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Palmer, Gregory M.

Overview:

Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therapeutic response. To this end he has implemented a model-based approach for extracting absorber and scatterer properties from diffuse reflectance and fluorescence measurements. More recently he has developed quantitative imaging methodologies for intravital microscopy to characterize tumor functional and molecular response to radiation and chemotherapy. His awards have included the Jack Fowler Award from the Radiation Research Society.

Laboratory Website:
https://radonc.duke.edu/research-education/research-labs/radiation-and-c... />

Positions:

Associate Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2005

Ph.D. — University of Wisconsin at Madison

News:

Grants:

Muscle-macrophage constructs for skeletal muscle repair

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2016
End Date
August 31, 2021

Sepsis-induced Red Cell Dysfunction (SiRD)

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
Washington University
Role
Investigator
Start Date
June 01, 2015
End Date
January 31, 2018

MAA drug PK and Efficiacy Study Phases I- II-III

Administered By
Radiation Oncology
AwardedBy
Preclinical Pathfinder Systems
Role
Principal Investigator
Start Date
September 29, 2016
End Date
September 22, 2017

Hand-held advanced functional imager for assessing local tissue oxygenation

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
Wasatch Photonics, Inc.
Role
Co-Principal Investigator
Start Date
September 15, 2016
End Date
June 30, 2017

Innate immune adaptations of hibernation as a new approach to protection against acute organ injury

Administered By
Anesthesiology, Cardiothoracic
AwardedBy
Society of Cardiovascular Anesthesiologists
Role
Significant Contributor
Start Date
July 01, 2015
End Date
June 30, 2017

Circumventing Therapeutic Resistance and the Emergence of Disseminated Breast Cancer Cells

Administered By
Chemistry
AwardedBy
United States Army Medical Research Acquisition Activity
Role
Assistant Research Professor
Start Date
July 01, 2013
End Date
June 30, 2017

Luminescent Oxygen Nanosensors for Tumor Hypoxia Imaging

Administered By
Radiation Oncology
AwardedBy
University of Virginia - Charlottesville
Role
Co-Principal Investigator
Start Date
September 25, 2012
End Date
June 30, 2017

A Novel Optical Spectral Imaging System for Rapid Imaging of Breast Tumor Margins

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
April 01, 2011
End Date
March 31, 2017

Janssen Research AGreement

Administered By
Radiation Oncology
AwardedBy
Janssen Research & Development, LLC
Role
Co Investigator
Start Date
November 27, 2014
End Date
December 31, 2016

HIF-1 driven therapeutic resistance mechanisms in chest wall recurrences of inflammatory breast cancer (IBC)

Administered By
Radiation Oncology
AwardedBy
Inflammatory Breast Cancer Research Foundation
Role
Collaborator
Start Date
December 01, 2013
End Date
December 31, 2016

Wound-Vac

Administered By
Radiation Oncology
AwardedBy
Preclinical Pathfinder Systems
Role
Principal Investigator
Start Date
December 10, 2015
End Date
December 09, 2016

Neocortical hemodynamics during epileptic activity in primates and humans

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 15, 2009
End Date
March 31, 2015

27-hydroxycholesterol as a link between obesity and breast cancer pathogenesis

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
January 01, 2013
End Date
August 31, 2014

Investigation of Anti-Angiogenic Mechanisms Using Novel Imaging Techniques

Administered By
Biomedical Engineering
AwardedBy
US Army Medical Research and Materiel Command
Role
Research Associate
Start Date
February 01, 2009
End Date
February 29, 2012
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Publications:

Luminescent Difluoroboron β-Diketonate PLA-PEG Nanoparticle.

Luminescent difluoroboron β-diketonate poly(lactic acid) (BF2bdkPLA) materials serve as biological imaging agents. In this study, dye structures were modified to achieve emission colors that span the visible region with potential for multiplexing applications. Four dyes with varying π-conjugation (phenyl, naphthyl) and donor groups (-OMe, -NMe2) were coupled to PLLA-PEG block copolymers (∼11 kDa) by a postpolymerization Mitsunobu reaction. The resulting dye-polymer conjugates were fabricated as nanoparticles (∼55 nm diameter) to produce nanomaterials with a range of emission colors (420-640 nm). For increased stability, dye-PLLA-PEG conjugates were also blended with dye-free PDLA-PEG to form stereocomplex nanoparticles of smaller size (∼45 nm diameter). The decreased dye loading in the stereoblocks blue-shifted the emission, generating a broader range of fluorescence colors (410-620 nm). Tumor accumulation was confirmed in a murine model through biodistribution studies with a red emitting dimethyl amino-substituted dye-polymer analogue. The synthesis, optical properties, oxygen-sensing capabilities, and stability of these block copolymer nanoparticles are presented.

Authors
Kerr, C; DeRosa, CA; Daly, ML; Zhang, H; Palmer, GM; Fraser, CL
MLA Citation
Kerr, C, DeRosa, CA, Daly, ML, Zhang, H, Palmer, GM, and Fraser, CL. "Luminescent Difluoroboron β-Diketonate PLA-PEG Nanoparticle." Biomacromolecules 18.2 (February 2, 2017): 551-561.
PMID
28150934
Source
epmc
Published In
Biomacromolecules
Volume
18
Issue
2
Publish Date
2017
Start Page
551
End Page
561
DOI
10.1021/acs.biomac.6b01708

Miniature spectral imaging device for wide-field quantitative functional imaging of the morphological landscape of breast tumor margins.

Authors
Nichols, BS; Llopis, A; Palmer, GM; McCachren, SS; Senlik, O; Miller, D; Brooke, MA; Jokerst, NM; Geradts, J; Greenup, R; Ramanujam, N
MLA Citation
Nichols, BS, Llopis, A, Palmer, GM, McCachren, SS, Senlik, O, Miller, D, Brooke, MA, Jokerst, NM, Geradts, J, Greenup, R, and Ramanujam, N. "Miniature spectral imaging device for wide-field quantitative functional imaging of the morphological landscape of breast tumor margins." Journal of biomedical optics 22.2 (February 2017): 26007-.
PMID
28241273
Source
epmc
Published In
Journal of Biomedical Optics
Volume
22
Issue
2
Publish Date
2017
Start Page
26007
DOI
10.1117/1.jbo.22.2.026007

Tunable and amplified Raman gold nanoprobes for effective tracking (TARGET): in vivo sensing and imaging.

We describe the development of a highly tunable, physiologically stable, and ultra-bright Raman probe, named as TARGET (Tunable and Amplified Raman Gold Nanoprobes for Effective Tracking), for in vitro and in vivo surface-enhanced Raman scattering (SERS) applications. The TARGET structure consists of a gold core inside a larger gold shell with a tunable interstitial gap similar to a "nanorattle" structure. The combination of galvanic replacement and the seed mediated growth method was employed to load Raman reporter molecules and subsequently close the pores to prevent leaking and degradation of reporters under physiologically extreme conditions. Precise tuning of the core-shell gap width, core size, and shell thickness allows us to modulate the plasmonic effect and achieve a maximum electric-field (E-field) intensity. The interstitial gap of TARGET nanoprobes can be designed to exhibit a plasmon absorption band at 785 nm, which is in resonance with the dye absorption maximum and lies in the "tissue optical window", resulting in ultra-bright SERS signals for in vivo studies. The results of in vivo measurements of TARGETs in laboratory mice illustrated the usefulness of these nanoprobes for medical sensing and imaging.

Authors
Gandra, N; Hendargo, HC; Norton, SJ; Fales, AM; Palmer, GM; Vo-Dinh, T
MLA Citation
Gandra, N, Hendargo, HC, Norton, SJ, Fales, AM, Palmer, GM, and Vo-Dinh, T. "Tunable and amplified Raman gold nanoprobes for effective tracking (TARGET): in vivo sensing and imaging." Nanoscale 8.16 (April 11, 2016): 8486-8494.
PMID
27064259
Source
epmc
Published In
Nanoscale
Volume
8
Issue
16
Publish Date
2016
Start Page
8486
End Page
8494
DOI
10.1039/c5nr08980h

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.

In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF-α-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-α-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and αvβ3 integrin, and leukocyte CD44 and β2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises.

Authors
Zhao, Y; Schwartz, EA; Palmer, GM; Zennadi, R
MLA Citation
Zhao, Y, Schwartz, EA, Palmer, GM, and Zennadi, R. "MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30.3 (March 2016): 1171-1186.
PMID
26631480
Source
epmc
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
30
Issue
3
Publish Date
2016
Start Page
1171
End Page
1186
DOI
10.1096/fj.15-278481

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.

To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

Authors
Ashcraft, KA; Boss, M-K; Tovmasyan, A; Roy Choudhury, K; Fontanella, AN; Young, KH; Palmer, GM; Birer, SR; Landon, CD; Park, W; Das, SK; Weitner, T; Sheng, H; Warner, DS; Brizel, DM; Spasojevic, I; Batinic-Haberle, I; Dewhirst, MW
MLA Citation
Ashcraft, KA, Boss, M-K, Tovmasyan, A, Roy Choudhury, K, Fontanella, AN, Young, KH, Palmer, GM, Birer, SR, Landon, CD, Park, W, Das, SK, Weitner, T, Sheng, H, Warner, DS, Brizel, DM, Spasojevic, I, Batinic-Haberle, I, and Dewhirst, MW. "Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model." International journal of radiation oncology, biology, physics 93.4 (November 2015): 892-900.
PMID
26530759
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
4
Publish Date
2015
Start Page
892
End Page
900
DOI
10.1016/j.ijrobp.2015.07.2283

Renitrosylation of banked human red blood cells improves deformability and reduces adhesivity.

Transfusion of red blood cells (RBCs) is a frequent health care practice. However, unfavorable consequences may occur from transfusions of stored RBCs and are associated with RBC changes during storage. Loss of S-nitrosohemoglobin (SNO-Hb) and other S-nitrosothiols (SNOs) during storage is implicated as a detriment to transfusion efficacy. It was hypothesized that restoring SNOs within banked RBCs would improve RBC functions relevant to successful transfusion outcomes, namely, increased deformability and decreased adhesivity.Stored human RBCs were incubated with nitric oxide (NO) donors PROLI/NO and DEA/NO (disodium 1-[2-(carboxylato)-pyrrolidin-1-yl]diazen-1-ium-1,2-diolate and diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate) under varying experimental conditions (e.g., aerobic/anaerobic incubation, NO donor to RBC ratio). SNO restoration was evaluated in vitro and in vivo as a means to improve RBC function after storage.Incubation of RBCs with the NO donors resulted in 10-fold greater levels of SNO-Hb versus untreated control or sham RBCs, with significantly higher Hb-bound NO yields from an NO dose delivered by DEA/NO. RBC incubation with DEA/NO at a stoichiometry of 1:62.5 NO:Hb significantly increased RBC deformabilty and reduced adhesion to cultured endothelial cells. RBC incubation with DEA/NO also increased S-nitrosylation of RBC cytoskeletal and membrane proteins, including the β-spectrin chain. Renitrosylation attenuated both RBC sequestration in the lung and the mild blood oxygen saturation impairments seen with banked RBCs in a mouse model of transfusion.RBC renitrosylation using NO donors has promise for correcting deficient properties (e.g., adhesivity, rigidity, and SNO loss) of banked RBCs and in turn improving transfusion outcomes.

Authors
Riccio, DA; Zhu, H; Foster, MW; Huang, B; Hofmann, CL; Palmer, GM; McMahon, TJ
MLA Citation
Riccio, DA, Zhu, H, Foster, MW, Huang, B, Hofmann, CL, Palmer, GM, and McMahon, TJ. "Renitrosylation of banked human red blood cells improves deformability and reduces adhesivity." Transfusion 55.10 (October 2015): 2452-2463.
PMID
26098062
Source
epmc
Published In
Transfusion
Volume
55
Issue
10
Publish Date
2015
Start Page
2452
End Page
2463
DOI
10.1111/trf.13189

Snap-shot multispectral imaging of vascular dynamics in a mouse window-chamber model.

Understanding tumor vascular dynamics through parameters such as blood flow and oxygenation can yield insight into tumor biology and therapeutic response. Hyperspectral microscopy enables optical detection of hemoglobin saturation or blood velocity by either acquiring multiple images that are spectrally distinct or by rapid acquisition at a single wavelength over time. However, the serial acquisition of spectral images over time prevents the ability to monitor rapid changes in vascular dynamics and cannot monitor concurrent changes in oxygenation and flow rate. Here, we introduce snap shot-multispectral imaging (SS-MSI) for use in imaging the microvasculature in mouse dorsal-window chambers. By spatially multiplexing spectral information into a single-image capture, simultaneous acquisition of dynamic hemoglobin saturation and blood flow over time is achieved down to the capillary level and provides an improved optical tool for monitoring rapid in vivo vascular dynamics.

Authors
Hendargo, HC; Zhao, Y; Allenby, T; Palmer, GM
MLA Citation
Hendargo, HC, Zhao, Y, Allenby, T, and Palmer, GM. "Snap-shot multispectral imaging of vascular dynamics in a mouse window-chamber model." Optics letters 40.14 (July 2015): 3292-3295.
Website
http://hdl.handle.net/10161/10324
PMID
26176452
Source
epmc
Published In
Optics Letters
Volume
40
Issue
14
Publish Date
2015
Start Page
3292
End Page
3295
DOI
10.1364/ol.40.003292

Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.

Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.

Authors
Betof, AS; Lascola, CD; Weitzel, D; Landon, C; Scarbrough, PM; Devi, GR; Palmer, G; Jones, LW; Dewhirst, MW
MLA Citation
Betof, AS, Lascola, CD, Weitzel, D, Landon, C, Scarbrough, PM, Devi, GR, Palmer, G, Jones, LW, and Dewhirst, MW. "Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise." Journal of the National Cancer Institute 107.5 (May 2015).
Website
http://hdl.handle.net/10161/12580
PMID
25780062
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
5
Publish Date
2015
DOI
10.1093/jnci/djv040

Oxygen Sensing Difluoroboron Dinaphthoylmethane Polylactide.

Dual emissive luminescence properties of solid-state difluoroboron β-diketonate-poly(lactic acid) (BF2bdk-PLA) materials have been utilized as biological oxygen sensors. Dyes with red-shifted absorption and emission are important for multiplexing and in vivo imaging, thus hydroxyl-functionalized dinaphthoylmethane initiators and dye-PLA conjugates BF2dnm(X)PLA (X = H, Br, I) with extended conjugation were synthesized. The luminescent materials show red-shifted absorbance (~435 nm) and fluorescence tunability by molecular weight. Fluorescence colors range from yellow (~530 nm) in 10 - 12 kDa polymers to green (~490 nm) in 20 - 30 kDa polymers. Room-temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) are present under a nitrogen atmosphere. For the iodine-substituted derivative, BF2dnm(I)PLA, clearly distinguishable fluorescence (green) and phosphorescence (orange) peaks are present, making it ideal for ratiometric oxygen-sensing and imaging. Bromide and hydrogen analogues with weaker relative phosphorescence intensities and longer phosphorescence lifetimes can be used as highly sensitive, concentration independent, lifetime-based oxygen sensors or for gated emission detection. BF2dnm(I)PLA nanoparticles were taken up by T41 mouse mammary cells and successfully demonstrated differences in vitro ratiometric measurement of oxygen.

