Page 294 - 2014 Printable Abstract Book
P. 294
(PS5-13) Total Body irradiation in the “hematopoietic” dose range induces substantial intestinal injury
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in Non-Human Primates. Junru Wang, MD, PhD ; Liya Liu, MS ; Simon Authie ; Mylene Pouliot ; and
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1;3
Martin Hauer-Jensen, MD, PhD ; University of Arkansas for Medical Sciences, Little Rock, AR ; CiToxLAB,
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2
Laval, Canada ; and Central Arkansas Veterans Healthcare System, Little Rock, AR
Background: So-called “gut associated sepsis” is a major cause of lethality after exposure to total
body irradiation (TBI) in nuclear accidents and radiological terrorism scenarios. While the Rhesus macaque
monkey is used as a model for acute radiation syndrome (ARS), structural changes in various parts of the
intestine after TBI have not been systematically studied. In the present study, we describe TBI-induced
intestinal structural injury of Rhesus macaque after TBI doses typically associated with the hematopoietic
ARS. Methods and Materials: 24 Rhesus macaque monkeys were divided into three groups: sham, 6.7Gy
60
(LD70/60) and 7.4Gy (LD90/60) total body Co gamma radiation. Groups of animals were euthanized at
4, 7 and 12 days after irradiation. Different parts of small intestines (duodenum, proximal jejunum, distal
jejunum, and ileum) were procured and fixed in 10% formalin. Thorough histopathologic analysis was
performed and intestinal mucosal surface length, villus height and crypt depth were assessed by
computer-assisted image analysis. Results: Histopathologically, all segments exhibited conspicuous
disappearance of plicae circulares and prominent atrophy of crypts and villi. Intestinal mucosal surface
length was significantly decreased in all intestinal segments on day 4, 7 and 12 after irradiation (p<0.02-
p<0.0002). Villus height was significantly reduced in all segments on day 4 and day 7 (p=0.02-0.005),
whereas it had recovered by day 12 (p>0.05). Crypt depth was also significantly reduced in all segments
on day 4, 7 and 12 after irradiation (p<0.04-p<0.00004). Summary: TBI in the “hematopoietic” dose range
induces consistent changes in several compartments and in all segments of the small bowel. These
findings point to the importance of maintaining the mucosal barrier that separates the gut microbiome
from the body’s interior after exposure to TBI.
(PS5-14) A model comparing the clinical application of a variable relative biological effectiveness based
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1
on high resolution in vitro studies. Thomas I. Marshall, MSci ; Pankaj Chaudhary, PhD ; Francesca M.
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Perozziello, MSc ; Lorenzo Manti, PhD ; Frederick J. f.j.currell@qub.ac.uk, PhD ; Stephen J. McMahon,
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PhD ; Joy N. Kavanagh, PhD ; Giuseppe A.P. Cirrone, PhD ; Francesco Romano, PhD ; Kevin M. Prise, PhD ;
1;4
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and Giuseppe Schettino, PhD ; Queen's University Belfast, Belfast, United Kingdom ; University of Naples
3
2
Federico II, Naples, Italy ; Istituto Nazionale di Fisica Nucleare, Catania, Italy ; and National Physical
Laboratory, Teddington, United Kingdom
4
The utilization of a constant, generic Relative Biological Effectiveness (RBE) of 1.1 in clinical proton
radiotherapy represents a broad average based on available experimental in vitro and in vivo data,
disregarding the significant increase of Linear Energy Transfer (LET) in the distal region of the Spread Out
Bragg Peak (SOBP). Based on previous high resolution in vitro measurements using 62 MeV proton beams
1
at the INFN-LNS (Catania, Italy) , observations of significant cell killing RBE variations along the ion path
suggest a clear RBE dependence on LET, with a sharp increase of RBE coinciding with the increase in LET
in the distal region. Validated by the Local Effect Model (LEM), the resultant biological dose sees increased
cell killing in the tumor region, as well as an extension of the biologically effective range, which may be of
significance in clinical treatment planning. The availability of high quality in vitro measurements of normal
