Lymphedema and Latest Research Initiatives for Lymphedema

Eva M. Sevick-Muraca, Ph.D.

October 21, 2011 Breast Health Summit, Houston, TX

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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.

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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.

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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?

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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

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Adams and Alitalo, 2007

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Melissa Aldrich, (CMI)

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Prox1 +/- (courtesy of G. Oliver)

Normal Mice

Fluorescence White Light

Images of 6 week old VEGFR3+/- (Chy) Mouse

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Possible lymphatic vessel

Swollen abdomen

Davies-Venn

STAGING OF DISEASE Some example results

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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

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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

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Rare Diseases

Common Diseases

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SO, WHAT TO DO? HOW TO DISCOVERY CURES FOR LYMPHEDEMA

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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.

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