Authors
DeRosa, CA; Samonina-Kosicka, J; Fan, Z; Hendargo, HC; Weitzel, DH; Palmer, GM; Fraser, CL
MLA Citation
DeRosa, CA, Samonina-Kosicka, J, Fan, Z, Hendargo, HC, Weitzel, DH, Palmer, GM, and Fraser, CL. "Oxygen Sensing Difluoroboron Dinaphthoylmethane Polylactide." Macromolecules 48.9 (May 2015): 2967-2977.
PMID
26056421
Source
epmc
Published In
Macromolecules
Volume
48
Issue
9
Publish Date
2015
Start Page
2967
End Page
2977
DOI
10.1021/acs.macromol.5b00394

Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging

© 2015 Wiley-VCH Verlag GmbH & Co. KGaA.Surface modification of nanoparticles and biosensors is a dynamic, expanding area of research for targeted delivery in vivo. For more efficient delivery, surfaces are PEGylated to impart stealth properties, long circulation, and enable enhanced permeability and retention (EPR) in tumor tissues. Previously, BF2dbm(I)PLA was proven to be a good oxygen nanosensor material for tumor hypoxia imaging in vivo, though particles were applied directly to the tumor and surrounding region. Further surface modification is needed for this dual-emissive oxygen sensitive material for effective intravenous (IV) administration and passive and active delivery to tumors. In this paper, an efficient synthesis of a new dual-emissive material BF2dbm(I)PLA-mPEG is presented and in vitro stability studies are conducted. It is found that fabricated nanoparticles are stable for 24 weeks as a suspension, while after 25 weeks the nanoparticles swell and both dye and polymer degradation escalates. Preliminary studies show BF2dbm(I) PLA-mPEG nanoparticle accumulation in a window chamber mammary tumor 24 h after IV injection into mice (C57Bl/6 strain) enabling tumor oxygen imaging. (Graph Presented)

Authors
Samonina-Kosicka, J; Weitzel, DH; Hofmann, CL; Hendargo, H; Hanna, G; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, J, Weitzel, DH, Hofmann, CL, Hendargo, H, Hanna, G, Dewhirst, MW, Palmer, GM, and Fraser, CL. "Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging." Macromolecular Rapid Communications 36.7 (April 1, 2015): 694-699.
Source
scopus
Published In
Macromolecular Rapid Communications
Volume
36
Issue
7
Publish Date
2015
Start Page
694
End Page
699
DOI
10.1002/marc.201500022

Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging.

Surface modification of nanoparticles and biosensors is a dynamic, expanding area of research for targeted delivery in vivo. For more efficient delivery, surfaces are PEGylated to impart stealth properties, long circulation, and enable enhanced permeability and retention (EPR) in tumor tissues. Previously, BF2 dbm(I)PLA was proven to be a good oxygen nanosensor material for tumor hypoxia imaging in vivo, though particles were applied directly to the tumor and surrounding region. Further surface modification is needed for this dual-emissive oxygen sensitive material for effective intravenous (IV) administration and passive and active delivery to tumors. In this paper, an efficient synthesis of a new dual-emissive material BF2 dbm(I)PLA-mPEG is presented and in vitro stability studies are conducted. It is found that fabricated nanoparticles are stable for 24 weeks as a suspension, while after 25 weeks the nanoparticles swell and both dye and polymer degradation escalates. Preliminary studies show BF2 dbm(I)PLA-mPEG nanoparticle accumulation in a window chamber mammary tumor 24 h after IV injection into mice (C57Bl/6 strain) enabling tumor oxygen imaging.

Authors
Samonina-Kosicka, J; Weitzel, DH; Hofmann, CL; Hendargo, H; Hanna, G; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, J, Weitzel, DH, Hofmann, CL, Hendargo, H, Hanna, G, Dewhirst, MW, Palmer, GM, and Fraser, CL. "Luminescent difluoroboron β-diketonate PEG-PLA oxygen nanosensors for tumor imaging." Macromolecular rapid communications 36.7 (April 2015): 694-699.
PMID
25753154
Source
epmc
Published In
Macromolecular Rapid Communications
Volume
36
Issue
7
Publish Date
2015
Start Page
694
End Page
699
DOI
10.1002/marc.201500022

Characterization of Inflammatory Cell Response to Implanted Porous P-HEMA in the Dermis Vs Subcutaneous Tissue

Authors
Boico, A; Cho, E; Liao, L; Register, J; Fales, A; Wisnewski, N; Pradhan, S; Vo-Dihn, T; Palmer, G; Klitzman, B
MLA Citation
Boico, A, Cho, E, Liao, L, Register, J, Fales, A, Wisnewski, N, Pradhan, S, Vo-Dihn, T, Palmer, G, and Klitzman, B. "Characterization of Inflammatory Cell Response to Implanted Porous P-HEMA in the Dermis Vs Subcutaneous Tissue." April 2015.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
29
Publish Date
2015

Vascularization of Porous PolyHEMA Scaffolds

Authors
Liao, L; Cho, E; Boico, A; Register, J; Fales, A; Helton, K; Wisniewski, N; Vo-Dinh, T; Palmer, G; Klitzman, B
MLA Citation
Liao, L, Cho, E, Boico, A, Register, J, Fales, A, Helton, K, Wisniewski, N, Vo-Dinh, T, Palmer, G, and Klitzman, B. "Vascularization of Porous PolyHEMA Scaffolds." April 2015.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
29
Publish Date
2015

Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis.

Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects.

Authors
Fontanella, AN; Boss, M-K; Hadsell, M; Zhang, J; Schroeder, T; Berman, KG; Dewhirst, MW; Chang, S; Palmer, GM
MLA Citation
Fontanella, AN, Boss, M-K, Hadsell, M, Zhang, J, Schroeder, T, Berman, KG, Dewhirst, MW, Chang, S, and Palmer, GM. "Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis." Radiation research 183.2 (February 2015): 147-158.
PMID
25574586
Source
epmc
Published In
Radiation Research
Volume
183
Issue
2
Publish Date
2015
Start Page
147
End Page
158
DOI
10.1667/rr13712.1

Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats.

Because the lung is a major target organ of metastatic disease, animal models to study the physiology of pulmonary metastases are of great importance. However, very few methods exist to date to investigate lung metastases in a dynamic fashion at the microcirculatory level, due to the difficulty to access the lung with a microscope. Here, an intravital microscopy method is presented to functionally image and quantify the microcirculation of superficial pulmonary metastases in rats, using a closed-chest pulmonary window and automated analysis of blood flow velocity and direction. The utility of this method is demonstrated to measure increases in blood flow velocity in response to pharmacological intervention, and to image the well-known tortuous vasculature of solid tumors. This is the first demonstration of intravital microscopy on pulmonary metastases in a closed-chest model. Because of its minimized invasiveness, as well as due to its relative ease and practicality, this technology has the potential to experience widespread use in laboratories that specialize on pulmonary tumor research.

Authors
Blueschke, G; Hanna, G; Fontanella, AN; Palmer, GM; Boico, A; Min, H; Dewhirst, MW; Irwin, DC; Zhao, Y; Schroeder, T
MLA Citation
Blueschke, G, Hanna, G, Fontanella, AN, Palmer, GM, Boico, A, Min, H, Dewhirst, MW, Irwin, DC, Zhao, Y, and Schroeder, T. "Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats." Journal of visualized experiments : JoVE 93 (November 30, 2014): e51630-.
PMID
25490280
Source
epmc
Published In
Journal of Visualized Experiments
Issue
93
Publish Date
2014
Start Page
e51630
DOI
10.3791/51630

Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

Metastatic dissemination requires carcinoma cells to detach from the primary tumor and invade through the basement membrane. To acquire these characteristics, epithelial tumor cells undergo epithelial-to-mesenchymal transitions (EMT), whereby cells lose polarity and E-cadherin-mediated cell-cell adhesion. Post-EMT cells have also been shown, or assumed, to be more migratory; however, there have been contradictory reports on an immortalized human mammary epithelial cell line (HMLE) that underwent EMT. In the context of carcinoma-associated EMT, it is not yet clear whether the change in migration and invasion must be positively correlated during EMT or whether enhanced migration is a necessary consequence of having undergone EMT. Here, we report that pre-EMT rat prostate cancer (PC) and HMLE cells are more migratory than their post-EMT counterparts. To determine a mechanism for increased epithelial cell migration, gene expression analysis was performed and revealed an increase in epidermal growth factor receptor (EGFR) expression in pre-EMT cells. Indeed, inhibition of EGFR in PC epithelial cells slowed migration. Importantly, while post-EMT PC and HMLE cell lines are less migratory, both remain invasive in vitro and, for PC cells, in vivo. Our study demonstrates that enhanced migration is not a phenotypic requirement of EMT, and migration and invasion can be uncoupled during carcinoma-associated EMT.

Authors
Schaeffer, D; Somarelli, JA; Hanna, G; Palmer, GM; Garcia-Blanco, MA
MLA Citation
Schaeffer, D, Somarelli, JA, Hanna, G, Palmer, GM, and Garcia-Blanco, MA. "Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition." Molecular and cellular biology 34.18 (September 2014): 3486-3499.
PMID
25002532
Source
epmc
Published In
Molecular and Cellular Biology
Volume
34
Issue
18
Publish Date
2014
Start Page
3486
End Page
3499
DOI
10.1128/mcb.00694-14

Systemic anti-tumour effects of local thermally sensitive liposome therapy.

There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment.Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy.Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay.The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment.

Authors
Viglianti, BL; Dewhirst, MW; Boruta, RJ; Park, J-Y; Landon, C; Fontanella, AN; Guo, J; Manzoor, A; Hofmann, CL; Palmer, GM
MLA Citation
Viglianti, BL, Dewhirst, MW, Boruta, RJ, Park, J-Y, Landon, C, Fontanella, AN, Guo, J, Manzoor, A, Hofmann, CL, and Palmer, GM. "Systemic anti-tumour effects of local thermally sensitive liposome therapy." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 30.6 (September 2014): 385-392.
PMID
25164143
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
30
Issue
6
Publish Date
2014
Start Page
385
End Page
392
DOI
10.3109/02656736.2014.944587

Tuning optical properties of difluoroboron beta-diketonate biomaterials for oxygen sensing

Authors
Fraser, CL; DeRosa, C; Samonina-Kosicka, J; Morris, WA; Fan, Z; Demas, JN; Mathew, A; Palmer, GM; Dewhirst, MW; Hofmann, CL; Hendargo, H
MLA Citation
Fraser, CL, DeRosa, C, Samonina-Kosicka, J, Morris, WA, Fan, Z, Demas, JN, Mathew, A, Palmer, GM, Dewhirst, MW, Hofmann, CL, and Hendargo, H. "Tuning optical properties of difluoroboron beta-diketonate biomaterials for oxygen sensing." August 10, 2014.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
248
Publish Date
2014

Boron nanoparticles for oxygen sensing: Material design, optical properties, and bioimaging

Authors
Samonina-Kosicka, J; DeRosa, C; Hofmann, CL; Hendargo, H; Dewhirst, MW; Palmer, GM; Fraser, CL
MLA Citation
Samonina-Kosicka, J, DeRosa, C, Hofmann, CL, Hendargo, H, Dewhirst, MW, Palmer, GM, and Fraser, CL. "Boron nanoparticles for oxygen sensing: Material design, optical properties, and bioimaging." August 10, 2014.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
248
Publish Date
2014

Measuring tumor cycling hypoxia and angiogenesis using a side-firing fiber optic probe.

Hypoxia and angiogenesis can significantly influence the efficacy of cancer therapy and the behavior of surviving tumor cells. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo to enable advances in drug development and optimization. This paper reports the use of frequency-domain photon migration with a side-firing probe to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human head/neck tumors administered with carbogen gas, cycling hypoxic gas or just room air. Significant increase (with carbogen gas breathing) or decrease (with hypoxic gas breathing) in tumor oxygenation was observed. The trend in tumor oxygenation during forced cycling hypoxia (CH) followed that of the blood oxygenation measured with a pulse oximeter. Natural CH was also observed in rats under room air. The studies demonstrated the potential of the technology for longitudinal monitoring of tumor CH during tumor growth or in response to therapy.

Authors
Yu, B; Shah, A; Wang, B; Rajaram, N; Wang, Q; Ramanujam, N; Palmer, GM; Dewhirst, MW
MLA Citation
Yu, B, Shah, A, Wang, B, Rajaram, N, Wang, Q, Ramanujam, N, Palmer, GM, and Dewhirst, MW. "Measuring tumor cycling hypoxia and angiogenesis using a side-firing fiber optic probe." J Biophotonics 7.7 (July 2014): 552-564.
PMID
23242854
Source
pubmed
Published In
Journal of biophotonics
Volume
7
Issue
7
Publish Date
2014
Start Page
552
End Page
564
DOI
10.1002/jbio.201200187

WE-E-BRE-06: High-Dose Microbeam Radiation Induces Different Responses in Tumor Microenvironment Compared to Conventional Seamless Radiation in Window Chamber Tumor Models.

Microbeam radiation therapy and GRID therapy are different forms of Spatially-Fractioned Radiation Therapy (SFRT) that is fundamentally different from the conventional seamless and temporally fractionated radiation therapy. SFRT is characterized by a ultra-high dose (10s -100s Gy) dose single treatment with drastic inhomogeneity pattern of given spatial frequencies. Preclinical and limited clinical studies have shown that the SFRT treatments may offer significant improvements in reducing treatment toxicity, especially for those patients who have not benefited from the state-of-the-art radiation therapy approaches. This preliminary study aims to elucidate the underlying working mechanisms of SFRT, which currently remains poorly understood.A genetically engineered 4T1 murine mammary carcinoma cell line and nude mice skin fold window chamber were used. A nanotechnology-based 160kV x-ray irradiator delivered 50Gy (entrance dose) single treatments of microbeam or seamless radiation. Animals were in 3 groups: mock, seamless radiation, and 300μm microbeam radiation. The windows were imaged using a hyperspectral system to capture total hemoglobin/saturation, GFP fluorescence emission, RFP fluorescence emission, and vessel density at 9 time points up to 7 days post radiation.We found unique physiologic changes in different tumor/normal tissue regions and differential effects between seamless and microbeam treatments. They include 1) compared to microbeam and mock radiation seamless radiation damaged more microvasculature in tumor-surrounding normal tissue, 2) a pronounced angiogenic effect was observed with vascular proliferation in the microbeam irradiated portion of the tumor days post treatment (no such effect observed in seamless and mock groups), and 3) a notable change in tumor vascular orientation was observed where vessels initially oriented parallel to the beam length were replaced by vessels running perpendicular to the irradiation portion of the tumor.Our preliminary study indicated that microbeam radiation modified tumor microenvironment in ways significantly different than of the conventional seamless radiation.

Authors
Chang, S; Fontanella, A; Boss, M; Zhang, J; Hadsell, M; Schroeder, T; Berman, K; Palmer, G; Dewhirst, M
MLA Citation
Chang, S, Fontanella, A, Boss, M, Zhang, J, Hadsell, M, Schroeder, T, Berman, K, Palmer, G, and Dewhirst, M. "WE-E-BRE-06: High-Dose Microbeam Radiation Induces Different Responses in Tumor Microenvironment Compared to Conventional Seamless Radiation in Window Chamber Tumor Models." Medical physics 41.6 (June 2014): 505-.
PMID
28037601
Source
epmc
Published In
Medical physics
Volume
41
Issue
6
Publish Date
2014
Start Page
505
DOI
10.1118/1.4889435

Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma.

BACKGROUND: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. METHODS: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. RESULTS: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. CONCLUSIONS: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, PJ, Beasley, GM, Jiang, B, Lidsky, ME, Palmer, GM, Scarbrough, PM, Mosca, PJ, Dewhirst, MW, and Tyler, DS. "Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma." Ann Surg Oncol 21.5 (May 2014): 1435-1440.
PMID
23982250
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Plasmonics-enhanced and optically modulated delivery of gold nanostars into brain tumor.

Plasmonics-active gold nanostars exhibiting strong imaging contrast and efficient photothermal transduction were synthesized for a novel pulsed laser-modulated plasmonics-enhanced brain tumor microvascular permeabilization. We demonstrate a selective, optically modulated delivery of nanoprobes into the tumor parenchyma with minimal off-target distribution.

Authors
Yuan, H; Wilson, CM; Xia, J; Doyle, SL; Li, S; Fales, AM; Liu, Y; Ozaki, E; Mulfaul, K; Hanna, G; Palmer, GM; Wang, LV; Grant, GA; Vo-Dinh, T
MLA Citation
Yuan, H, Wilson, CM, Xia, J, Doyle, SL, Li, S, Fales, AM, Liu, Y, Ozaki, E, Mulfaul, K, Hanna, G, Palmer, GM, Wang, LV, Grant, GA, and Vo-Dinh, T. "Plasmonics-enhanced and optically modulated delivery of gold nanostars into brain tumor." Nanoscale 6.8 (April 21, 2014): 4078-4082.
PMID
24619405
Source
pubmed
Published In
Nanoscale
Volume
6
Issue
8
Publish Date
2014
Start Page
4078
End Page
4082
DOI
10.1039/c3nr06770j

Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo.