and radioresistant cell lines has allowed the formulation of a model predicting RBE in terms of LET and
intrinsic radiosensitivity. By applying this model in basic treatment plans alongside Monte Carlo
292 | P a g e
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2
1
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in Non-Human Primates. Junru Wang, MD, PhD ; Liya Liu, MS ; Simon Authie ; Mylene Pouliot ; and
1
1;3
Martin Hauer-Jensen, MD, PhD ; University of Arkansas for Medical Sciences, Little Rock, AR ; CiToxLAB,
3
2
Laval, Canada ; and Central Arkansas Veterans Healthcare System, Little Rock, AR
Background: So-called “gut associated sepsis” is a major cause of lethality after exposure to total
body irradiation (TBI) in nuclear accidents and radiological terrorism scenarios. While the Rhesus macaque
monkey is used as a model for acute radiation syndrome (ARS), structural changes in various parts of the
intestine after TBI have not been systematically studied. In the present study, we describe TBI-induced
intestinal structural injury of Rhesus macaque after TBI doses typically associated with the hematopoietic
ARS. Methods and Materials: 24 Rhesus macaque monkeys were divided into three groups: sham, 6.7Gy
60
(LD70/60) and 7.4Gy (LD90/60) total body Co gamma radiation. Groups of animals were euthanized at
4, 7 and 12 days after irradiation. Different parts of small intestines (duodenum, proximal jejunum, distal
jejunum, and ileum) were procured and fixed in 10% formalin. Thorough histopathologic analysis was
performed and intestinal mucosal surface length, villus height and crypt depth were assessed by
computer-assisted image analysis. Results: Histopathologically, all segments exhibited conspicuous
disappearance of plicae circulares and prominent atrophy of crypts and villi. Intestinal mucosal surface
length was significantly decreased in all intestinal segments on day 4, 7 and 12 after irradiation (p<0.02-
p<0.0002). Villus height was significantly reduced in all segments on day 4 and day 7 (p=0.02-0.005),
whereas it had recovered by day 12 (p>0.05). Crypt depth was also significantly reduced in all segments
on day 4, 7 and 12 after irradiation (p<0.04-p<0.00004). Summary: TBI in the “hematopoietic” dose range
induces consistent changes in several compartments and in all segments of the small bowel. These
findings point to the importance of maintaining the mucosal barrier that separates the gut microbiome
from the body’s interior after exposure to TBI.
(PS5-14) A model comparing the clinical application of a variable relative biological effectiveness based
1
1
on high resolution in vitro studies. Thomas I. Marshall, MSci ; Pankaj Chaudhary, PhD ; Francesca M.
2
1
2
Perozziello, MSc ; Lorenzo Manti, PhD ; Frederick J. f.j.currell@qub.ac.uk, PhD ; Stephen J. McMahon,
3
1
1
3
1
PhD ; Joy N. Kavanagh, PhD ; Giuseppe A.P. Cirrone, PhD ; Francesco Romano, PhD ; Kevin M. Prise, PhD ;
1;4
1
and Giuseppe Schettino, PhD ; Queen's University Belfast, Belfast, United Kingdom ; University of Naples
3
2
Federico II, Naples, Italy ; Istituto Nazionale di Fisica Nucleare, Catania, Italy ; and National Physical
Laboratory, Teddington, United Kingdom
4
The utilization of a constant, generic Relative Biological Effectiveness (RBE) of 1.1 in clinical proton
radiotherapy represents a broad average based on available experimental in vitro and in vivo data,
disregarding the significant increase of Linear Energy Transfer (LET) in the distal region of the Spread Out
Bragg Peak (SOBP). Based on previous high resolution in vitro measurements using 62 MeV proton beams
1
at the INFN-LNS (Catania, Italy) , observations of significant cell killing RBE variations along the ion path
suggest a clear RBE dependence on LET, with a sharp increase of RBE coinciding with the increase in LET
in the distal region. Validated by the Local Effect Model (LEM), the resultant biological dose sees increased
cell killing in the tumor region, as well as an extension of the biologically effective range, which may be of
significance in clinical treatment planning. The availability of high quality in vitro measurements of normal
and radioresistant cell lines has allowed the formulation of a model predicting RBE in terms of LET and
intrinsic radiosensitivity. By applying this model in basic treatment plans alongside Monte Carlo
292 | P a g e
