipment
   – Government Emergency Telecommunication Service
     (GETS) calling cards
   – Satellite telephones
• Contracted HLA typing laboratories 6 – 10,000 per week
  during an emergency
• Internet based cord blood unit searching
• Data collection protocol
 41
 41
                   Office of Assistant Secretary
                   for Preparedness and Response

                                        ASPR


                         Immediate Office
                           of the ASPR




                             Biomedical
                                                                      Office of
                         Advanced Research   Office of Medicine,
    Office of Policy &                                             Preparedness &
                                 &                Science
    Strategic Planning                                               Emergency
                            Development       & Public Health
                                                                     Operations
                              Authority




http://www.hhs.gov/aspr/
                                                                                    42
                     Concerns
• Funding to cover cost of treatment

• Catastrophic event may overwhelm national

  capabilities

     – 10KT device → 30,000+ victims for treatment??

• Complacency in absence of an actual event

• International coordination
43
      For treatment guidelines,
       training & references:
www.RITN.net




www.REMM.NLM.gov




 44
• Why is it so hard to find radiation
  mitigators?
        Development of Radiation Injury


•   Initial Physical Interaction   Excitation, Ionization
•   Physiochemical                 Free Radical Formation
•   Chemical Damage                Radical Attack
•   Biomolecular Damage            DNA, Proteins, etc.
•   Early Biological Effects       Toxicity, Mutation
•   Late Biological Effects        Cancer, Genetic Effects
         Radiation Effects on DNA
• Chromosome Breaks are DNA Double-Strand Breaks

• >90% of Low LET-Induced Breaks are Rejoined

• Restitution; No Repair; Mis repair

• Misrepair
  – Only broken ends (telomeres?)
  – symmetric/asymmetric
  – interchromosome/intrachromosome
  – Time/dose dependent
         Necrosis                Apoptosis
All Cells                Some Cells
Passive Event            Active Process
Mitosis Dependent        Mitosis Independent

                         DNA Degradation,
Giant Cells,             Nuclear Condensation,
Micronuclei,             Apoptotic Bodies,
Abortive Colonies,       Cell Membrane Alterations,
Inflammatory Response    Phagocytosis
3-5 Divisions            Minutes to Hours
Lethal Event: Mutation   Multiple Lethal Events
Irreversible             Reversible
Why Is It Difficult to Find Mitigators?
   Multiple Pathways
   Multiple Targets – opposite effects
   Multiple Modifiers of Response
   • Repair
      – Induced
      – Cell Cycle
   • Signal Transduction
      – Mitotic Death/Apoptosis
      – Cell Cycle Arrest
             Best Practice
•   First do no harm…
•   Antibiotics/antivirals/antifungals
•   Control of GI symptoms
•   Mitigation of hematopoietic impact
•   Mitigation of skin toxicity
Devising Treatment Strategies:
Example of Intestinal Radiation Toxicity
 Pathophysiologic Process               Intervention
                               ROS scavengers, antioxidants,
     ROS-induced injury           cytoprotective agents

                                    Nutrients, GI peptides,
    Enterocyte depletion           epithelial growth factors


  Mucosal barrier breakdown   Modulators of intraluminal factors


                               Immunomodulators, cytokines,
          Mucositis           endothelial-oriented interventions

      Secretory diarrhea          Antidiarrheal interventions

    Bacterial translocation          Antibiotics, probiotics


                                          Antifibrotic
  Adverse tissue remodeling               strategies
Radiation Countermeasure Mission Space
 • ARS
   – Hematopoietic ARS:
      •   Neutropenia
      •   Thrombocytopenia
      •   Anemia
      •   Lymphopenia
   – GI ARS
   – Lung Injury
   – Kidney Injury
 • Cutaneous Radiation Syndrome
 • Combined Injury
Devising Treatment Strategies:
Example of Hematopoietic Toxicity
   Pathophysiologic Process                       Intervention
                                        ROS scavengers, antioxidants,
       ROS-induced injury                  cytoprotective agents

                                         Nutrients, Growth factors, anti-
  Committed precursor depletion                 apoptotic agents


Stem cell depletion/Stromal Damage   Modulators of cell death [MSCs, EPCs]


                                        Immunomodulators, cytokines,
           Cytopenias                  endothelial-oriented interventions

