**[Annual Report NTROI Workshop]{.smallcaps}**

**[October 30-31, 2006]{.smallcaps}**

**[Annual Report NTROI Workshop October 30-31, 2006]{.smallcaps}**

**[Table of Contents]{.smallcaps}**

**[A. Program Background 3]{.smallcaps}**

**[B. Executive Summary 6]{.smallcaps}**

**[C. Network progress 8]{.smallcaps}**

**[C.1. Clinical translation 8]{.smallcaps}**

**[C.2. Advances in the Field 10]{.smallcaps}**

**[C.3. Publications and presentations 12]{.smallcaps}**

**[C.4. Corporate Partnerships 13]{.smallcaps}**

**[D. Working Groups 14]{.smallcaps}**

**[D.1. Pathology Working Group 14]{.smallcaps}**

**[D.2. Information technologies Working Group 15]{.smallcaps}**

**[D.3. Imaging and Drug Development Working Group 16]{.smallcaps}**

**[D.4. Clinical Studies Working Group 16]{.smallcaps}**

**[D.5. Industry Working Group 17]{.smallcaps}**

**[E. Progress and Future Aims for Individual Teams 18]{.smallcaps}**

**[E.1. Team 1: University of California Irvine 18]{.smallcaps}**

**[E.2. Team 2: Boston University 21]{.smallcaps}**

**[E.3. Team 3: University of pennsylvania 24]{.smallcaps}**

**[E.4. Team 4: Stanford University 26]{.smallcaps}**

**[Appendix A: Total NTROI Publications 30]{.smallcaps}**

**[Appendix B: Agendas from Recent Annual Retreats 41]{.smallcaps}**

> The following Report of the third Workshop of the Network for
> Translational Research in Optical Imaging (NTROI) is organized in
> Sections A through E, starting with the Program Director's Background
> section, followed by the Principal Investigators' Report: Executive
> Summary, Overall NTROI progress, Working Group progress, and closing
> with four reports on individual Team advances and accomplishments.

-   Section A: Background.

-   Section B: Executive Summary

-   Section C: NTROI progress as a Network of networks

-   Section D: NTROI Working Group progress

-   Section E: Progress by Each Team: Teams1-4

**[A. Program's Background statement:]{.smallcaps}**

The NTROI Steering Committee convened their third annual workshop on
October 30-31^st^, 2006 in Silver Spring MD to review progress, update
plans, and make mid-course adjustments to maximize translational
efficiency during the two remaining years of the current funding cycle.
Seventy-one NTROI-affiliated investigators and interested parties
participated. In addition, six outside scientists were invited to attend
as observers. These individuals were asked to provide candid
observations on NTROI strengths, weaknesses, and make recommendations.

NTROI consists of four funded U54 cooperative agreements organized as
four networks under an umbrella network that is coordinated by a
Steering Committee. Each U54 "Team" draws investigators from multiple
sites, mainly academic and industrial. While most of these cooperating
sites are domestic, ten sites are non-USA labs and businesses.
NTROI-funded investigators lead Primary, Developmental and Core
Projects. Associate Members (collaborators), an important source of
leverage for NTROI activities, have independently funded projects that
align with Team objectives. Independent interested parties and advisors
from academic, non-profit labs, businesses large and small, federal labs
(including several intramural labs from NIH ICs), and Federal Agencies
(FDA, CMS, NSF, NIST) participate as observers, consultants, clinical
collaborators, etc. Many of them serve regularly or occasionally on 6
NTROI-organized Working Groups that address specialized needs of the
NTROI Steering Committee as well as interests of the wider optical
community on the subjects of Informatics, Pathology, Industry, Drug
Development and Therapeutic Response, Clinical Studies, and
Standardization and Quality Control. The background and structure
underlying NTROI is described elsewhere:
<http://imaging.cancer.gov/programsandresources/specializedinitiatives/ntroi>\]

CIP intent from inception of the NTROI concept was to engineer a
paradigm shift toward faster, effective translation of leading prototype
medical optical systems into clinical use. Clear early signs of high
potential were there to see: pulse oximetry and ear-canal IR thermometry
had already joined the automated blood pressure cuff as clinical
staples. The fundamental concept underlying the NTROI program was that
organized teams (each operating as a network) of laboratories working on
related optical technologies could solve both their specialized problems
and their common problems of translational research more efficiently and
quickly than research laboratories operating independently. An extension
of this concept was that an umbrella network of these networks to share
ideas and results in areas such as phantom development, software
integration, and device performance validation---an extended team
approach to translational research---could further shorten the time to
bring imaging devices to clinical utility.