Tissue-engineered skeletal muscle can serve as a physiological model of natural muscle and a potential therapeutic vehicle for rapid repair of severe muscle loss and injury. Here, we describe a platform for engineering and testing highly functional biomimetic muscle tissues with a resident satellite cell niche and capacity for robust myogenesis and self-regeneration in vitro. Using a mouse dorsal window implantation model and transduction with fluorescent intracellular calcium indicator, GCaMP3, we nondestructively monitored, in real time, vascular integration and the functional state of engineered muscle in vivo. During a 2-wk period, implanted engineered muscle exhibited a steady ingrowth of blood-perfused microvasculature along with an increase in amplitude of calcium transients and force of contraction. We also demonstrated superior structural organization, vascularization, and contractile function of fully differentiated vs. undifferentiated engineered muscle implants. The described in vitro and in vivo models of biomimetic engineered muscle represent enabling technology for novel studies of skeletal muscle function and regeneration.

Authors
Juhas, M; Engelmayr, GC; Fontanella, AN; Palmer, GM; Bursac, N
MLA Citation
Juhas, M, Engelmayr, GC, Fontanella, AN, Palmer, GM, and Bursac, N. "Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo." Proceedings of the National Academy of Sciences of the United States of America 111.15 (April 2014): 5508-5513.
Website
http://hdl.handle.net/10161/8413
PMID
24706792
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
15
Publish Date
2014
Start Page
5508
End Page
5513
DOI
10.1073/pnas.1402723111

Tissue integration of porous polyHEMA scaffold

Authors
Cho, E; Boico, A; Brown, N; Wisniewski, N; Helton, K; Register, J; Fales, A; Vo-Dinh, T; Schroeder, T; Klitzman, B; Palmer, G
MLA Citation
Cho, E, Boico, A, Brown, N, Wisniewski, N, Helton, K, Register, J, Fales, A, Vo-Dinh, T, Schroeder, T, Klitzman, B, and Palmer, G. "Tissue integration of porous polyHEMA scaffold." April 2014.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
28
Issue
1
Publish Date
2014

Oxygen nanosensors based on dual emissive difluoroboron naphthyl alpha-diketonate polylactides for ratiometric tumor hypoxia imaging

Authors
DeRosa, CA; Samonina-Kosicka, J; Fan, Z; Hofmann, CL; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
DeRosa, CA, Samonina-Kosicka, J, Fan, Z, Hofmann, CL, Palmer, GM, Dewhirst, MW, and Fraser, CL. "Oxygen nanosensors based on dual emissive difluoroboron naphthyl alpha-diketonate polylactides for ratiometric tumor hypoxia imaging." March 16, 2014.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
247
Publish Date
2014

Abstract 88: microvascular integration into versatile tissue engineering platforms.

Authors
Cho, EH; Boico, A; Wisniewski, NA; Helton, KL; Register, JK; Fales, AM; Palmer, GM; Vo-Dinh, T; Schroeder, T; Klitzman, B
MLA Citation
Cho, EH, Boico, A, Wisniewski, NA, Helton, KL, Register, JK, Fales, AM, Palmer, GM, Vo-Dinh, T, Schroeder, T, and Klitzman, B. "Abstract 88: microvascular integration into versatile tissue engineering platforms." March 2014.
PMID
25942199
Source
epmc
Published In
Plastic and Reconstructive Surgery
Volume
133
Issue
3 Suppl
Publish Date
2014
Start Page
102
DOI
10.1097/01.prs.0000445121.15610.63

Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm (vol 20, pg 724, 2013)

Authors
Fontanella, AN; Schroeder, T; Hochman, DW; Chen, RE; Hanna, G; Haglund, MM; Secomb, TW; Palmer, GM; Dewhirst, MW
MLA Citation
Fontanella, AN, Schroeder, T, Hochman, DW, Chen, RE, Hanna, G, Haglund, MM, Secomb, TW, Palmer, GM, and Dewhirst, MW. "Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm (vol 20, pg 724, 2013)." MICROCIRCULATION 21.2 (February 2014): 196-196.
Source
wos-lite
Published In
Microcirculation
Volume
21
Issue
2
Publish Date
2014
Start Page
196
End Page
196
DOI
10.1111/micc.12118

Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma

Background: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. Methods: Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. Results: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. Conclusions: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment. © 2013 Society of Surgical Oncology.

Authors
Speicher, PJ; Beasley, GM; Jiang, B; Lidsky, ME; Palmer, GM; Scarbrough, PM; Mosca, PJ; Dewhirst, MW; Tyler, DS
MLA Citation
Speicher, PJ, Beasley, GM, Jiang, B, Lidsky, ME, Palmer, GM, Scarbrough, PM, Mosca, PJ, Dewhirst, MW, and Tyler, DS. "Hypoxia in melanoma: Using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma." Annals of Surgical Oncology 21.5 (January 1, 2014): 1435-1440.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1435
End Page
1440
DOI
10.1245/s10434-013-3222-0

Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.

Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.

Authors
Radiloff, D; Zhao, Y; Boico, A; Blueschke, G; Palmer, G; Fontanella, A; Dewhirst, M; Piantadosi, CA; Noveck, R; Irwin, D; Hamilton, K; Klitzman, B; Schroeder, T
MLA Citation
Radiloff, D, Zhao, Y, Boico, A, Blueschke, G, Palmer, G, Fontanella, A, Dewhirst, M, Piantadosi, CA, Noveck, R, Irwin, D, Hamilton, K, Klitzman, B, and Schroeder, T. "Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude." PloS one 9.6 (January 2014): e99309-.
Website
http://hdl.handle.net/10161/10340
PMID
24960187
Source
epmc
Published In
PloS one
Volume
9
Issue
6
Publish Date
2014
Start Page
e99309
DOI
10.1371/journal.pone.0099309

Abstract B151: Monitoring tumor microenvironment (Hb saturation and oxygenation) in response to plasmonics-assisted photothermal cancer therapy.

Authors
Yuan, H; Hofmann, CL; Samonina-Kosicka, J; Hendargo, H; Hanna, G; Vo-Dinh, T; Fraser, CL; Dewhirst, MW; Palmer, GM
MLA Citation
Yuan, H, Hofmann, CL, Samonina-Kosicka, J, Hendargo, H, Hanna, G, Vo-Dinh, T, Fraser, CL, Dewhirst, MW, and Palmer, GM. "Abstract B151: Monitoring tumor microenvironment (Hb saturation and oxygenation) in response to plasmonics-assisted photothermal cancer therapy." Molecular Cancer Therapeutics 12.11_Supplement (November 1, 2013): B151-B151.
Source
crossref
Published In
Molecular cancer therapeutics
Volume
12
Issue
11_Supplement
Publish Date
2013
Start Page
B151
End Page
B151
DOI
10.1158/1535-7163.TARG-13-B151

Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm.

OBJECTIVE: Hemodynamic properties of vascular beds are of great interest in a variety of clinical and laboratory settings. However, there presently exists no automated, accurate, technically simple method for generating blood velocity maps of complex microvessel networks. METHODS: Here, we present a novel algorithm that addresses the problem of acquiring quantitative maps by applying pixel-by-pixel cross-correlation to video data. Temporal signals at every spatial coordinate are compared with signals at neighboring points, generating a series of correlation maps from which speed and direction are calculated. User-assisted definition of vessel geometries is not required, and sequential data are analyzed automatically, without user bias. RESULTS: Velocity measurements were validated against the dual-slit method and against in vitro capillary flow with known velocities. The algorithm was tested in three different biological models in order to demonstrate its versatility. CONCLUSIONS: The hemodynamic maps presented here demonstrate an accurate, quantitative method of analyzing dynamic vascular systems.

Authors
Fontanella, AN; Schroeder, T; Hochman, DW; Chen, RE; Hanna, G; Haglund, MM; Rajaram, N; Frees, AE; Secomb, TW; Palmer, GM; Dewhirst, MW
MLA Citation
Fontanella, AN, Schroeder, T, Hochman, DW, Chen, RE, Hanna, G, Haglund, MM, Rajaram, N, Frees, AE, Secomb, TW, Palmer, GM, and Dewhirst, MW. "Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm." Microcirculation 20.8 (November 2013): 724-735.
PMID
23781901
Source
pubmed
Published In
Microcirculation
Volume
20
Issue
8
Publish Date
2013
Start Page
724
End Page
735
DOI
10.1111/micc.12072

18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model.

UNLABELLED: Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). METHODS: Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. RESULTS: The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. CONCLUSION: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.

Authors
Chitneni, SK; Bida, GT; Yuan, H; Palmer, GM; Hay, MP; Melcher, T; Wilson, WR; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Yuan, H, Palmer, GM, Hay, MP, Melcher, T, Wilson, WR, Zalutsky, MR, and Dewhirst, MW. "18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model." J Nucl Med 54.8 (August 2013): 1339-1346.
PMID
23740105
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
54
Issue
8
Publish Date
2013
Start Page
1339
End Page
1346
DOI
10.2967/jnumed.112.116293

IN VIVO IMAGING OF NF-kappa B ACTIVITY AND CORRELATION TO PAIN IN A MODEL OF INFLAMMATORY ARTHRITIS

Authors
Bowles, RD; Mata, BA; Mwangi, TK; Palmer, GM; Setton, LA
MLA Citation
Bowles, RD, Mata, BA, Mwangi, TK, Palmer, GM, and Setton, LA. "IN VIVO IMAGING OF NF-kappa B ACTIVITY AND CORRELATION TO PAIN IN A MODEL OF INFLAMMATORY ARTHRITIS." April 2013.
Source
wos-lite
Published In
Osteoarthritis and Cartilage
Volume
21
Publish Date
2013
Start Page
S266
End Page
S267

Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy.

Intravital microscopy of the pulmonary microcirculation in research animals is of great scientific interest for its utility in identifying regional changes in pulmonary microcirculatory blood flow. Although feasibility studies have been reported, the pulmonary window can be further refined into a practical tool for pharmaceutical research and drug development. We have established a method to visualize and quantify dynamic changes in three key features of lung function: microvascular red blood cell velocity, flow direction, and hemoglobin saturation. These physiological parameters were measured in an acute closed-chest pulmonary window, which allows real-time images to be captured by fluorescence and multispectral absorption microscopy; images were subsequently quantified using computerized analysis. We validated the model by quantifying changes in microcirculatory blood flow and hemoglobin saturation in two ways: 1) after changes in inspired oxygen content and 2) after pharmacological reduction of pulmonary blood flow via treatment with the β1 adrenergic receptor blocker metoprolol. This robust and relatively simple system facilitates pulmonary intravital microscopy in laboratory rats for pharmacological and physiological research.

Authors
Hanna, G; Fontanella, A; Palmer, G; Shan, S; Radiloff, DR; Zhao, Y; Irwin, D; Hamilton, K; Boico, A; Piantadosi, CA; Blueschke, G; Dewhirst, M; McMahon, T; Schroeder, T
MLA Citation
Hanna, G, Fontanella, A, Palmer, G, Shan, S, Radiloff, DR, Zhao, Y, Irwin, D, Hamilton, K, Boico, A, Piantadosi, CA, Blueschke, G, Dewhirst, M, McMahon, T, and Schroeder, T. "Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy." Am J Physiol Lung Cell Mol Physiol 304.2 (January 15, 2013): L86-L91.
PMID
23161885
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
304
Issue
2
Publish Date
2013
Start Page
L86
End Page
L91
DOI
10.1152/ajplung.00178.2012

Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

Authors
Terman, DS; Viglianti, BL; Zennadi, R; Fels, D; Boruta, RJ; Yuan, H; Dreher, MR; Grant, G; Rabbani, ZN; Moon, E; Lan, L; Eble, J; Cao, Y; Sorg, B; Ashcraft, K; Palmer, G; Telen, MJ; Dewhirst, MW
MLA Citation
Terman, DS, Viglianti, BL, Zennadi, R, Fels, D, Boruta, RJ, Yuan, H, Dreher, MR, Grant, G, Rabbani, ZN, Moon, E, Lan, L, Eble, J, Cao, Y, Sorg, B, Ashcraft, K, Palmer, G, Telen, MJ, and Dewhirst, MW. "Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response." PLoS One 8.1 (2013): e52543-.
Website
http://hdl.handle.net/10161/11164
PMID
23326340
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e52543
DOI
10.1371/journal.pone.0052543

Wavelength optimization for quantitative spectral imaging of breast tumor margins.

A wavelength selection method that combines an inverse Monte Carlo model of reflectance and a genetic algorithm for global optimization was developed for the application of spectral imaging of breast tumor margins. The selection of wavelengths impacts system design in cost, size, and accuracy of tissue quantitation. The minimum number of wavelengths required for the accurate quantitation of tissue optical properties is 8, with diminishing gains for additional wavelengths. The resulting wavelength choices for the specific probe geometry used for the breast tumor margin spectral imaging application were tested in an independent pathology-confirmed ex vivo breast tissue data set and in tissue-mimicking phantoms. In breast tissue, the optical endpoints (hemoglobin, β-carotene, and scattering) that provide the contrast between normal and malignant tissue specimens are extracted with the optimized 8-wavelength set with <9% error compared to the full spectrum (450-600 nm). A multi-absorber liquid phantom study was also performed to show the improved extraction accuracy with optimization and without optimization. This technique for selecting wavelengths can be used for designing spectral imaging systems for other clinical applications.

Authors
Lo, JY; Brown, JQ; Dhar, S; Yu, B; Palmer, GM; Jokerst, NM; Ramanujam, N
MLA Citation
Lo, JY, Brown, JQ, Dhar, S, Yu, B, Palmer, GM, Jokerst, NM, and Ramanujam, N. "Wavelength optimization for quantitative spectral imaging of breast tumor margins. (Published online)" PLoS One 8.4 (2013): e61767-.
PMID
23613927
Source
pubmed
Published In
PloS one
Volume
8
Issue
4
Publish Date
2013
Start Page
e61767
DOI
10.1371/journal.pone.0061767

Monitoring of cycling hypoxia and angiogenesis in FaDu head and neck tumors using a side-firing sensor

Many studies have found that hypoxia, particularly cycling hypoxia (CH), can lead to enhanced tumor metastasis and resistance to radiation and chemotherapy. It was also reported that tumor total hemoglobin content (THb), which is directly related to tumor angiogenesis, can have significant impact on tumor's response to radiation and neoadjuvant chemotherapy. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo. In this paper, a side-firing fiber optic sensor based on a multi-wavelength frequency-domain near infrared spectroscopy (FD-NIRS) instrument was used to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human FaDu head and neck (H & N) tumors during normoxia and forced hyperoxia and cyclic hypoxia. Significant increase (with carbogen gas inhalation) or decrease (with reduced O2 supply) in tumor oxygenation was observed. The studies demonstrated the feasibility of the technology for longitudinal monitoring of H and N tumor's response to therapy. © 2013 Copyright SPIE.

Authors
Yu, B; Shah, A; Wang, B; Rajaram, N; Wang, Q; Ramanujam, N; Palmer, GM; Dewhirst, MW
MLA Citation
Yu, B, Shah, A, Wang, B, Rajaram, N, Wang, Q, Ramanujam, N, Palmer, GM, and Dewhirst, MW. "Monitoring of cycling hypoxia and angiogenesis in FaDu head and neck tumors using a side-firing sensor." Progress in Biomedical Optics and Imaging - Proceedings of SPIE 8578 (2013).
Source
scival
Published In
Proceedings of SPIE
Volume
8578
Publish Date
2013
DOI
10.1117/12.2002837

A diffuse reflectance spectral imaging system for tumor margin assessment using custom annular photodiode arrays.

Diffuse reflectance spectroscopy (DRS) is a well-established method to quantitatively distinguish between benign and cancerous tissue for tumor margin assessment. Current multipixel DRS margin assessment tools are bulky fiber-based probes that have limited scalability. Reported herein is a new approach to multipixel DRS probe design, which utilizes direct detection of the DRS signal by using optimized custom photodetectors in direct contact with the tissue. This first fiberless DRS imaging system for tumor margin assessment consists of a 4 × 4 array of annular silicon photodetectors and a constrained free-space light delivery tube optimized to deliver light across a 256 mm(2) imaging area. This system has 4.5 mm spatial resolution. The signal-to-noise ratio measured for normal and malignant breast tissue-mimicking phantoms was 35 dB to 45 dB for λ = 470 nm to 600 nm.