    Immunological compromise                Reconstitution of immunity

  Bacteremia, Fungemia, Viremia        Antibiotics, antifungals, antivirals


                                               Antifibrotic strategies
    Adverse tissue remodeling
Hematopoietic Syndrome
 Neutropenia
     ― Neupogen/Neulasta                         Licensed
     ― Leukine                                   Licensed
     ― Human Growth Hormone                      Licensed
     ― Endothelial Cell Transplantation          Preclinical
     ― Myeloid Progenitor Cell Transplantation   Preclinical

 Thrombocytopenia
     ― AMG 531                                   Licensed
     ― Eltrombopag                               Licensed
     ― AKR 501                                   Phase II Clinical Trial
     ― Peg-TPOmp                                 Phase III Clinical Trial
     ― TPIAO                                     Licensed in China
Neupogen




       Kuderer, et al. JCO 2007
Neupogen
TPO Survival Benefit



                                           Placebo (n=54)
                                           Placebo (n=19)
                                           0.3 ug TPO x 7d (2h; n=30)
                                           0.3 ug TPO (2h; n=10)




            (8 Gy)


                Mouthon M-A, et al. Int J Rad Onc Biol Phys 1999;43:867-875.
Median Platelet Counts and Percentages of Patients Who Completed the 12-Week Antiviral
                                    Treatment Phase




                  McHutchison J et al. N Engl J Med 2007;357:2227-2236
Novel Cell Therapy Approaches


 Myeloid Progenitor Cells   Preclinical
 Mesenchymal Stem Cells     Phase III Clinical Trial
 Endothelial Cells          Preclinical
 Mesenchymal Stem Cells (MSCs)
 “Magic” Stem Cells
     ―Home to injured tissue (whether radiation, trauma, or
     burn-induced, with engraftment shown in BM, intestines,
     kidney, lung, liver, thymus, skin)
     ―Have immunomodulatory properties, reducing inflammation
     ―Promote tissue regeneration
     ―Secrete hematopoietic cytokines, facilitating hematopoietic
     reconstitution
 Demonstrated efficacy in combined injury
     ―Accelerated healing of full-thickness round incision wound +
     20 Gy local irradiation
     ―Facilitate wound healing in general
MSCs – Radiation Skin Injury
                                Control                 Treated
                                                                             30 Gy limb irradiation
                                                                             MSCs infused 24
                                                                             hours post-irradiation




                           Human MSC-injected NOD/scid mice
Francois S, et al. Human mesenchymal stem cells favor healing of the cutaneous radiation syndrome in a
xenogenic transplant model. Ann Hematol 2007;86:1-8.
  MSCs – Thermal Injury
32 days after 30% BSA
third-degree burns
3 days after topical
application of allo MSCs
Note extensive capillary
neoangiogenesis




  Rasulov MF, et al. First experience in the use of bone marrow mesenchymal stem cells for the treatment of
  a patient with deep skin burns. Bull Exp Biol Med 2005;139:141-144.
  MSCs – Thermal Injury




Skin grafting performed
33 days after injury with
additional application of
allo MSCs




  Rasulov MF, et al. First experience in the use of bone marrow mesenchymal stem cells for the treatment of
  a patient with deep skin burns. Bull Exp Biol Med 2005;139:141-144.
MSCs – Thermal Injury
                                                            24 hours after skin graft: pain
                                                            relief
                                                            7-8 days after skin graft: blood
                                                            chemistries begin to normalize
                                                            10 days after skin graft: 99% take
                                                            observed
                                                            28 days after skin graft: patient
                                                            discharged
                                                            50 days after skin graft: patient
                                                            returns to work




Rasulov MF, et al. First experience in the use of bone marrow mesenchymal stem cells for the treatment of
a patient with deep skin burns. Bull Exp Biol Med 2005;139:141-144.
                                     Octreotide

                               500

                                                                                XRT + Vehicle
  GMP Excretion (g/g feces)