Why choose medical optical technologies? CIP staff recognized that
optical technologies, which exploit the physics of optical photon
diffusion in tissue, could add many important advantages to the imaging
options currently available to physicians and researchers. Optical
methods offer low cost imaging designs based on robust physical
principles. They are fast, safe, and non-ionizing. Most provide
excellent to outstanding signal-to-noise capabilities. Time resolutions
span the range from nanoseconds to continuous. Spatial resolutions span
from sub-cellular micro-structural anatomy through meso- to
macro-features. There are optical technology capacities to measure
multiple molecular properties simultaneously, and unobtrusive enough
with fiber optics to enable concurrent measurements in established
medical imaging systems---optical/MRI and optical/ultrasound are notable
combinations. Optical imaging technologies can provide dynamic molecular
and functional imaging with impressive specifications. Optical imaging
and spectroscopic technologies show potential to expand clinical
opportunities for screening, early detection, diagnosis, image guided
intervention, therapy, and monitoring therapeutic response. Expectations
are high for major impact on research, clinical care, and drug
development.

There are other reasons why optical imaging was seen as an opportune
arena in which to interject the concept of networking as a method for
reducing translation time. Optical technologies are relatively new as
compared to other imaging modalities such as PET, CT, and ultrasound. As
a result, the optical imaging area is not excessively burdened by
infrastructural features such as major commercial vendors competing for
customer bases. The latter create market-driven hardware designs,
established software functionality, rigid use protocols, and other
obstacles to implementing a networking strategy into translational
research.

The NTROI initiative has been a creative stimulus to a number of ongoing
federal activities in imaging science. It anticipated by several years a
number of recent initiatives, e.g., FDA's New Pathways Initiative, NCI
emphasis on accelerating translational research (reflected in the
mid-2005 organization of the Translational Research Working
Group---TRWG), its new push for molecular imaging and the identification
of imaging biomarkers, the Nanotechnology Initiative, and the
FDA-NCI-CMS Oncology Biomarker Qualification Initiative (OBQI), to name
a few.

The Steering Committee deserves special mention for its role in
achievement of NTROI Objectives. It assures focus, coordination, a
greater range of views brought into discussion, rapid response to
opportunities, and collaborations---all to accelerate translations of
leading optical developments from prototype to applications in
laboratories and clinics. Some activities include the following:

-   Collaborations intra-team, inter-team and outside for multiple
    purposes:

    -   Cross validations of early detection, diagnosis, and therapeutic
        response of breast, gastrointestinal and other cancers.

    -   Animal model development for molecular imaging research in
        cancer cell biology, cell pathways, imaging agent development,
        drug development and therapeutic response.

    -   Molecular imaging for high specificity detection, diagnosis and
        therapeutic response.

    -   Cross-validation studies with established and emerging methods.

    -   Wide capacity phantoms, consensus protocols and other means of
        quality control to better compare and understand results across
        multiple sites, kinds of devices, imaging agents, platform
        technologies.

    -   Consensus methods for data collection, processing, and data
        sharing; introduction of web based access.

    -   Research collaborations with SPOREs and Clinical Cancer Centers
        to assure more robust tests, validations and seamless
        introductions of the community of practicing physicians to the
        new technologies.

-   Organization of Working Groups to assure participation and
    engagements by the wider research community for broader expert
    input. Engage community knowledge bases in Pathology, Informatics,
    Industry, Drug Development and Therapeutic Response, Clinical
    Studies, and (added during the Oct 2006 Workshop) Standards and
    Quality Assurance. Representation includes NICHD, NIBIB, NSF, FDA,
    NIST; Pharmaceutical, Biotechnology, Device and System manufacturers
    large and small. Address of broad problems in validation, quality
    assurance, standardization, performance standards, pathology;
    industrial translation to self-sustaining (profitable) products;
    platform approaches to collection, processing, and internet sharing
    of large datasets and analyses; clinical studies and protocols; drug
    development and therapeutic response.

-   Promulgated leveraged funding to enhance NTROI success and impact
    (U54 Hub and R01/SBIR/STTR/R21/R33 Spoke Model).

-   Established collaborations to accelerate both development and
    dissemination of preclinical animal models pertinent to
    pre-validation developments of drugs, optical molecular probes and
    systems, therapy of model diseases and tracking therapeutic
    response.

**[B. Executive Summary]{.smallcaps}**

The Third Annual NTROI Workshop brought together investigators
interested in advancing optical imaging of cancer for the purpose of
reviewing progress and refining objectives for the integrated and highly
collaborative Teams that comprise the NTROI. The goals of the NTROI are
to accelerate the translation of optical methods for early detection of
malignancy, rapid monitoring of disease progression and development of
therapeutic interventions. The objective of accelerating translation of
optical methods and preclinical information to the clinic is the
foundation of each of the four Teams and each have, to date, exceeded
the initial aims through strong synergistic interactions among the four
Teams, effective integration with NCI Program, and development of
targeted Working Groups. Outside advisors were invited to attend the
Third Annual NTROI Workshop, and this offered an opportunity to
strengthen ongoing and potential joint activities within the NTROI
through advice and comments, and to form bridges between the NTROI other
NCI funded programs further supporting a network structure.