Authors
Dhar, S; Lo, JY; Palmer, GM; Brooke, MA; Nichols, BS; Yu, B; Ramanujam, N; Jokerst, NM
MLA Citation
Dhar, S, Lo, JY, Palmer, GM, Brooke, MA, Nichols, BS, Yu, B, Ramanujam, N, and Jokerst, NM. "A diffuse reflectance spectral imaging system for tumor margin assessment using custom annular photodiode arrays." Biomed Opt Express 3.12 (December 1, 2012): 3211-3222.
PMID
23243571
Source
pubmed
Published In
Biomed Opt Express
Volume
3
Issue
12
Publish Date
2012
Start Page
3211
End Page
3222
DOI
10.1364/BOE.3.003211

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude.

Decreased physical performance is a well-known consequence of rapid ascent to high altitude. Hypoxic pulmonary vasoconstriction (HPV) potentially limits cardiac output and systemic blood flow, thus preventing successful adaptation to rapid ascent. We hypothesized that pharmacological enhancement of the heart rate with theophylline, combined with reversal of HPV via endothelin blockade, could increase exercise performance at high altitude. Female Sprague-Dawley rats were treated with combinations of 1) theophylline, 2) the endothelin receptor antagonists sitaxsentan/ambrisentan, and/or 3) phosphodiesterase-5 inhibitor sildenafil and exposed to either a simulated high altitude (4,267 m) or 12% oxygen. Exercise capacity, peripheral blood flow, hemodynamics, and pulmonary leak were examined. Combination treatment with theophylline and endothelin blockade, but not with the respective single compounds, significantly prolonged run-to-fatigue time under simulated high altitude. No such efficacy was found when theophylline was combined with sildenafil. Neither theophylline nor sitaxsentan or their combination influenced breathing rates and hemoglobin oxygen saturation. Whereas under hypoxia, theophylline significantly increased muscular blood flow, and sitaxsentan increased tissue oxygenation, the combination improved both parameters but in a reduced manner. Under hypoxia, the combination treatment but not the single compounds significantly enhanced pulmonary arterial pressure compared with controls (13.1 ± 6.3 vs. 11.9 ± 5.2 mmHg), whereas mean arterial pressure remained unaffected. Pulmonary wet-to-dry weight ratios were unaffected by combination treatment. We conclude that concomitant dosing with a cardiac stimulant and endothelin antagonist can partially reverse loss of physical performance capacity under hypobaric hypoxia, independent from improving blood oxygen saturation.

Authors
Radiloff, DR; Zhao, Y; Boico, A; Wu, C; Shan, S; Palmer, G; Hamilton, K; Irwin, D; Hanna, G; Piantadosi, CA; Schroeder, T
MLA Citation
Radiloff, DR, Zhao, Y, Boico, A, Wu, C, Shan, S, Palmer, G, Hamilton, K, Irwin, D, Hanna, G, Piantadosi, CA, and Schroeder, T. "The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude." J Appl Physiol (1985) 113.8 (October 15, 2012): 1243-1252.
PMID
22898548
Source
pubmed
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
113
Issue
8
Publish Date
2012
Start Page
1243
End Page
1252
DOI
10.1152/japplphysiol.01622.2011

Experimental validation of an inverse fluorescence Monte Carlo model to extract concentrations of metabolically relevant fluorophores from turbid phantoms and a murine tumor model (vol 17, 078003, 2012)

Authors
Liu, C; Rajaram, N; Vishwanath, K; Jiang, T; Palmer, GM; Ramanujam, N
MLA Citation
Liu, C, Rajaram, N, Vishwanath, K, Jiang, T, Palmer, GM, and Ramanujam, N. "Experimental validation of an inverse fluorescence Monte Carlo model to extract concentrations of metabolically relevant fluorophores from turbid phantoms and a murine tumor model (vol 17, 078003, 2012)." JOURNAL OF BIOMEDICAL OPTICS 17.7 (July 2012).
Source
wos-lite
Published In
Journal of Biomedical Optics
Volume
17
Issue
7
Publish Date
2012
DOI
10.1117/1.JBO.17.7.079805

Experimental validation of an inverse fluorescence Monte Carlo model to extract concentrations of metabolically relevant fluorophores from turbid phantoms and a murine tumor model.

An inverse Monte Carlo based model has been developed to extract intrinsic fluorescence from turbid media. The goal of this work was to experimentally validate the model to extract intrinsic fluorescence of three biologically meaningful fluorophores related to metabolism from turbid media containing absorbers and scatterers. Experimental studies were first carried out on tissue-mimicking phantoms that contained individual fluorophores and their combinations, across multiple absorption, scattering, and fluorophore concentrations. The model was then tested in a murine tumor model to determine both the kinetics of fluorophore uptake as well as overall tissue fluorophore concentration through extraction of the intrinsic fluorescence of an exogenous contrast agent that reports on glucose uptake. Results show the model can be used to recover the true intrinsic fluorescence spectrum with high accuracy (R(2)=0.988) as well as accurately compute fluorophore concentration in both single and multiple fluorophores phantoms when appropriate calibration standards are available. In the murine tumor, the model-corrected intrinsic fluorescence could be used to differentiate drug dose injections between different groups. A strong linear correlation was observed between the extracted intrinsic fluorescence intensity and injected drug dose, compared with the distorted turbid tissue fluorescence.

Authors
Liu, C; Rajaram, N; Vishwanath, K; Jiang, T; Palmer, GM; Ramanujam, N
MLA Citation
Liu, C, Rajaram, N, Vishwanath, K, Jiang, T, Palmer, GM, and Ramanujam, N. "Experimental validation of an inverse fluorescence Monte Carlo model to extract concentrations of metabolically relevant fluorophores from turbid phantoms and a murine tumor model." J Biomed Opt 17.7 (July 2012): 077012-.
PMID
22894524
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
17
Issue
7
Publish Date
2012
Start Page
077012
DOI
10.1117/1.JBO.17.7.077012

Vascular Response to Microbeam Radiation Therapy In Vivo Using a Murine Window Chamber Tumor Model

Authors
Dewhirst, M; Fontanella, A; Palmer, G; Boss, M; Zhang, J; Hadsell, M; Chang, S
MLA Citation
Dewhirst, M, Fontanella, A, Palmer, G, Boss, M, Zhang, J, Hadsell, M, and Chang, S. "Vascular Response to Microbeam Radiation Therapy In Vivo Using a Murine Window Chamber Tumor Model." June 2012.
Source
wos-lite
Published In
Medical physics
Volume
39
Issue
6
Publish Date
2012
Start Page
3983
End Page
3983

Application of optical imaging and spectroscopy to radiation biology.

Optical imaging and spectroscopy is a diverse field that has been of critical importance in a wide range of areas in radiation research. It is capable of spanning a wide range of spatial and temporal scales, and has the sensitivity and specificity needed for molecular and functional imaging. This review will describe the basic principles of optical imaging and spectroscopy, highlighting a few relevant applications to radiation research.

Authors
Palmer, GM; Vishwanath, K; Dewhirst, MW
MLA Citation
Palmer, GM, Vishwanath, K, and Dewhirst, MW. "Application of optical imaging and spectroscopy to radiation biology." Radiat Res 177.4 (April 2012): 365-375. (Review)
PMID
22360397
Source
pubmed
Published In
Radiation Research
Volume
177
Issue
4
Publish Date
2012
Start Page
365
End Page
375

A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization.

BACKGROUND AND PURPOSE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. EXPERIMENTAL APPROACH: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. KEY RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS AND IMPLICATIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.

Authors
Palmer, GM; Tiran, Z; Zhou, Z; Capozzi, ME; Park, W; Coletta, C; Pyriochou, A; Kliger, Y; Levy, O; Borukhov, I; Dewhirst, MW; Rotman, G; Penn, JS; Papapetropoulos, A
MLA Citation
Palmer, GM, Tiran, Z, Zhou, Z, Capozzi, ME, Park, W, Coletta, C, Pyriochou, A, Kliger, Y, Levy, O, Borukhov, I, Dewhirst, MW, Rotman, G, Penn, JS, and Papapetropoulos, A. "A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization." Br J Pharmacol 165.6 (March 2012): 1891-1903.
PMID
21943108
Source
pubmed
Published In
British Journal of Pharmacology
Volume
165
Issue
6
Publish Date
2012
Start Page
1891
End Page
1903
DOI
10.1111/j.1476-5381.2011.01677.x

High-resolution in vivo imaging of fluorescent proteins using window chamber models.

Fluorescent proteins enable in vivo characterization of a wide and growing array of morphological and functional biomarkers. To fully capitalize on the spatial and temporal information afforded by these reporter proteins, a method for imaging these proteins at high resolution longitudinally is required. This chapter describes the use of window chamber models as a means of imaging fluorescent proteins and other optical parameters. Such models essentially involve surgically implanting a window through which tumor or normal tissue can be imaged using existing microscopy techniques. This enables acquisition of high-quality images down to the cellular or subcellular scale, exploiting the diverse array of optical contrast mechanisms, while also maintaining the native microenvironment of the tissue of interest. This makes these techniques applicable to a wide array of problems in the biomedical sciences.

Authors
Palmer, GM; Fontanella, AN; Shan, S; Dewhirst, MW
MLA Citation
Palmer, GM, Fontanella, AN, Shan, S, and Dewhirst, MW. "High-resolution in vivo imaging of fluorescent proteins using window chamber models." Methods Mol Biol 872 (2012): 31-50.
PMID
22700402
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
872
Publish Date
2012
Start Page
31
End Page
50
DOI
10.1007/978-1-61779-797-2_3

Luminescent boron b-diketonate biomaterials: Synthesis, properties and applications

Authors
Fraser, CL; Zhang, G; Nguyen, ND; Xu, S; Zestos, AG; Palmer, GM; Dewhirst, MW; Hochman, D; Haglund, MM; Neal, RA; Murray, RA; Botchwey, EA; Peirce-Cottler, SM; Seaman, SA; Brayman, KL; Lin, KYK
MLA Citation
Fraser, CL, Zhang, G, Nguyen, ND, Xu, S, Zestos, AG, Palmer, GM, Dewhirst, MW, Hochman, D, Haglund, MM, Neal, RA, Murray, RA, Botchwey, EA, Peirce-Cottler, SM, Seaman, SA, Brayman, KL, and Lin, KYK. "Luminescent boron b-diketonate biomaterials: Synthesis, properties and applications." August 28, 2011.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
242
Publish Date
2011

In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters.

Optical techniques for functional imaging in mice have a number of key advantages over other common imaging modalities such as magnetic resonance imaging, positron emission tomography or computed tomography, including high resolution, low cost and an extensive library of available contrast agents and reporter genes. A major challenge to such work is the limited penetration depth imposed by tissue turbidity. We describe a window chamber technique by which these limitations can be avoided. This facilitates the study of a wide range of processes, with potential endpoints including longitudinal gene expression, vascular remodeling and angiogenesis, and tumor growth and invasion. We further describe several quantitative imaging and analysis techniques for characterizing in vivo fluorescence properties and functional endpoints, including vascular morphology and oxygenation. The procedure takes ∼2 h to complete, plus up to several weeks for tumor growth and treatment procedures.

Authors
Palmer, GM; Fontanella, AN; Shan, S; Hanna, G; Zhang, G; Fraser, CL; Dewhirst, MW
MLA Citation
Palmer, GM, Fontanella, AN, Shan, S, Hanna, G, Zhang, G, Fraser, CL, and Dewhirst, MW. "In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters. (Published online)" Nat Protoc 6.9 (August 18, 2011): 1355-1366.
PMID
21886101
Source
pubmed
Published In
Nature Protocols
Volume
6
Issue
9
Publish Date
2011
Start Page
1355
End Page
1366
DOI
10.1038/nprot.2011.349

Molecular imaging of hypoxia.

A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine has seen the development of several radiolabeled hypoxia markers and is the preferred method for imaging of tumor hypoxia. Hypoxia imaging is increasingly being used in the clinical setting and is progressing from a mere detection method to application in individualization of chemoradiotherapy.

Authors
Chitneni, SK; Palmer, GM; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Palmer, GM, Zalutsky, MR, and Dewhirst, MW. "Molecular imaging of hypoxia." J Nucl Med 52.2 (February 2011): 165-168. (Review)
PMID
21233176
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
52
Issue
2
Publish Date
2011
Start Page
165
End Page
168
DOI
10.2967/jnumed.110.075663

Optical imaging of tumor hypoxia dynamics.

The influence of the tumor microenvironment and hypoxia plays a significant role in determining cancer progression, treatment response, and treatment resistance. That the tumor microenvironment is highly heterogeneous with significant intratumor and intertumor variability presents a significant challenge in developing effective cancer therapies. Critical to understanding the role of the tumor microenvironment is the ability to dynamically quantify oxygen levels in the vasculature and tissue in order to elucidate the roles of oxygen supply and consumption, spatially and temporally. To this end, we describe the use of hyperspectral imaging to characterize hemoglobin absorption to quantify hemoglobin content and oxygen saturation, as well as dual emissive fluorescent∕phosphorescent boron nanoparticles, which serve as ratiometric indicators of tissue oxygen tension. Applying these techniques to a window-chamber tumor model illustrates the role of fluctuations in hemoglobin saturation in driving changes in tissue oxygenation, the two being significantly correlated (r = 0.77). Finally, a green-fluorescence-protein reporter for hypoxia inducible factor-1 (HIF-1) provides an endpoint for hypoxic stress in the tumor, which is used to demonstrate a significant association between tumor hypoxia dynamics and HIF-1 activity in an in vivo demonstration of the technique.

Authors
Palmer, GM; Fontanella, AN; Zhang, G; Hanna, G; Fraser, CL; Dewhirst, MW
MLA Citation
Palmer, GM, Fontanella, AN, Zhang, G, Hanna, G, Fraser, CL, and Dewhirst, MW. "Optical imaging of tumor hypoxia dynamics." J Biomed Opt 15.6 (November 2010): 066021-.
PMID
21198195
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
15
Issue
6
Publish Date
2010
Start Page
066021
DOI
10.1117/1.3523363

Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual-emissive boron dyes for tumor accumulation.

Responsive biomaterials play important roles in imaging, diagnostics, and therapeutics. Polymeric nanoparticles (NPs) containing hydrophobic and hydrophilic segments are one class of biomaterial utilized for these purposes. The incorporation of luminescent molecules into NPs adds optical imaging and sensing capability to these vectors. Here we report on the synthesis of dual-emissive, pegylated NPs with "stealth"-like properties, delivered intravenously (IV), for the study of tumor accumulation. The NPs were created by means of stereocomplexation using a methoxy-terminated polyethylene glycol and poly(D-lactide) (mPEG-PDLA) block copolymer combined with iodide-substituted difluoroboron dibenzoylmethane-poly(L-lactide) (BF2dbm(I)PLLA). Boron nanoparticles (BNPs) were fabricated in two different solvent compositions to study the effects on BNP size distribution. The physical and photoluminescent properties of the BNPs were studied in vitro over time to determine stability. Finally, preliminary in vivo results show that stereocomplexed BNPs injected IV are taken up by tumors, an important prerequisite to their use as hypoxia imaging agents in preclinical studies.

Authors
Kersey, FR; Zhang, G; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
Kersey, FR, Zhang, G, Palmer, GM, Dewhirst, MW, and Fraser, CL. "Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual-emissive boron dyes for tumor accumulation." ACS Nano 4.9 (September 28, 2010): 4989-4996.
Website
http://hdl.handle.net/10161/4104
PMID
20704337
Source
pubmed
Published In
ACS Nano
Volume
4
Issue
9
Publish Date
2010
Start Page
4989
End Page
4996
DOI
10.1021/nn901873t

A low-cost, portable, and quantitative spectral imaging system for application to biological tissues.

The ability of diffuse reflectance spectroscopy to extract quantitative biological composition of tissues has been used to discern tissue types in both pre-clinical and clinical cancer studies. Typically, diffuse reflectance spectroscopy systems are designed for single-point measurements. Clinically, an imaging system would provide valuable spatial information on tissue composition. While it is feasible to build a multiplexed fiber-optic probe based spectral imaging system, these systems suffer from drawbacks with respect to cost and size. To address these we developed a compact and low cost system using a broadband light source with an 8-slot filter wheel for illumination and silicon photodiodes for detection. The spectral imaging system was tested on a set of tissue mimicking liquid phantoms which yielded an optical property extraction accuracy of 6.40 +/- 7.78% for the absorption coefficient (micro(a)) and 11.37 +/- 19.62% for the wavelength-averaged reduced scattering coefficient (micro(s)').