                               400



                               300



                               200


                                                             XRT + Octreotide
                               100

                                                 Sham
                                 0

                                     1   3   7     9    11     13        +1                 +7

4.2 Gy x 16:
                                                   Time (days)
 Cutaneous Radiation Syndrome
 Ulceration/Necrosis
     ―Curcumin                       Phase I/II Clinical Trial
     ―Esculentoside A (EsA)          Preclinical
     ―Celecoxib                      Licensed
     ―Mesenchymal Stem Cells         Phase III Clinical Trial
 Fibrosis
     ―Pentoxifylline (+ Vitamin E)   Licensed
     ―MnSOD                          Phase I/II Clinical Trial
Curcumin




       Okunieff P, et al. Int J Radiat Oncol Biol Phys 2006;65:890-898.
 Radiation-induced Lung Injury
 Pneumonitis
     ―KGF (palifermin)     Licensed
     ―Pentoxifylline       Licensed
     ―AEOL 10150           Phase Ib Clinical Trial
     ―MnSOD Gene Therapy   Preclinical
 Fibrosis
     ―KGF (palifermin)     Licensed
     ―Pirfenidone          Phase III Clinical Trial
     ―AEOL 10150           Phase Ib Clinical Trial
     ―Imatinib             Licensed
KGF (palifermin)
                                                           n=6 rats per group
                                                           8 Gy/d x 5d
                                                           KGF given on d5




          Chen L, et al. Int J Radiat Oncol Biol Phys 2004;60:1520-1529.
AEOL 10150




      n=16 rats per group
      28 Gy to right lung
      AEOL 10150 given by continuous infusion from d1 to 10 weeks

Rabbani ZN, et al. Long-term administration of a small molecular weight catalytic metalloporphyrin
antioxidant, AEOL 10150, protects lungs from radiation-induced injury. Int J Radiat Oncol Biol Phys
2007;67:573-580.
One Organism Has Figured It Out
• Deinococcus Radiodurans
  – Isolated from samples of canned meat
    thought to be sterilized by radiation as well
    as radioactive waste pools
  – Ancient, 2 mill years old
  – Non-pathogenic
  – Survives 1.5 x 10e6 rads
  – Grows in 6000 rads/hr conditions
  – Rapid and proper correction of double
    stranded DNA breaks
 Medications (helpful in BMT)
- Cytokines (some exist, other such as
  platelet agents are promising,
  keratinocyte growth factor (KGF),
  human growth hormone (HGH)
- Cells (hematopoetic stem cells,
  mesenchymal stem cells, endothelial
  progenitors), skin stem cells
- Supportive care: anti-diarrheals, anti-
  emetics, artificial barriers
              Technologies
• Lyophilized blood cells
  – Red, white, platelets
• Rapid dosimetry
  – Blood, teeth, hair, silica chips
• Radioprotective clothing
                    Summary

• The U.S. response to a radiation emergency is governed
  by the National Response Framework (NRF)

• NRF assigns medical care responsibilities to the
  Department of Health and Human Services

• RITN functions as a Non-Governmental Organization
  (NGO) in partnership with DHHS, ASPR to provide
  specialized care for mass casualty radiation victims
                      Resources
• Incidents:
   – IAEA nuclear incidents list: http://www-news.iaea.org/news/
   – Database of Radiological Incidents and Related Incidents:
     www.johnstonsarchive.net/nuclear/radevents/index.html
• Treatment:
   – Radiation Injury Treatment Network (RITN): www.RITN.net
   – Radiation Event Medical Management (REMM): www.remm.nlm.gov
   – Radiation Emergency Assistance Center/Training Site (REAC/TS):
     www.orau.gov/reacts
   – Radiation Countermeasures Center of Research Excellence
     (RadCCORE): www.radccore.org
• Bio-dosimetry & Treatment:
   – Armed Forces Radiobiology Research Institute (AFRRI):
     www.afrri.usuhs.mil
• Other:
   – IAEA Library:
     http://www.iaea.org/DataCenter/Library/catresources.html
   – Radiation Emergency Medical Preparedness and Assistance Network
  81 (REMPAN): www.who.int/ionizing_radiation/a_e/rempan/
  81
            Acknowledgements
•   Dennis Confer
•   Cullen Case
•   Alan Leahigh
•   Robert Krawicz
•   Daniel Weisdorf
•   David Weinstock
•   Participating BMT centers
•   Norm Coleman
•   Richard Hatchett
•   Judy Bader
•   Narayani Ramakrishnan
•   Richard Hatchett

				
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