The four Teams have effectively organized into a Network of networks,
which is led by the Steering Committee. The Steering Committee meets
regularly to discuss cooperative efforts that facilitate collaborations
within and outside the NTROI, to address problems of common interest and
to take advantage of complementary capabilities. This was apparent from
the advances made by working groups, the number of interactive projects,
and the breadth of each of the teams that have successfully integrated
academic and industrial partners. The Network has driven
cross-validation, standardization, single and multi-site clinical
studies, and data sharing to accelerate the translation and refinement
of optical tools for clinical evaluation. The network has demonstrated
breadth and depth in optics and medicine that extend from the analysis
of molecular pathways in cancer for improved therapies to new clinical
imaging devices for early detection and risk assessment.

There is a strong industrial presence in the Network with substantial
evidence of successful collaboration between all Teams and industrial
partners and associate members. The Working Groups form a conduit for
this interaction and were set up to address the common needs of the
Teams. The Working Groups have become sterling examples of NTROI success
and have made substantial progress in moving the field forward. Much of
this success has led to new opportunities for interaction and
technological advances and these have been supported through
developmental funds. These funds provide an agility to the teams and the
Network to move into important areas quickly, and this was evident as
the teams develop new probes, target additional markers, and address
other unmet clinical needs. The translational aspects of this Network
were apparent in each team (see section C1) and clinical studies are
underway to evaluate instruments and probes. Translation of preclinical
data to clinical studies is facilitated through the use of advanced
animal models that improve preclinical information that can inform and
direct clinical studies that are designed to evaluate novel tools and
therapies. In the first three years of existence the NTROI has made
substantive progress in their specific areas of endeavor, and has
provided significant 'value added' to the optics field by successfully
demonstrating proof-of-concept for an accelerated translational research
paradigm.

**The value of the Network for effective translation of optical tools to
the clinic includes:**

> • Standardization of data collection and establishment of standard
> practices for clinical translation
>
> • Improved databases for imaging and managing patient data integrated
> with various modalities
>
> • Standardization of methods for data acquisition and analyses
>
> • Standardization of quantitative pathology
>
> • New tools, methods, multi-site collaborations, validations, data,
> and focus that have helped build the emerging field of in vivo
> pathology
>
> • Development of combined probes and multi-modality approaches
>
> • Creation of a technological and administrative hub on which other
> investigators can build for evaluating optical technologies
>
> • Dissemination of information on optical methods to medical centers
> through scientific presentations and clinical trials
>
> • Bringing academic and corporate scientists together to advance a
> common mission
>
> • Development of clinical protocols for implementing novel
> technologies for early detection while minimizing disruption to
> standards of care
>
> • Extensive preclinical expertise and established preclinical models
> for drug development and evaluation.
>
> • Bringing physical scientists, practicing physicians, and industrial
> teams together from the very outset of research design so as to
> maximize strategic alignment of technologies with clinical needs

**The NTROI structure effectively supports the translational objectives
by:**

> • Creating a Network that is greater than the sum of the individual
> teams through synergistic interactions and an "adhesive function" of
> several strong and active working groups
>
> • Developing an administrative structure that ensures that the overall
> mission drives the research within and among teams with a focus on
> translation of tools and protocols
>
> • Enabling regular, dynamic interaction with NCI program staff. This
> has guided the network and helped establish strong interactive
> programs well integrated into the mission of the NCI and its funded
> programs.
>
> • Effectively integrating NIBIB, FDA and NIST staff into the Steering
> Committee and Working Groups to ensure excellence in technological
> development, effective translation, and appropriate standards
>
> • Ensuring early involvement of corporate partners and protected
> intellectual property to allow effective commercialization of
> developed tools, probes and methods.
>
> • Encouraging interaction among the teams, steering committee, and
> advisory committees thereby securing regular feedback that has helped
> shape individual teams and enhance their progress.
>
> • Providing technical resources and infrastructure that are benefiting
> a number of other programs, including R01s, R21s, and BRGs and SPORES,
> Comprehensive Cancer Centers, ICMICs and SAIRs.