Authors
Fu, HL; Yu, B; Lo, JY; Palmer, GM; Kuech, TF; Ramanujam, N
MLA Citation
Fu, HL, Yu, B, Lo, JY, Palmer, GM, Kuech, TF, and Ramanujam, N. "A low-cost, portable, and quantitative spectral imaging system for application to biological tissues." Opt Express 18.12 (June 7, 2010): 12630-12645.
Website
http://hdl.handle.net/10161/4239
PMID
20588390
Source
pubmed
Published In
Optics express
Volume
18
Issue
12
Publish Date
2010
Start Page
12630
End Page
12645

Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy.

Optical spectroscopy was used to monitor changes in tumor physiology with therapy, and its influence on drug delivery and treatment efficacy for hyperthermia treatment combined with free doxorubicin or a low-temperature sensitive liposomal formulation. Monte Carlo-based modeling techniques were used to characterize the intrinsic absorption, scattering, and fluorescence properties of tissue. Fluorescence assessment of drug concentration was validated against HPLC and found to be significantly linearly correlated (r=0.88). Cluster analysis on the physiologic data obtained by optical spectroscopy revealed two physiologic phenotypes prior to treatment. One of these was relatively hypoxic, with relatively low total hemoglobin content. This hypoxic group was found to have a significantly shorter time to reach 3 times pre-treatment volume, indicating a more treatment resistant phenotype (p=0.003). Influence of tumor physiology was assessed in more detail for the liposomal doxorubicin+hyperthermia group, which demonstrated a highly significant correlation between pre-treatment hemoglobin saturation and tumor growth delay, and also between post-hyperthermia total hemoglobin content and tumor drug delivery. Finally, it was found that the doxorubicin concentration, measured in vivo using fluorescence techniques significantly predicted for chemoresponse (hazard ratio: 0.34, p=0.0007). The ability to characterize drug delivery and tumor physiology in vivo makes this a potentially useful tool for evaluating the efficacy of targeted delivery systems in preclinical studies, and may be translatable for monitoring and predicting individual treatment responses in the clinic.

Authors
Palmer, GM; Boruta, RJ; Viglianti, BL; Lan, L; Spasojevic, I; Dewhirst, MW
MLA Citation
Palmer, GM, Boruta, RJ, Viglianti, BL, Lan, L, Spasojevic, I, and Dewhirst, MW. "Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy." J Control Release 142.3 (March 19, 2010): 457-464.
PMID
19896999
Source
pubmed
Published In
Journal of Controlled Release
Volume
142
Issue
3
Publish Date
2010
Start Page
457
End Page
464
DOI
10.1016/j.jconrel.2009.10.034

Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy.

The purpose of this review is to examine the roles that functional imaging may play in prediction of treatment response and determination of overall prognosis in patients who are enrolled in thermotherapy trials, either in combination with radiotherapy, chemotherapy or both. Most of the historical work that has been done in this field has focused on magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) methods, so the emphasis will be there, although some discussion of the role that positron emission tomography (PET) might play will also be examined. New optical technologies also hold promise for obtaining low cost, yet valuable physiological data from optically accessible sites. The review is organised by traditional outcome parameters: local response, local control and progression-free or overall survival. Included in the review is a discussion of future directions for this type of translational work.

Authors
Dewhirst, MW; Thrall, DE; Palmer, G; Schroeder, T; Vujaskovic, Z; Cecil Charles, H; Macfall, J; Wong, T
MLA Citation
Dewhirst, MW, Thrall, DE, Palmer, G, Schroeder, T, Vujaskovic, Z, Cecil Charles, H, Macfall, J, and Wong, T. "Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy." Int J Hyperthermia 26.3 (2010): 283-293. (Review)
PMID
20170362
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
26
Issue
3
Publish Date
2010
Start Page
283
End Page
293
DOI
10.3109/02656730903286214

Variation in Microenvironmental Effects and Drug Delivery between Different Classes of Antiangiogenic Drugs

Authors
Hanna, G; Palmer, G; Park, W; Herbert, J; Cao, Y; Schroeder, T; Vlahovic, G; Nixon, A; Dewhirst, M
MLA Citation
Hanna, G, Palmer, G, Park, W, Herbert, J, Cao, Y, Schroeder, T, Vlahovic, G, Nixon, A, and Dewhirst, M. "Variation in Microenvironmental Effects and Drug Delivery between Different Classes of Antiangiogenic Drugs." 2010.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
78
Issue
3
Publish Date
2010
Start Page
S164
End Page
S165

A dual-emissive-materials design concept enables tumour hypoxia imaging.

Luminescent materials are widely used for imaging and sensing owing to their high sensitivity, rapid response and facile detection by many optical technologies. Typically materials must be chemically tailored to achieve intense, photostable fluorescence, oxygen-sensitive phosphorescence or dual emission for ratiometric sensing, often by blending two dyes in a matrix. Dual-emissive materials combining all of these features in one easily tunable molecular platform are desirable, but when fluorescence and phosphorescence originate from the same dye, it can be challenging to vary relative fluorescence/phosphorescence intensities for practical sensing applications. Heavy-atom substitution alone increases phosphorescence by a given, not variable amount. Here, we report a strategy for modulating fluorescence/phosphorescence for a single-component, dual-emissive, iodide-substituted difluoroboron dibenzoylmethane-poly(lactic acid) (BF(2)dbm(I)PLA) solid-state sensor material. This is accomplished through systematic variation of the PLA chain length in controlled solvent-free lactide polymerization combined with heavy-atom substitution. We demonstrate the versatility of this approach by showing that films made from low-molecular-weight BF(2)dbm(I)PLA with weak fluorescence and strong phosphorescence are promising as 'turn on' sensors for aerodynamics applications, and that nanoparticles fabricated from a higher-molecular-weight polymer with balanced fluorescence and phosphorescence intensities serve as ratiometric tumour hypoxia imaging agents.

Authors
Zhang, G; Palmer, GM; Dewhirst, MW; Fraser, CL
MLA Citation
Zhang, G, Palmer, GM, Dewhirst, MW, and Fraser, CL. "A dual-emissive-materials design concept enables tumour hypoxia imaging." Nat Mater 8.9 (September 2009): 747-751.
PMID
19668206
Source
pubmed
Published In
Nature Materials
Volume
8
Issue
9
Publish Date
2009
Start Page
747
End Page
751
DOI
10.1038/nmat2509

POLY 216-Boron biomaterials for imaging and oxygen sensing

Authors
Zhang, G; Fraser, CL; Hamm-Alvarez, S; Xie, J; Price, RJ; Palmer, GM; Dewhirst, MW
MLA Citation
Zhang, G, Fraser, CL, Hamm-Alvarez, S, Xie, J, Price, RJ, Palmer, GM, and Dewhirst, MW. "POLY 216-Boron biomaterials for imaging and oxygen sensing." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 238 (August 16, 2009).
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
238
Publish Date
2009

Quantitative optical spectroscopy: a robust tool for direct measurement of breast cancer vascular oxygenation and total hemoglobin content in vivo.

We propose the use of a robust, biopsy needle-based, fiber-optic tool for routine clinical quantification of tumor oxygenation at the time of diagnostic biopsy for breast cancer. The purpose of this study was to show diffuse reflectance spectroscopy as a quantitative tool to measure oxygenation levels in the vascular compartment of breast cancers in vivo via an optical biopsy technique. Thirty-five patients undergoing surgical treatment for breast cancer were recruited for the study at Duke University Medical Center. Diffuse reflectance spectroscopy was performed on the tumors in situ before surgical resection, followed by needle-core biopsy of the optically measured tissue. Hemoglobin saturation and total hemoglobin content were quantified from 76 optical spectra-tissue biopsy pairs, consisting of 20 malignant, 23 benign, and 33 adipose tissues. Hemoglobin saturation in malignant tissues was significantly lower than nonmalignant tissues (P<0.002) and was negatively correlated with tumor size and pathologic tumor category (P<0.05). Hemoglobin saturation was positively correlated with total hemoglobin content in malignant tissues (P<0.02). HER2/neu-amplified tumors exhibited significantly higher total hemoglobin content (P<0.05) and significantly higher hemoglobin saturation (P<0.02), which is consistent with a model of increased angiogenesis and tumor perfusion promoted by HER2/neu amplification. Diffuse reflectance spectroscopy could aid in prognosis and prediction in breast cancer via quantitative assessment of tumor physiology at the time of diagnostic biopsy.

Authors
Brown, JQ; Wilke, LG; Geradts, J; Kennedy, SA; Palmer, GM; Ramanujam, N
MLA Citation
Brown, JQ, Wilke, LG, Geradts, J, Kennedy, SA, Palmer, GM, and Ramanujam, N. "Quantitative optical spectroscopy: a robust tool for direct measurement of breast cancer vascular oxygenation and total hemoglobin content in vivo." Cancer Res 69.7 (April 1, 2009): 2919-2926.
PMID
19293184
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
7
Publish Date
2009
Start Page
2919
End Page
2926
DOI
10.1158/0008-5472.CAN-08-3370

A robust Monte Carlo model for the extraction of biological absorption and scattering in vivo.

We have a toolbox to quantify tissue optical properties that is composed of specialized fiberoptic probes for UV-visible diffuse reflectance spectroscopy and a fast, scalable inverse Monte Carlo (MC) model. In this paper, we assess the robustness of the toolbox for quantifying physiologically relevant parameters from turbid tissue-like media. In particular, we consider the effects of using different instruments, fiberoptic probes, and instrument-specific settings for a wide range of optical properties. Additionally, we test the quantitative accuracy of the inverse MC model for extracting the biologically relevant parameters of hemoglobin saturation and total hemoglobin concentration. We also test the effect of double-absorber phantoms (hemoglobin and crocin to model the absorption of hemoglobin and beta carotene, respectively, in the breast) for a range of absorption and scattering properties. We include an assessment on which reference phantom serves as the best calibration standard to enable accurate extraction of the absorption and scattering properties of the target sample. We found the best reference-target phantom combinations to be ones with similar scattering levels. The results from these phantom studies provide a set of guidelines for extracting optical parameters from clinical studies.

Authors
Bender, JE; Vishwanath, K; Moore, LK; Brown, JQ; Chang, V; Palmer, GM; Ramanujam, N
MLA Citation
Bender, JE, Vishwanath, K, Moore, LK, Brown, JQ, Chang, V, Palmer, GM, and Ramanujam, N. "A robust Monte Carlo model for the extraction of biological absorption and scattering in vivo." IEEE Trans Biomed Eng 56.4 (April 2009): 960-968.
PMID
19423425
Source
pubmed
Published In
IEEE Transactions on Biomedical Engineering
Volume
56
Issue
4
Publish Date
2009
Start Page
960
End Page
968
DOI
10.1109/TBME.2008.2005994

Quantitative physiology of the precancerous cervix in vivo through optical spectroscopy.

Cervical cancer is the second most common female cancer worldwide. The ability to quantify physiological and morphological changes in the cervix is not only useful in the diagnosis of cervical precancers but also important in aiding the design of cost-effective detection systems for use in developing countries that lack well-established screening and diagnostic programs. We assessed the capability of a diffuse reflectance spectroscopy technique to identify contrasts in optical biomarkers that vary with different grades of cervical intraepithelial neoplasia (CIN) from normal cervical tissues. The technology consists of an optical probe and an instrument (with broadband light source, dispersive element, and detector), and a Monte Carlo algorithm to extract optical biomarker contributions including total hemoglobin (Hb) concentration, Hb saturation, and reduced scattering coefficient from the measured spectra. Among 38 patients and 89 sites examined, 46 squamous normal sites, 18 CIN 1, and 15 CIN 2(+) sites were included in the analysis. Total Hb was statistically higher in CIN 2(+) (18.3 +/- 3.6 microM, mean +/- SE) compared with normal (9.58 +/- 1.91 microM) and CIN 1 (12.8 +/- 2.6 microM), whereas scattering was significantly reduced in CIN 1 (8.3 +/- 0.8 cm(-1)) and CIN 2(+) (8.6 +/- 1.0 cm(-1)) compared with normal (10.2 +/- 1.1 cm(-1)). Hemoglobin saturation was not significantly altered in CIN 2(+) compared with normal and CIN 1. The difference in total Hb is likely because of stromal angiogenesis, whereas decreased scattering can be attributed to breakdown of collagen network in the cervical stroma.

Authors
Chang, VT-C; Cartwright, PS; Bean, SM; Palmer, GM; Bentley, RC; Ramanujam, N
MLA Citation
Chang, VT-C, Cartwright, PS, Bean, SM, Palmer, GM, Bentley, RC, and Ramanujam, N. "Quantitative physiology of the precancerous cervix in vivo through optical spectroscopy." Neoplasia 11.4 (April 2009): 325-332.
PMID
19308287
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
11
Issue
4
Publish Date
2009
Start Page
325
End Page
332

Light emitting boron biomaterials for imaging and oxygen sensing

Authors
Zhang, G; Evans, RE; Palmer, GM; Dewhirst, MW; Xie, J; Hamm-Alvarez, S; Price, RJ; Fraser, CL
MLA Citation
Zhang, G, Evans, RE, Palmer, GM, Dewhirst, MW, Xie, J, Hamm-Alvarez, S, Price, RJ, and Fraser, CL. "Light emitting boron biomaterials for imaging and oxygen sensing." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 237 (March 22, 2009).
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
237
Publish Date
2009

Quantitative diffuse reflectance and fluorescence spectroscopy: tool to monitor tumor physiology in vivo.

This study demonstrates the use of optical spectroscopy for monitoring tumor oxygenation and metabolism in response to hyperoxic gas breathing. Hemoglobin saturation and redox ratio were quantified for a set of 14 and 9 mice, respectively, measured at baseline and during carbogen breathing (95% O(2), 5% CO(2)). In particular, significant increases in hemoglobin saturation and fluorescence redox ratio were observed upon carbogen breathing. These data were compared with data obtained concurrently using an established invasive technique, the OxyLite partial oxygen pressure (pO(2)) system, which also showed a significant increase in pO(2). It was found that the direction of changes were generally the same between all of the methods, but that the OxyLite system was much more variable in general, suggesting that optical techniques may provide a better assessment of global tumor physiology. Optical spectroscopy measurements are demonstrated to provide a reliable, reproducible indication of changes in tumor physiology in response to physiologic manipulation.

Authors
Palmer, GM; Viola, RJ; Schroeder, T; Yarmolenko, PS; Dewhirst, MW; Ramanujam, N
MLA Citation
Palmer, GM, Viola, RJ, Schroeder, T, Yarmolenko, PS, Dewhirst, MW, and Ramanujam, N. "Quantitative diffuse reflectance and fluorescence spectroscopy: tool to monitor tumor physiology in vivo." J Biomed Opt 14.2 (March 2009): 024010-.
PMID
19405740
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
14
Issue
2
Publish Date
2009
Start Page
024010
DOI
10.1117/1.3103586

A strategy for quantitative spectral imaging of tissue absorption and scattering using light emitting diodes and photodiodes.

A diffuse reflectance spectroscopy system was modified as a step towards miniaturization and spectral imaging of tissue absorption and scattering. The modified system uses a tunable source and an optical fiber for illumination and a photodiode in contact with tissue for detection. Compared to the previous system, it is smaller, less costly, and has comparable performance in extracting optical properties in tissue phantoms. Wavelength reduction simulations show the feasibility of replacing the source with LEDs to further decrease system size and cost. Simulated crosstalk analysis indicates that this evolving system can be multiplexed for spectral imaging in the future.

Authors
Lo, JY; Yu, B; Fu, HL; Bender, JE; Palmer, GM; Kuech, TF; Ramanujam, N
MLA Citation
Lo, JY, Yu, B, Fu, HL, Bender, JE, Palmer, GM, Kuech, TF, and Ramanujam, N. "A strategy for quantitative spectral imaging of tissue absorption and scattering using light emitting diodes and photodiodes." Opt Express 17.3 (February 2, 2009): 1372-1384.
PMID
19188966
Source
pubmed
Published In
Optics express
Volume
17
Issue
3
Publish Date
2009
Start Page
1372
End Page
1384

Advances in quantitative UV-visible spectroscopy for clinical and pre-clinical application in cancer.

