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Lymphedema and Latest Research Initiatives for Lymphedema
Eva M. Sevick-Muraca, Ph.D.
October 21, 2011 Breast Health Summit, Houston, TX
10/26/2011 1
Disclosures
• Investigational human studies presented herein were funded by the National Institutes of Health
• Investigational studies were approved by the FDA under several INDs and institutional IRBs.
• Investigators could receive financial gain associated with imaging techniques developed in the course of these studies.
10/26/2011 2
Acknowledgements
Center for Molecular Imaging/IMM
Milton Marshall, Ph.D.
Ali Azhdarina, Ph.D.; John C. Rasmussen, Ph.D.; Sunkuk Kwon, Ph.D.; Kristen Adams, Ph.D
Melissa Aldrich, Ph.D.; Sukhen Ghosh, Ph.D.; Pradeed Ghosh, Ph.D.; Yujie Lu, Ph.D.; I-Chih Tan, Ph.D.; Banghe Zhu, Ph.D.
Chinmay Darne, Ph.D.; Lakshmi Sampath, M.S.; Pier- Anne Lachance, B.S.; Cynthia Davies-Venn, B.S.; Germaine Agollah, M.S., Nathaniel Wilganowski, B.S.; Holly Robinson; Karen Gore
Memorial Herman Hospital/UT
Caroline E. Fife, M.D.; Erik A. Maus, M.D.; Latisha Smith, M.D., Lisa Kinder, B.S.
M.D. Anderson Cancer Center
Janice Cormier, M.D., and Funda Meric Bernstam, M.D.
Next Generation Sequencing Center/IMM
Manuel Gonzalez-Garay, Ph.D.; Otis Hall; C. Thomas Caskey, M.D.
The >250 volunteer subjects who generously gave their time and bodies for research
THE LYMPHATICS An Introduction
4
http://www.tqnyc.org/NYC04071
9/lymphatic_system.htm
Initial and Collecting Lymphatics
Lymphangion Valves
www.thodgeslmp.com
www.thodgeslmp.com
www.thodgeslmp.com
Alitalo, K., et.al., Nature, 2005.
10/26/2011 6
Lymphedema
• 3-5 million Americans suffer from lymphedema; 12 million are at risk
• Occurs months to years after cancer treatment, estimated to afflict between 9 – 40% of all breast cancer survivors
• Increased risk with axillary lymph node dissection
• Increased risk with radiation treatment
• Also occurs rarely as a congenital disease
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HOW TO IMAGE THE LYMPHATICS?
8
Current “State-of-the Art”
lymphatic capillaries
pre-collectors
collectors
lymph node
systemic circulation
NIR Fluorescent Lymphatic Contrast Agent
Melissa Aldrich, (CMI) 10/26/2011 9
NIR Fluorescence Imaging Device
10
Melissa Aldrich, (CMI) 10/26/2011
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a b
d
Axilla Shoulder
Forearm
Upper arm
Elbow
Thigh
Groin
Thigh
Calf
c
Upper arm
Mic
rod
osi
ng:
Sev
ick-
Mu
raca
, et
al.,
Rad
iolo
gy, 2
00
8
NIRFLI versus lymphoscintigraphy
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DISEASED LYMPHATICS
Some example results
Rasmussen, et al., 2009, 2010
14
Adams and Alitalo, 2007
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Melissa Aldrich, (CMI)
10/26/2011 18
Prox1 +/- (courtesy of G. Oliver)
Normal Mice
Fluorescence White Light
Images of 6 week old VEGFR3+/- (Chy) Mouse
19/30
Possible lymphatic vessel
Swollen abdomen
Davies-Venn
STAGING OF DISEASE Some example results
20
Imaging progression of BCRL
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Melissa Aldrich, (CMI)
hyperplasia of vessels/tortuous
lymphatic bundles
a b c
nonmobile extravascular
ICG/hypoplasia
“starry night” mobile
extravascular ICG/hypoplasia
d
Lymphatic architectural anomalies observed in BCRL subjects.
Melissa Aldrich, (CMI)
STIMULATION OF LYMPHATIC FUNCTION
Some example results
Adams, et al., 2010, Tan et al., 2011
23
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Pneumatic Compression Devices (PCDs)
Vessel recruitment
THE GENETICS OF RARE LYMPHATIC DISORDERS
An Introduction
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The “Genotype”
10/26/2011 35 Adapted from Trusolino, et al., 2010
Whole Exome Sequencing
Exons, information necessary to generate proteins
Introns
5' 3' GENE1
• The Human Genome has 6 billion base pairs, but only 1-2 % of the Genome has Information necessary to generate proteins
• (90 million base pairs)
• Genes are blocks of Exons
• Exome = all exons
10/26/2011 37 The “Phenotype”
Family Studies
• Rare diseases provide insight into more common diseases
• Efficient genetic studies require entire family studies for gene discovery
10/26/2011 38
Rare Diseases
Common Diseases
10/26/2011 39
SO, WHAT TO DO? HOW TO DISCOVERY CURES FOR LYMPHEDEMA
10/26/2011 40
Summary/Speculations
• Lymphatic involvement plays a significant role in the development of lymphedema.
• NIR fluorescence lymphatic imaging could play a role in diagnosing, identifying treatment.
• Family genetic studies of rare diseases could provide opportunities to understand breast cancer related lymphedema.
10/26/2011 41