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Image-based 3D modeling study of the influence of vessel density and blood hemoglobin concentration on tumor oxygenation and response to irradiation

Lagerlöf, Jakob H ; Kindblom, Jon ; Cortez, Eliane ; Pietras, Kristian LU and Bernhardt, Peter (2013) In Medical Physics 40(2). p.024101-024101
Abstract

PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation.

METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the... (More)

PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation.

METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model).

RESULTS: Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations.

CONCLUSIONS: Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Blood Vessels/metabolism, Hemoglobins/metabolism, Insulinoma/blood, Mice, Models, Biological, Oxygen/metabolism, Pancreatic Neoplasms/blood, Treatment Outcome
in
Medical Physics
volume
40
issue
2
pages
024101 - 024101
publisher
American Association of Physicists in Medicine
external identifiers
  • pmid:23387780
  • scopus:84873592570
ISSN
0094-2405
DOI
10.1118/1.4773886
language
English
LU publication?
yes
id
bb073169-3842-4be6-8de4-00eb1bf804db
date added to LUP
2019-06-19 21:26:10
date last changed
2020-09-23 07:46:56
@article{bb073169-3842-4be6-8de4-00eb1bf804db,
  abstract     = {<p>PURPOSE: Hypoxia is one of the most important factors influencing clinical outcome after radiotherapy. Improved knowledge of factors affecting the levels and distribution of oxygen within a tumor is needed. The authors constructed a theoretical 3D model based on histological images to analyze the influence of vessel density and hemoglobin (Hb) concentration on the response to irradiation.</p><p>METHODS: The pancreases of a Rip-Tag2 mouse, a model of malignant insulinoma, were excised, cryosectioned, immunostained, and photographed. Vessels were identified by image thresholding and a 3D vessel matrix assembled. The matrix was reduced to functional vessel segments and enlarged by replication. The steady-state oxygen tension field of the tumor was calculated by iteratively employing Green's function method for diffusion and the Michaelis-Menten model for consumption. The impact of vessel density on the radiation response was studied by removing a number of randomly selected vessels. The impact of Hb concentration was studied by independently changing vessel oxygen partial pressure (pO(2)). For each oxygen distribution, the oxygen enhancement ratio (OER) was calculated and the mean absorbed dose at which the tumor control probability (TCP) was 0.99 (D(99)) was determined using the linear-quadratic cell survival model (LQ model).</p><p>RESULTS: Decreased pO(2) shifted the oxygen distribution to lower values, whereas decreased vessel density caused the distribution to widen and shift to lower values. Combined scenarios caused lower-shifted distributions, emphasising log-normal characteristics. Vessel reduction combined with increased blood pO(2) caused the distribution to widen due to a lack of vessels. The most pronounced radiation effect of increased pO(2) occurred with tumor tissue with 50% of the maximum vessel density used in the simulations. A 51% decrease in D(99), from 123 to 60 Gy, was found between the lowest and highest pO(2) concentrations.</p><p>CONCLUSIONS: Our results indicate that an intermediate vascular density region exists where enhanced blood oxygen concentration may be beneficial for radiation response. The results also suggest that it is possible to distinguish between diffusion-limited and anemic hypoxia from the characteristics of the pO(2) distribution.</p>},
  author       = {Lagerlöf, Jakob H and Kindblom, Jon and Cortez, Eliane and Pietras, Kristian and Bernhardt, Peter},
  issn         = {0094-2405},
  language     = {eng},
  number       = {2},
  pages        = {024101--024101},
  publisher    = {American Association of Physicists in Medicine},
  series       = {Medical Physics},
  title        = {Image-based 3D modeling study of the influence of vessel density and blood hemoglobin concentration on tumor oxygenation and response to irradiation},
  url          = {http://dx.doi.org/10.1118/1.4773886},
  doi          = {10.1118/1.4773886},
  volume       = {40},
  year         = {2013},
}