Methods of optical spectroscopy that provide quantitative, physically or physiologically meaningful measures of tissue properties are an attractive tool for the study, diagnosis, prognosis, and treatment of various cancers. Recent development of methodologies to convert measured reflectance and fluorescence spectra from tissue to cancer-relevant parameters such as vascular volume, oxygenation, extracellular matrix extent, metabolic redox states, and cellular proliferation have significantly advanced the field of tissue optical spectroscopy. The number of publications reporting quantitative tissue spectroscopy results in the UV-visible wavelength range has increased sharply in the past three years, and includes new and emerging studies that correlate optically measured parameters with independent measures such as immunohistochemistry, which should aid in increased clinical acceptance of these technologies.

Authors
Brown, JQ; Vishwanath, K; Palmer, GM; Ramanujam, N
MLA Citation
Brown, JQ, Vishwanath, K, Palmer, GM, and Ramanujam, N. "Advances in quantitative UV-visible spectroscopy for clinical and pre-clinical application in cancer." Curr Opin Biotechnol 20.1 (February 2009): 119-131. (Review)
PMID
19268567
Source
pubmed
Published In
Current Opinion in Biotechnology
Volume
20
Issue
1
Publish Date
2009
Start Page
119
End Page
131
DOI
10.1016/j.copbio.2009.02.004

Intraoperative optical breast tissue characterization device for tumor margin assessment

Authors
Brown, JQ; Bydlon, TM; Kennedy, SA; Richards, L; Junker, MS; Palmer, GM; Geradts, J; Wilke, LG; Ramanujam, N
MLA Citation
Brown, JQ, Bydlon, TM, Kennedy, SA, Richards, L, Junker, MS, Palmer, GM, Geradts, J, Wilke, LG, and Ramanujam, N. "Intraoperative optical breast tissue characterization device for tumor margin assessment." CANCER RESEARCH 69.2 (January 15, 2009): 101S-101S.
Source
wos-lite
Published In
Cancer Research
Volume
69
Issue
2
Publish Date
2009
Start Page
101S
End Page
101S

Cost-effective diffuse reflectance spectroscopy device for quantifying tissue absorption and scattering in vivo.

A hybrid optical device that uses a multimode fiber coupled to a tunable light source for illumination and a 2.4-mm photodiode for detection in contact with the tissue surface is developed as a first step toward our goal of developing a cost-effective, miniature spectral imaging device to map tissue optical properties in vivo. This device coupled with an inverse Monte Carlo model of reflectance is demonstrated to accurately quantify tissue absorption and scattering in tissue-like turbid synthetic phantoms with a wide range of optical properties. The overall errors for quantifying the absorption and scattering coefficients are 6.0+/-5.6 and 6.1+/-4.7%, respectively. Compared with fiber-based detection, having the detector right at the tissue surface can significantly improve light collection efficiency, thus reducing the requirement for sophisticated detectors with high sensitivity, and this design can be easily expanded into a quantitative spectral imaging system for mapping tissue optical properties in vivo.

Authors
Yu, B; Lo, JY; Kuech, TF; Palmer, GM; Bender, JE; Ramanujam, N
MLA Citation
Yu, B, Lo, JY, Kuech, TF, Palmer, GM, Bender, JE, and Ramanujam, N. "Cost-effective diffuse reflectance spectroscopy device for quantifying tissue absorption and scattering in vivo." J Biomed Opt 13.6 (November 2008): 060505-.
PMID
19123646
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
13
Issue
6
Publish Date
2008
Start Page
060505
DOI
10.1117/1.3041500

Electromagnetic spectroscopy of normal breast tissue specimens obtained from reduction surgeries: comparison of optical and microwave properties.

Techniques utilizing electromagnetic energy at microwave and optical frequencies have been shown to be promising for breast cancer detection and diagnosis. Since different biophysical mechanisms are exploited at these frequencies to discriminate between healthy and diseased tissue, combining these two modalities may result in a more powerful approach for breast cancer detection and diagnosis. Toward this end, we performed microwave dielectric spectroscopy and optical diffuse reflectance spectroscopy measurements at the same sites on freshly excised normal breast tissues obtained from reduction surgeries at the University of Wisconsin Hospital, using microwave and optical probes with very similar sensing volumes. We found that the microwave dielectric constant and effective conductivity are correlated with tissue composition across the entire measurement frequency range (|r| approximately 0.5-0.6, p<0.01) and that the optical absorption coefficient at 460 nm and optical scattering coefficient are correlated with tissue composition (|r| approximately 0.4-0.6, p<0.02). Finally, we found that the optical absorption coefficient at 460 nm is correlated with the microwave dielectric constant and effective conductivity (r=-0.55, p<0.01). Our results suggest that combining optical and microwave modalities for analyzing breast tissue samples may serve as a crosscheck and provide complementary information about tissue composition.

Authors
Lazebnik, M; Zhu, C; Palmer, GM; Harter, J; Sewall, S; Ramanujam, N; Hagness, SC
MLA Citation
Lazebnik, M, Zhu, C, Palmer, GM, Harter, J, Sewall, S, Ramanujam, N, and Hagness, SC. "Electromagnetic spectroscopy of normal breast tissue specimens obtained from reduction surgeries: comparison of optical and microwave properties." IEEE Trans Biomed Eng 55.10 (October 2008): 2444-2451.
PMID
18838370
Source
pubmed
Published In
IEEE Transactions on Biomedical Engineering
Volume
55
Issue
10
Publish Date
2008
Start Page
2444
End Page
2451
DOI
10.1109/TBME.2008.925700

Diagnosis of breast cancer using fluorescence and diffuse reflectance spectroscopy: a Monte-Carlo-model-based approach.

We explore the use of Monte-Carlo-model-based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from breast tissues. These models are used to extract the absorption, scattering, and fluorescence properties of malignant and nonmalignant tissues and to diagnose breast cancer based on these intrinsic tissue properties. Absorption and scattering properties, including beta-carotene concentration, total hemoglobin concentration, hemoglobin saturation, and the mean reduced scattering coefficient are derived from diffuse reflectance spectra using a previously developed Monte Carlo model of diffuse reflectance. A Monte Carlo model of fluorescence described in an earlier manuscript was employed to retrieve the intrinsic fluorescence spectra. The intrinsic fluorescence spectra were decomposed into several contributing components, which we attribute to endogenous fluorophores that may present in breast tissues including collagen, NADH, and retinol/vitamin A. The model-based approaches removes any dependency on the instrument and probe geometry. The relative fluorescence contributions of individual fluorescing components, as well as beta-carotene concentration, hemoglobin saturation, and the mean reduced scattering coefficient display statistically significant differences between malignant and adipose breast tissues. The hemoglobin saturation and the reduced scattering coefficient display statistically significant differences between malignant and fibrous/benign breast tissues. A linear support vector machine classification using (1) fluorescence properties alone, (2) absorption and scattering properties alone, and (3) the combination of all tissue properties achieves comparable classification accuracies of 81 to 84% in sensitivity and 75 to 89% in specificity for discriminating malignant from nonmalignant breast tissues, suggesting each set of tissue properties are diagnostically useful for the discrimination of breast malignancy.

Authors
Zhu, C; Palmer, GM; Breslin, TM; Harter, J; Ramanujam, N
MLA Citation
Zhu, C, Palmer, GM, Breslin, TM, Harter, J, and Ramanujam, N. "Diagnosis of breast cancer using fluorescence and diffuse reflectance spectroscopy: a Monte-Carlo-model-based approach." J Biomed Opt 13.3 (May 2008): 034015-.
PMID
18601560
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
13
Issue
3
Publish Date
2008
Start Page
034015
DOI
10.1117/1.2931078

Monte-Carlo-based model for the extraction of intrinsic fluorescence from turbid media.

A Monte-Carlo-based model of fluorescence is developed that is capable of extracting the intrinsic fluorescence properties of tissue, which are independent of the absorption and scattering properties of tissue. This model is flexible in its applicability to different illumination-collection geometries and is also valid for a wide range of optical properties, representative of tissue in the UV-visible spectrum. This is potentially useful in a variety of biomedical applications, including cancer diagnostics and monitoring the physiological response to therapy. The model is validated using phantoms composed of hemoglobin (absorber), polystyrene spheres (scatterer), and furan-2 (fluorophore). It is found that this model is able to retrieve the intrinsic fluorescence spectra of the tissue phantoms and recover the intrinsic fluorescence intensity of furan within the phantoms to within a mean error of less than 10%.

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Monte-Carlo-based model for the extraction of intrinsic fluorescence from turbid media." J Biomed Opt 13.2 (March 2008): 024017-.
PMID
18465980
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
13
Issue
2
Publish Date
2008
Start Page
024017
DOI
10.1117/1.2907161

A miniature optical device for noninvasive, fast characterization of tumor pathology

An optical spectroscopy system for cancer diagnostics is miniaturized. The performance of the device is validated with phantom studies. Absorption and scattering coefficients are extracted with high accuracy with an inverse Monte Carlo model. © 2008 Optical Society of America.

Authors
Lo, JY; Yu, B; Palmer, GM; Kuech, TF; Ramanujam, N
MLA Citation
Lo, JY, Yu, B, Palmer, GM, Kuech, TF, and Ramanujam, N. "A miniature optical device for noninvasive, fast characterization of tumor pathology." Biomedical Optics, BIOMED 2008 (2008): BTuF55-.
Source
scival
Published In
Biomedical Optics, BIOMED 2008
Publish Date
2008
Start Page
BTuF55

Intraoperative in vivo reflectance spectroscopy for discrimination of normal, benign, and malignant breast tissues

Authors
Brown, JQ; Wilke, LG; Kennedy, S; Palmer, GM; Geradts, J; Ramanujam, N
MLA Citation
Brown, JQ, Wilke, LG, Kennedy, S, Palmer, GM, Geradts, J, and Ramanujam, N. "Intraoperative in vivo reflectance spectroscopy for discrimination of normal, benign, and malignant breast tissues." BREAST CANCER RESEARCH AND TREATMENT 106 (December 2007): S209-S210.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
106
Publish Date
2007
Start Page
S209
End Page
S210

Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms (vol 45, pg 1062, 2006)

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms (vol 45, pg 1062, 2006)." APPLIED OPTICS 46.27 (September 20, 2007): 6847-6847.
Source
wos-lite
Published In
Applied Optics
Volume
46
Issue
27
Publish Date
2007
Start Page
6847
End Page
6847
DOI
10.1364/AO.46.006847

Use of genetic algorithms to optimize fiber optic probe design for the extraction of tissue optical properties.

This paper outlines a framework by which the optimal illumination/collection geometry can be identified for a particular biomedical application. In this paper, this framework was used to identify the optimal probe geometry for the accurate determination of tissue optical properties representative of that in the ultraviolet-visible (UV-VIS) spectral range. An optimal probe geometry was identified which consisted of a single illumination and two collection fibers, one of which is insensitive to changes in scattering properties, and the other is insensitive to changes in the attenuation coefficient. Using this probe geometry in conjunction with a neural network algorithm, the optical properties could be extracted with root-mean-square errors of 0.30 cm(-1) for the reduced scattering coefficient (tested range of 3-40 cm(-1)), and 0.41 cm(-1) for the absorption coefficient (tested range of 0-80 cm(-1)).

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Use of genetic algorithms to optimize fiber optic probe design for the extraction of tissue optical properties." IEEE Trans Biomed Eng 54.8 (August 2007): 1533-1535.
PMID
17694876
Source
pubmed
Published In
IEEE Transactions on Biomedical Engineering
Volume
54
Issue
8
Publish Date
2007
Start Page
1533
End Page
1535
DOI
10.1109/TBME.2006.889779

Comparison of a physical model and principal component analysis for the diagnosis of epithelial neoplasias in vivo using diffuse reflectance spectroscopy.

We explored the use of diffuse reflectance spectroscopy in the ultraviolet-visible (UV-VIS) spectrum for the diagnosis of epithelial precancers and cancers in vivo. A physical model (Monte Carlo inverse model) and an empirical model (principal component analysis, (PCA)) based approach were compared for extracting diagnostic features from diffuse reflectance spectra measured in vivo from the dimethylbenz[alpha]anthracene-treated hamster cheek pouch model of oral carcinogenesis. These diagnostic features were input into a support vector machine algorithm to classify each tissue sample as normal (n=10) or neoplastic (dysplasia to carcinoma, n=10) and cross-validated using a leave one out method. There was a statistically significant decrease in the absorption and reduced scattering coefficient at 460 nm in neoplastic compared to normal tissues, and these two features provided 90% classification accuracy. The first two principal components extracted from PCA provided a classification accuracy of 95%. The first principal component was highly correlated with the wavelength-averaged reduced scattering coefficient. Although both methods show similar classification accuracy, the physical model provides insight into the physiological and structural features that discriminate between normal and neoplastic tissues and does not require a priori, a representative set of spectral data from which to derive the principal components.

Authors
Skala, MC; Palmer, GM; Vrotsos, KM; Gendron-Fitzpatrick, A; Ramanujam, N
MLA Citation
Skala, MC, Palmer, GM, Vrotsos, KM, Gendron-Fitzpatrick, A, and Ramanujam, N. "Comparison of a physical model and principal component analysis for the diagnosis of epithelial neoplasias in vivo using diffuse reflectance spectroscopy." Opt Express 15.12 (June 11, 2007): 7863-7875.
PMID
17912337
Source
pubmed
Published In
Optics express
Volume
15
Issue
12
Publish Date
2007
Start Page
7863
End Page
7875
DOI
10.1364/OE.15.007863

Erratum: Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms (Applied Optics (2006) 45 (1062))

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Erratum: Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms (Applied Optics (2006) 45 (1062))." Applied Optics 46.27 (2007): 6847--.
Source
scival
Published In
Applied Optics
Volume
46
Issue
27
Publish Date
2007
Start Page
6847-
DOI
10.1364/AO.46.006847

Effect of optical clearing agents on the in vivo optical properties of squamous epithelial tissue.

BACKGROUND AND OBJECTIVES: Optical clearing agents (OCAs) have previously been shown to increase depth penetration within turbid tissue ex vivo. This paper quantifies tissue optical properties of the hamster cheek pouch model in order to provide a means to assess the effect of OCAs quantitatively in vivo. STUDY DESIGN/MATERIALS AND METHODS: Diffuse reflectance spectra were obtained from both cheeks of 12 hamsters before and after immersion in dimethyl sulfoxide (DMSO), glycerol or a phosphate buffer saline (PBS) control for 20 minutes. A Monte Carlo model was then utilized to derive the wavelength dependent reduced scattering and absorption coefficients. RESULTS: DMSO caused a statistically significant decrease in the absorption and reduced scattering coefficients derived by the model. Glycerol caused a statistically significant increase in the wavelength dependent absorption coefficient, but no statistically significant changes in the reduced scattering coefficient. CONCLUSIONS: DMSO and glycerol act upon tissues differently as reflected by the tissue optical properties, implying that not all OCAs are equally effective in optically clearing tissues.

Authors
Millon, SR; Roldan-Perez, KM; Riching, KM; Palmer, GM; Ramanujam, N
MLA Citation
Millon, SR, Roldan-Perez, KM, Riching, KM, Palmer, GM, and Ramanujam, N. "Effect of optical clearing agents on the in vivo optical properties of squamous epithelial tissue." Lasers Surg Med 38.10 (December 2006): 920-927.
PMID
17163473
Source
pubmed
Published In
Lasers in Surgery and Medicine
Volume
38
Issue
10
Publish Date
2006
Start Page
920
End Page
927
DOI
10.1002/lsm.20451

Diagnosis of breast cancer using diffuse reflectance spectroscopy: Comparison of a Monte Carlo versus partial least squares analysis based feature extraction technique.

BACKGROUND AND OBJECTIVE: We explored the use of diffuse reflectance spectroscopy in the ultraviolet-visible (UV-VIS) spectrum for the diagnosis of breast cancer. A physical model (Monte Carlo inverse model) and an empirical model (partial least squares analysis) based approach, were compared for extracting diagnostic features from the diffuse reflectance spectra. STUDY DESIGN/METHODS: The physical model and the empirical model were employed to extract features from diffuse reflectance spectra measured from freshly excised breast tissues. A subset of extracted features obtained using each method showed statistically significant differences between malignant and non-malignant breast tissues. These features were separately input to a support vector machine (SVM) algorithm to classify each tissue sample as malignant or non-malignant. RESULTS AND CONCLUSIONS: The features extracted from the Monte Carlo based analysis were hemoglobin saturation, total hemoglobin concentration, beta-carotene concentration and the mean (wavelength averaged) reduced scattering coefficient. Beta-carotene concentration was positively correlated and the mean reduced scattering coefficient was negatively correlated with percent adipose tissue content in normal breast tissues. In addition, there was a statistically significant decrease in the beta-carotene concentration and hemoglobin saturation, and a statistically significant increase in the mean reduced scattering coefficient in malignant tissues compared to non-malignant tissues. The features extracted from the partial least squares analysis were a set of principal components. A subset of principal components showed that the diffuse reflectance spectra of malignant breast tissues displayed an increased intensity over wavelength range of 440-510 nm and a decreased intensity over wavelength range of 510-600 nm, relative to that of non-malignant breast tissues. The diagnostic performance of the classification algorithms based on both feature extraction techniques yielded similar sensitivities and specificities of approximately 80% for discriminating between malignant and non-malignant breast tissues. While both methods yielded similar classification accuracies, the model based approach provided insight into the physiological and structural features that discriminate between malignant and non-malignant breast tissues.

Authors
Zhu, C; Palmer, GM; Breslin, TM; Harter, J; Ramanujam, N
MLA Citation
Zhu, C, Palmer, GM, Breslin, TM, Harter, J, and Ramanujam, N. "Diagnosis of breast cancer using diffuse reflectance spectroscopy: Comparison of a Monte Carlo versus partial least squares analysis based feature extraction technique." Lasers Surg Med 38.7 (August 2006): 714-724.
PMID
16799981
Source
pubmed
Published In
Lasers in Surgery and Medicine
Volume
38
Issue
7
Publish Date
2006
Start Page
714
End Page
724
DOI
10.1002/lsm.20356

Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms.

A flexible and fast Monte Carlo-based model of diffuse reflectance has been developed for the extraction of the absorption and scattering properties of turbid media, such as human tissues. This method is valid for a wide range of optical properties and is easily adaptable to existing probe geometries, provided a single phantom calibration measurement is made. A condensed Monte Carlo method was used to speed up the forward simulations. This model was validated by use of two sets of liquid-tissue phantoms containing Nigrosin or hemoglobin as absorbers and polystyrene spheres as scatterers. The phantoms had a wide range of absorption (0-20 cm(-1)) and reduced scattering coefficients (7-33 cm(-1)). Mie theory and a spectrophotometer were used to determine the absorption and reduced scattering coefficients of the phantoms. The diffuse reflectance spectra of the phantoms were measured over a wavelength range of 350-850 nm. It was found that optical properties could be extracted from the experimentally measured diffuse reflectance spectra with an average error of 3% or less for phantoms containing hemoglobin and 12% or less for phantoms containing Nigrosin.

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Monte Carlo-based inverse model for calculating tissue optical properties. Part I: Theory and validation on synthetic phantoms." Appl Opt 45.5 (February 10, 2006): 1062-1071.
PMID
16512550
Source
pubmed
Published In
Applied Optics
Volume
45
Issue
5
Publish Date
2006
Start Page
1062
End Page
1071

Monte Carlo-based inverse model for calculating tissue optical properties. Part II: Application to breast cancer diagnosis.

The Monte Carlo-based inverse model of diffuse reflectance described in part I of this pair of companion papers was applied to the diffuse reflectance spectra of a set of 17 malignant and 24 normal-benign ex vivo human breast tissue samples. This model allows extraction of physically meaningful tissue parameters, which include the concentration of absorbers and the size and density of scatterers present in tissue. It was assumed that intrinsic absorption could be attributed to oxygenated and deoxygenated hemoglobin and beta-carotene, that scattering could be modeled by spheres of a uniform size distribution, and that the refractive indices of the spheres and the surrounding medium are known. The tissue diffuse reflectance spectra were evaluated over a wavelength range of 400-600 nm. The extracted parameters that showed the statistically most significant differences between malignant and nonmalignant breast tissues were hemoglobin saturation and the mean reduced scattering coefficient. Malignant tissues showed decreased hemoglobin saturation and an increased mean reduced scattering coefficient compared with nonmalignant tissues. A support vector machine classification algorithm was then used to classify a sample as malignant or nonmalignant based on these two extracted parameters and produced a cross-validated sensitivity and specificity of 82% and 92%, respectively.

Authors
Palmer, GM; Zhu, C; Breslin, TM; Xu, F; Gilchrist, KW; Ramanujam, N
MLA Citation
Palmer, GM, Zhu, C, Breslin, TM, Xu, F, Gilchrist, KW, and Ramanujam, N. "Monte Carlo-based inverse model for calculating tissue optical properties. Part II: Application to breast cancer diagnosis." Appl Opt 45.5 (February 10, 2006): 1072-1078.
PMID
16512551
Source
pubmed
Published In
Applied Optics
Volume
45
Issue
5
Publish Date
2006
Start Page
1072
End Page
1078

Use of genetic algorithms to optimize fiber optic probe design for the extraction of tissue optical properties

An approach for optimizing the probe geometry for extracting optical properties is developed. It was found that optical properties could be extracted with accuracies of better than 0.5 cm-1, while requiring no a priori assumptions. © 2005 Optical Society of America.

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Use of genetic algorithms to optimize fiber optic probe design for the extraction of tissue optical properties." Optics InfoBase Conference Papers (January 1, 2006).
Source
scopus
Published In
Optics InfoBase Conference Papers
Publish Date
2006

Monte carlo based model of fluorescence: Theory and application to breast cancer diagnosis

A Monte Carlo model of fluorescence is developed that can extract intrinsic fluorescence properties of tissue, independent of absorption and scattering. This model is shown to elucidate significant contrast between malignant and non-malignant breast tissues. © 2005 Optical Society of America.

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Monte carlo based model of fluorescence: Theory and application to breast cancer diagnosis." Optics InfoBase Conference Papers (January 1, 2006).
Source
scopus
Published In
Optics InfoBase Conference Papers
Publish Date
2006

Effect of optical clearing agents on the optical properties of squamous epithelial tissue

Authors
Chiles, S; Roldan-Perez, K; Riching, K; Palmer, G; Ramanujam, N
MLA Citation
Chiles, S, Roldan-Perez, K, Riching, K, Palmer, G, and Ramanujam, N. "Effect of optical clearing agents on the optical properties of squamous epithelial tissue." 2006.
Source
wos-lite
Published In
Lasers in Surgery and Medicine
Publish Date
2006
Start Page
2
End Page
2

Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer

We explore the effects of the illumination and collection geometry on optical spectroscopic diagnosis of breast cancer. Fluorescence and diffuse reflectance spectroscopy in the UV-visible spectral range are made with a multiseparation probe at three illuminationcollection separations of 735, 980, and 1225 μm, respectively, from 13 malignant and 34 nonmalignant breast tissues. Statistical analysis is carried out on two types of data inputs: (1) the fluorescence and diffuse reflectance spectra recorded at each of the three illuminationcollection separations and (2) the integrated fluorescence (at each excitation wavelength) or diffuse reflectance over the entire spectrum at all three illumination-collection separations. The results show that using the integrated fluorescence intensities recorded at a single excitation wavelength at all three illumination-collection separations can discriminate malignant from nonmalignant breast tissues with similar classification accuracy to that using spectral data measured at several excitation wavelengths with a single illumination-collection separation. These findings have significant implications with respect to the design of an optical system for breast cancer diagnosis. Examining the intensity attenuation at a single wavelength rather than spectral intensities at multiple wavelengths can significantly reduce the measurement and data processing time in a clinical setting as well as the cost and complexity of the optical system. © 2005 Society of Photo-Optical Instrumentation Engineers.

Authors
Zhu, C; Palmer, GM; Breslin, TM; Xu, F; Ramanujam, N
MLA Citation
Zhu, C, Palmer, GM, Breslin, TM, Xu, F, and Ramanujam, N. "Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer." Journal of Biomedical Optics 10.2 (March 1, 2005).
Source
scopus
Published In
Journal of Biomedical Optics
Volume
10
Issue
2
Publish Date
2005
DOI
10.1117/1.1897398

Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer.

We explore the effects of the illumination and collection geometry on optical spectroscopic diagnosis of breast cancer. Fluorescence and diffuse reflectance spectroscopy in the UV-visible spectral range are made with a multiseparation probe at three illumination-collection separations of 735, 980, and 1225 microm, respectively, from 13 malignant and 34 nonmalignant breast tissues. Statistical analysis is carried out on two types of data inputs: (1) the fluorescence and diffuse reflectance spectra recorded at each of the three illumination-collection separations and (2) the integrated fluorescence (at each excitation wavelength) or diffuse reflectance over the entire spectrum at all three illumination-collection separations. The results show that using the integrated fluorescence intensities recorded at a single excitation wavelength at all three illumination-collection separations can discriminate malignant from nonmalignant breast tissues with similar classification accuracy to that using spectral data measured at several excitation wavelengths with a single illumination-collection separation. These findings have significant implications with respect to the design of an optical system for breast cancer diagnosis. Examining the intensity attenuation at a single wavelength rather than spectral intensities at multiple wavelengths can significantly reduce the measurement and data processing time in a clinical setting as well as the cost and complexity of the optical system.

Authors
Zhu, C; Palmer, GM; Breslin, TM; Xu, F; Ramanujam, N
MLA Citation
Zhu, C, Palmer, GM, Breslin, TM, Xu, F, and Ramanujam, N. "Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer." J Biomed Opt 10.2 (March 2005): 024032-.
PMID
15910105
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
10
Issue
2
Publish Date
2005
Start Page
024032
DOI
10.1117/1.1897398

Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer

We explore the effects of the illumination and collection geometry on optical spectroscopic diagnosis of breast cancer. Fluorescence and diffuse reflectance spectroscopy in the UV-visible spectral range are made with a multiseparation probe at three illumination-collection separations of 735, 980, and 1225 μm, respectively, from 13 malignant and 34 nonmalignant breast tissues. Statistical analysis is carried out on two types of data inputs: (1) the fluorescence and diffuse reflectance spectra recorded at each of the three illumination-collection separations and (2) the integrated fluorescence :(at each excitation wavelength) or diffuse reflectance over the entire spectrum at all three illumination-collection separations. The results show that using the integrated fluorescence intensities recorded at a single excitation wavelength at all three illumination-collection separations can discriminate malignant from nonmalignant breast tissues with similar classification accuracy to that using spectral data measured at several excitation wavelengths with a single illumination-collection separation. These findings have significant implications with respect to the design of an optical system for breast cancer diagnosis. Examining the intensity attenuation at a single wavelength rather than spectral intensities at multiple wavelengths can significantly reduce the measurement and data processing time in a clinical setting as well as the cost and complexity of the optical system. © 2005 Society of Photo-Optical Instrumentation Engineers.

Authors
Zhu, C; Palmer, GM; Breslin, TM; Xu, F; Ramanujam, N
MLA Citation
Zhu, C, Palmer, GM, Breslin, TM, Xu, F, and Ramanujam, N. "Use of a multiseparation fiber optic probe for the optical diagnosis of breast cancer." Journal of Biomedical Optics 10.2 (2005): 1-13.
Source
scival
Published In
Journal of Biomedical Optics
Volume
10
Issue
2
Publish Date
2005
Start Page
1
End Page
13
DOI
10.1117/1.1897398

Autofluorescence and diffuse reflectance properties of malignant and benign breast tissues.

BACKGROUND: Fluorescence spectroscopy is an evolving technology that can rapidly differentiate between benign and malignant tissues. These differences are thought to be due to endogenous fluorophores, including nicotinamide adenine dinucleotide, flavin adenine dinucleotide, and tryptophan, and absorbers such as beta-carotene and hemoglobin. We hypothesized that a statistically significant difference would be demonstrated between benign and malignant breast tissues on the basis of their unique fluorescence and reflectance properties. METHODS: Optical measurements were performed on 56 samples of tumor or benign breast tissue. Autofluorescence spectra were measured at excitation wavelengths ranging from 300 to 460 nm, and diffuse reflectance was measured between 300 and 600 nm. Principal component analysis to dimensionally reduce the spectral data and a Wilcoxon ranked sum test were used to determine which wavelengths showed statistically significant differences. A support vector machine algorithm compared classification results with the histological diagnosis (gold standard). RESULTS: Several excitation wavelengths and diffuse reflectance spectra showed significant differences between tumor and benign tissues. By using the support vector machine algorithm to incorporate relevant spectral differences, a sensitivity of 70.0% and specificity of 91.7% were achieved. CONCLUSIONS: A statistically significant difference was demonstrated in the diffuse reflectance and fluorescence emission spectra of benign and malignant breast tissue. These differences could be exploited in the development of adjuncts to diagnostic and surgical procedures.

Authors
Breslin, TM; Xu, F; Palmer, GM; Zhu, C; Gilchrist, KW; Ramanujam, N
MLA Citation
Breslin, TM, Xu, F, Palmer, GM, Zhu, C, Gilchrist, KW, and Ramanujam, N. "Autofluorescence and diffuse reflectance properties of malignant and benign breast tissues." Ann Surg Oncol 11.1 (January 2004): 65-70.
PMID
14699036
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
11
Issue
1
Publish Date
2004
Start Page
65
End Page
70

Investigation of fiber-optic probe designs for optical spectroscopic diagnosis of epithelial pre-cancers.

BACKGROUND AND OBJECTIVES: The first objective of this study was to evaluate the performance of fluorescence spectroscopy for diagnosing pre-cancers in stratified squamous epithelial tissues in vivo using two different probe geometries with (1) overlapping versus (2) non-overlapping illumination and collection areas on the tissue surface. Probe (1) and probe (2) are preferentially sensitive to the fluorescence originating from the tissue surface and sub-surface tissue depths, respectively. The second objective was to design a novel, angled illumination fiber-optic probe to maximally exploit the depth-dependent fluorescence properties of epithelial tissues. STUDY DESIGN/MATERIALS AND METHODS: In the first study, spectra were measured from epithelial pre-cancers and normal tissues in the hamster cheek pouch and analyzed with a non-parametric classification algorithm. In the second study, Monte Carlo modeling was used to simulate fluorescence measurements from an epithelial tissue model with the angled illumination probe. RESULTS: An unbiased classification algorithm based on spectra measured with probes (1) and (2), classified pre-cancerous and normal tissues with 78 and 94% accuracy, respectively. The angled illumination probe design provides the capability to detect fluorescence from a wide range of tissue depths in an epithelial tissue model. CONCLUSIONS: The first study demonstrates that fluorescence originating from sub-surface tissue depths (probe (2)) is more diagnostic than fluorescence originating from the tissue surface (probe (1)) in the hamster cheek pouch model. However in general, it is difficult to know a priori the optimal probe geometry for pre-cancer detection in a particular epithelial tissue model. The angled illumination probe provides the capability to measure tissue fluorescence selectively from different depths within epithelial tissues, thus obviating the need to select a single optimal probe design for the fluorescence-based diagnosis of epithelial pre-cancers.

Authors
Skala, MC; Palmer, GM; Zhu, C; Liu, Q; Vrotsos, KM; Marshek-Stone, CL; Gendron-Fitzpatrick, A; Ramanujam, N
MLA Citation
Skala, MC, Palmer, GM, Zhu, C, Liu, Q, Vrotsos, KM, Marshek-Stone, CL, Gendron-Fitzpatrick, A, and Ramanujam, N. "Investigation of fiber-optic probe designs for optical spectroscopic diagnosis of epithelial pre-cancers." Lasers Surg Med 34.1 (2004): 25-38.
PMID
14755422
Source
pubmed
Published In
Lasers in Surgery and Medicine
Volume
34
Issue
1
Publish Date
2004
Start Page
25
End Page
38
DOI
10.1002/lsm.10239

Autofluorescence and diffuse reflectance properties of malignant and benign breast tissues

Authors
Breslin, TM; Xu, F; Palmer, GM; Drezek, RA
MLA Citation
Breslin, TM, Xu, F, Palmer, GM, and Drezek, RA. "Autofluorescence and diffuse reflectance properties of malignant and benign breast tissues." Breast Diseases 15.3 (2004): 256-257.
Source
scival
Published In
Breast Diseases
Volume
15
Issue
3
Publish Date
2004
Start Page
256
End Page
257

Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003).

Nonmalignant (n = 36) and malignant (n = 20) tissue samples were obtained from breast cancer and breast reduction surgeries. These tissues were characterized using multiple excitation wavelength fluorescence spectroscopy and diffuse reflectance spectroscopy in the ultraviolet-visible wavelength range, immediately after excision. Spectra were then analyzed using principal component analysis (PCA) as a data reduction technique. PCA was performed on each fluorescence spectrum, as well as on the diffuse reflectance spectrum individually, to establish a set of principal components for each spectrum. A Wilcoxon rank-sum test was used to determine which principal components show statistically significant differences between malignant and nonmalignant tissues. Finally, a support vector machine (SVM) algorithm was utilized to classify the samples based on the diagnostically useful principal components. Cross-validation of this nonparametric algorithm was carried out to determine its classification accuracy in an unbiased manner. Multiexcitation fluorescence spectroscopy was successful in discriminating malignant and nonmalignant tissues, with a sensitivity and specificity of 70% and 92%, respectively. The sensitivity (30%) and specificity (78%) of diffuse reflectance spectroscopy alone was significantly lower. Combining fluorescence and diffuse reflectance spectra did not improve the classification accuracy of an algorithm based on fluorescence spectra alone. The fluorescence excitation-emission wavelengths identified as being diagnostic from the PCA-SVM algorithm suggest that the important fluorophores for breast cancer diagnosis are most likely tryptophan, NAD(P)H and flavoproteins.

Authors
Palmer, GM; Zhu, C; Breslin, TM; Xu, F; Gilchrist, KW; Ramanujam, N
MLA Citation
Palmer, GM, Zhu, C, Breslin, TM, Xu, F, Gilchrist, KW, and Ramanujam, N. "Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003)." IEEE Trans Biomed Eng 50.11 (November 2003): 1233-1242.
PMID
14619993
Source
pubmed
Published In
IEEE Transactions on Biomedical Engineering
Volume
50
Issue
11
Publish Date
2003
Start Page
1233
End Page
1242
DOI
10.1109/TBME.2003.818488

Autofluorescence spectroscopy of normal and malignant human breast cell lines.

The fluorescence of tryptophan, reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) were characterized in normal human breast cells as well as in malignant human breast cells of similar and dissimilar genetic origins. Fluorescence measurements of each cell line were made over a wide range of cell concentrations, and the fluorescence per cell was determined from the slope in the linear range of the fluorescence intensity vs cell concentration plot. All of the malignant cells showed a statistically significant decrease in the tryptophan fluorescence per cell relative to that of the normal cells. No statistically significant differences were observed in the NAD(P)H or FAD fluorescence per cell between the normal and any of the malignant cell types. NAD(P)H fluorescence was also imaged from monolayers of the normal and malignant cells (of similar genetic origin) using two-photon fluorescence microscopy. A statistically significant decrease in the NAD(P)H fluorescence with malignancy was observed, suggesting that fluorescence imaging of single cells or the cell monolayer preparation may provide more contrast than volume-averaged fluorescence measurements of cells in suspension. In conclusion, the differences in normal and malignant human breast tissue fluorescence spectra may be attributed in part to differences in the intrinsic cellular fluorescence of normal and malignant breast epithelial cells.

Authors
Palmer, GM; Keely, PJ; Breslin, TM; Ramanujam, N
MLA Citation
Palmer, GM, Keely, PJ, Breslin, TM, and Ramanujam, N. "Autofluorescence spectroscopy of normal and malignant human breast cell lines." Photochem Photobiol 78.5 (November 2003): 462-469.
PMID
14653577
Source
pubmed
Published In
Photochemistry & Photobiology
Volume
78
Issue
5
Publish Date
2003
Start Page
462
End Page
469

Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003)

Authors
Palmer, GM; Zhu, CF; Breslin, TM; Xu, FS; Gilchrist, KW; Ramanujam, N
MLA Citation
Palmer, GM, Zhu, CF, Breslin, TM, Xu, FS, Gilchrist, KW, and Ramanujam, N. "Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003)." IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING 50.11 (November 2003): 1233-1242.
Source
wos-lite
Published In
IEEE Transactions on Biomedical Engineering
Volume
50
Issue
11
Publish Date
2003
Start Page
1233
End Page
1242
DOI
10.1109/TMBE.2003.818488

Auto fluorescence and diffuse reflectance properties of malignant and benign breast tissues

Authors
Breslin, TM; Palmer, G; Fang, C; Gilchrist, KW; Xu, F; Ramanujam, N
MLA Citation
Breslin, TM, Palmer, G, Fang, C, Gilchrist, KW, Xu, F, and Ramanujam, N. "Auto fluorescence and diffuse reflectance properties of malignant and benign breast tissues." January 2003.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
10
Issue
1
Publish Date
2003
Start Page
S16
End Page
S16

Diagnosis of Breast Cancer Using Optical Spectroscopy

Fluorescence and diffuse reflectance spectroscopy have shown great promise in diagnosing cancer at a number of organ sites, including the cervix, bronchus, and colon. Recent research has also found that similar techniques, when applied to the breast, can provide fast, accurate diagnosis of breast cancer. An additional avenue of research has focused on investigating the biological basis of spectroscopic differences seen in tissue. This manuscript serves as a review of these recent studies, as well as providing an outline of future work yet to be accomplished to further the use of these techniques as a clinical tool.

Authors
Palmer, GM; Ramanujam, N
MLA Citation
Palmer, GM, and Ramanujam, N. "Diagnosis of Breast Cancer Using Optical Spectroscopy." Medical Laser Application 18.3 (2003): 233-248.
Source
scival
Published In
Medical Laser Application
Volume
18
Issue
3
Publish Date
2003
Start Page
233
End Page
248
DOI
10.1078/1615-1615-00106

Steady-state fluorescence imaging of neoplasia.

Authors
Gill, EM; Palmer, GM; Ramanujam, N
MLA Citation
Gill, EM, Palmer, GM, and Ramanujam, N. "Steady-state fluorescence imaging of neoplasia." Methods Enzymol 361 (2003): 452-481.
PMID
12624924
Source
pubmed
Published In
Methods in Enzymology
Volume
361
Publish Date
2003
Start Page
452
End Page
481

Optimal methods for fluorescence and diffuse reflectance measurements of tissue biopsy samples.

BACKGROUND AND OBJECTIVE: In developing fluorescence spectroscopy systems for the in vivo detection of pre-cancer and cancer, it is often necessary to perform preliminary testing on tissue biopsies. Current standard protocols call for the tissue to be immediately frozen after biopsy and later thawed for spectroscopic analysis, but this process can have profound effects on the spectroscopic properties of tissue. This study investigates the optimal tissue handling methods for in vitro fluorescence spectroscopy studies. STUDY DESIGN/MATERIALS AND METHODS: The epithelial tissue of the Golden Syrian hamster cheek pouch was used in this study. Three specific experiments were carried out. First, the fluorescence properties of tissues in vivo and of frozen and thawed tissue biopsies were characterized at multiple excitation wavelengths spanning the ultraviolet-visible (UV-VIS) spectrum. Next, comparison of tissue fluorescence emission spectra in vivo, ex vivo (immediately after biopsy), and after the freeze and thaw process were systematically carried out at the excitation wavelengths corresponding to the previously identified fluorescence peaks. Lastly, intensities at the excitation and emission wavelength pairs corresponding to the fluorescence peaks were measured as a function of time after biopsy. Diffuse reflectance measurements over the UV-VIS spectrum were also made to evaluate the effects of oxygenation, blood volume, and scattering on the tissue fluorescence at these different excitation-emission wavelengths. RESULTS: This study indicates that the freezing and thawing process produces a significant deviation in intensity and lineshape relative to the in vivo fluorescence emission spectral data over the entire UV-VIS range between 300 and 700 nm. By contrast, examination of ex vivo emission spectra reveals that it closely preserves both the intensity and lineshape of the in vivo emission spectra except between 500 and 700 nm. The observed deviations can be explained by the diffuse reflectance measurements, which suggest increased hemoglobin deoxygenation and wavelength dependent changes in scattering in ex vivo tissues, and increased total hemoglobin absorption in the frozen and thawed samples. Furthermore, it was found that over a time window of 1.5 hours, spectroscopic changes brought about by degradation of the tissue due to biopsy or other factors are significantly smaller (10-30% variations in intensity) than those associated with the freezing and thawing process (50-70% decrease in intensity). CONCLUSIONS: It was found that the effects of freezing and thawing on the fluorescence properties of tissue are greater than any changes brought about by degradation of tissue over a time frame of 90 minutes after biopsy. Performing ex vivo fluorescence measurements within a reasonable time window has the advantage of more accurately reproducing the clinically relevant in vivo conditions in the case of the hamster cheek pouch tissue. Therefore, in tissue biopsy studies, the tissue sample should ideally be maintained in an unfrozen state prior to measurement.

Authors
Palmer, GM; Marshek, CL; Vrotsos, KM; Ramanujam, N
MLA Citation
Palmer, GM, Marshek, CL, Vrotsos, KM, and Ramanujam, N. "Optimal methods for fluorescence and diffuse reflectance measurements of tissue biopsy samples." Lasers Surg Med 30.3 (2002): 191-200.
PMID
11891738
Source
pubmed
Published In
Lasers in Surgery and Medicine
Volume
30
Issue
3
Publish Date
2002
Start Page
191
End Page
200

Diagnosis of breast cancer using auto fluorescence and diffuse reflectance spectroscopy

Proof-of-principle studies were carried out to assess the diagnostic potential of auto fluorescence and diffuse reflectance spectroscopy for discriminating between malignant and non-malignant breast tissues, ex vivo. Auto fluorescence spectra at excitation wavelengths of 300, 320 and 340 nm were found to be most effective in differentiating malignant (13) from non-malignant tissues (25) in this pilot investigation.

Authors
Ramanujam, N; Palmer, G; Breslin, T; Gichrist, K
MLA Citation
Ramanujam, N, Palmer, G, Breslin, T, and Gichrist, K. "Diagnosis of breast cancer using auto fluorescence and diffuse reflectance spectroscopy." Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings 3 (2002): 2279-2280.
Source
scival
Published In
Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings
Volume
3
Publish Date
2002
Start Page
2279
End Page
2280

Fluorescence spectroscopy of DMBA induced hamster cheek pouch model: Analysis of fluorescence and diffuse reflectance changes with disease progression

Authors
Palmer, GM; Nimunkar, AJ; Marshek, CL; Vrotsos, KM; Ramanujam, N
MLA Citation
Palmer, GM, Nimunkar, AJ, Marshek, CL, Vrotsos, KM, and Ramanujam, N. "Fluorescence spectroscopy of DMBA induced hamster cheek pouch model: Analysis of fluorescence and diffuse reflectance changes with disease progression." LASERS IN SURGERY AND MEDICINE (2002): 2-2.
Source
wos-lite
Published In
Lasers in Surgery and Medicine
Publish Date
2002
Start Page
2
End Page
2

Ex vivo diagnosis of breast cancer using fluorescence and reflectance spectroscopy

Authors
Palmer, GM; Keely, PJ; Breslin, TM; Gilchrist, KW; Ramanujam, N
MLA Citation
Palmer, GM, Keely, PJ, Breslin, TM, Gilchrist, KW, and Ramanujam, N. "Ex vivo diagnosis of breast cancer using fluorescence and reflectance spectroscopy." LASERS IN SURGERY AND MEDICINE (2002): 76-76.
Source
wos-lite
Published In
Lasers in Surgery and Medicine
Publish Date
2002
Start Page
76
End Page
76
Show More

Research Areas:

  • Absorption
  • Adipose Tissue
  • Adult
  • Algorithms
  • Altitude
  • Anemia, Sickle Cell
  • Angiogenesis Inhibitors
  • Angiopoietins
  • Animals
  • Anoxia
  • Antibiotics, Antineoplastic
  • Arterial Pressure
  • Artificial Intelligence
  • Biological Transport
  • Biopsy
  • Blood Flow Velocity
  • Blood Vessels
  • Blood flow
  • Blotting, Western
  • Brain
  • Breast
  • Breast Neoplasms
  • Carcinoma in Situ
  • Carcinoma, Ductal, Breast
  • Carcinoma, Lobular
  • Cell Adhesion
  • Cell Hypoxia
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Tracking
  • Cell Transformation, Neoplastic
  • Cervical Intraepithelial Neoplasia
  • Cheek
  • Chickens
  • Chromatography, High Pressure Liquid
  • Colorectal Neoplasms
  • Combined Modality Therapy
  • Computer Simulation
  • Computer-Aided Design
  • Contrast Media
  • Cricetinae
  • Cyclic N-Oxides
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cytotoxicity, Immunologic
  • Diagnosis, Computer-Assisted
  • Diagnostic Imaging
  • Disease Models, Animal
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Doxorubicin
  • Drug Delivery Systems
  • Drug Evaluation, Preclinical
  • Drug Monitoring
  • Drug Synergism
  • Electric Capacitance
  • Electric Conductivity
  • Electromagnetic Phenomena
  • Equipment Design
  • Erythrocytes
  • Erythrocytes, Abnormal
  • Exercise
  • Feasibility Studies
  • Female
  • Fiber Optic Technology
  • Fibrocystic Breast Disease
  • Gene Expression Regulation
  • Glycerol
  • HCT116 Cells
  • Head and Neck Neoplasms
  • Heart Rate
  • Heme Oxygenase-1
  • Hemin
  • Hemodynamics
  • Hemoglobins
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hydrogen Peroxide
  • Hyperthermia, Induced
  • Image Interpretation, Computer-Assisted
  • Image Processing, Computer-Assisted
  • Image processing
  • Immunotherapy, Adoptive
  • Isoxazoles
  • Lactic Acid
  • Lasers
  • Least-Squares Analysis
  • Light
  • Lighting
  • Liposomes
  • Luminescent Proteins
  • Lung
  • Lung Neoplasms
  • Mammary Neoplasms, Experimental
  • Mesocricetus
  • Metoprolol
  • Mice
  • Mice, Nude
  • Microcirculation
  • Microscopy
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Microvessels
  • Microwaves
  • Middle Aged
  • Misonidazole
  • Models, Animal
  • Models, Biological
  • Models, Chemical
  • Models, Statistical
  • Molecular Imaging
  • Monte Carlo Method
  • Mouth Mucosa
  • Mouth Neoplasms
  • Muscle, Skeletal
  • NADP
  • Nanomedicine
  • Nanoparticles
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Neoplasms
  • Neoplasms, Experimental
  • Neoplasms, Fibrous Tissue
  • Neovascularization, Pathologic
  • Nephelometry and Turbidimetry
  • Optical Fibers
  • Optical Phenomena
  • Optics and Photonics
  • Oximetry
  • Oxygen
  • Oxygen Consumption
  • Pattern Recognition, Automated
  • Phantoms, Imaging
  • Phenylpropionates
  • Photoacoustic Techniques
  • Photometry
  • Physical Conditioning, Animal
  • Pilot Projects
  • Positron-Emission Tomography
  • Precancerous Conditions
  • Predictive Value of Tests
  • Principal Component Analysis
  • Prodrugs
  • Prognosis
  • Protoporphyrins
  • Pulmonary Artery
  • Radiometry
  • Radiopharmaceuticals
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Receptor, erbB-2
  • Receptors, Endothelin
  • Reflectance
  • Refractometry
  • Renal Circulation
  • Reproducibility of Results
  • Respiration
  • Scattering, Radiation
  • Sensitivity and Specificity
  • Spectrometry, Fluorescence
  • Spectrophotometry
  • Spectrophotometry, Ultraviolet
  • Spectroscopy, Near-Infrared
  • Spectrum Analysis
  • Theophylline
  • Treatment Outcome
  • Triazines
  • Tumor Markers, Biological
  • Tumor Microenvironment
  • United States
  • Uterine Cervical Neoplasms
  • Vasoconstriction
  • Xenograft Model Antitumor Assays
  • beta Carotene