**The Workshop Highlighted the accomplishments of the NTROI (Years 1-3)
that include:**

> • 167 total publications in the field
>
> • Over 150 invited lectures at international conferences and symposia
>
> • Annual NTROI retreats, involving all principals, all key
> collaborators, and staff from NCI, NIBIB, FDA and NIST
>
> • Involvement of caBIG, ACRIN and other programs that can aid the
> clinical translation process
>
> • Increased impact through additional grants to support activities
> synergistic with the NTROI mission.
>
> • Demonstration of strong corporate partnerships and creation of new
> start-up companies to advance the goals of translation
>
> • Well-developed interactions with Cancer Centers, SPOREs, GCRCs,
> ICMICs, SAIRPs and P01s.
>
> • 30 ongoing clinical studies and a number that are under IRB review
>
> • Numerous preclinical studies to evaluate new therapies, test new
> instruments and develop new probes
>
> • Robust and interactive Industrial interactions, and collaborations
> with sponsorships in excess of \$1M

Due to the significant impact that the NTROI has already had on a number
of fields, the Network has attained a reputation well-recognized by
industry and academic centers. The corporate and clinical impact of the
Network is significant and accelerating as the science advances and the
influence of the program expands over the remaining 2 grant years.

**[C. Overview of Network Progress---]{.smallcaps}** Optical methods of
disease detection, diagnosis and prognosis hold tremendous potential for
clinical monitoring, especially in the areas of pre-cancer
determination, early cancer detection and risk assessment where frequent
monitoring is necessary. In addition, optical tools are key technologies
in molecular imaging and have also become the core technology for
advancing preclinical development of novel therapies by rapid evaluation
in animal models through imaging. The NTROI has focused on critical
areas where optical methods excel over other modalities, among them
readying novel "bedside" tools for the clinic, developing methods for
refining drug development, and advancing targeted molecular therapies.
The program has already made significant contributions to the field and
has made tremendous progress in moving these emerging technologies into
important clinical niches.

It was recognized from program inception that there was a need to
establish clear standards for developing and cross validation of new
optical modalities, and that standardization in several areas would be
critical for both development of these tools and their effective
integration into clinical practice and drug development programs. For
this purpose NTROI investigators have been working to establish
pathology standards for assessing the predictability of novel optical
technologies, and create informatics solutions to standardize both data
collection and analysis across different imaging platforms and to manage
large data sets for the first time in medical imaging. These were the
first areas where trans-NTROI Working Groups were established, and
significant advances have already been made among the teams through the
Pathology and Information Technology (IT) Working Groups. Following
advances in these areas the Network has pushed to create standard
preclinical cancer models and establish good practices and policies for
clinical translation of optical tools. Lastly, none of this could be
accomplished without the help of industrial partners, a strong component
of the Network since inception. Translation to the clinic depends on
sustained industrial involvement and commitment to developing a
user-friendly, robust, dependable version of the development, gaining
regulatory approval, establishing marketing, maintenance and all the
necessary details for a self-sustaining (profitable) system that meets
needs of the clinical community. Working Groups in each of these areas
support advances made by the Network in effectively translating optical
imaging and spectroscopy. The following sections B1 to B4 below address
the overall NTROI progress in greater detail.

**[C.1. Clinical Translation:]{.smallcaps}**

The essence of the NTROI is translation of technologies and information
from the laboratory to the clinic. The NTROI investigators are actively
developing clinical studies to test new tools, optimize approaches and
evaluate reagents. They are actively developing new animals models for
significant preclinical studies and new ways of advancing drug studies.

**C.1.1.** [Existing protocols.]{.underline} The number of approved
protocols is extensive---a list of ongoing clinical studies is contained
in Table 1. Several of these protocols aim to test a given instrument at
different sites; others involve single site testing of an individual
tool or method. An objective for the Network is to make the clinical
data available to other investigators through publication and access to
raw data, when appropriate. The distribution of this information is a
primary goal for the IT Working Group. They are developing software to
facilitate information transfer and leveraging the effort with other
interested parties---see descriptions below.

**Table 1. Approved NTROI Studies in Clinical Translation**

+--------------------------------+------------+--------+---------------+
| **IRB Protocol**               | **Target   | **     | **            |
|                                | Number**   | Number | Institution** |
|                                |            | of**   |               |
|                                | **of       |        |               |
|                                | Patients** | **Pa   |               |
|                                |            | tients |               |
|                                |            | to     |               |
|                                |            | date** |               |
+--------------------------------+------------+--------+---------------+
| Measurement of breast tissue   | 600        | 389    | UCI           |
| optical properties             |            |        |               |
+--------------------------------+------------+--------+---------------+
| Monitoring response to         | 90         | 40     | UCI           |
| chemotherapy on breast cancer  |            |        |               |
| tumors by photon migration     |            |        |               |
| spectroscopy                   |            |        |               |
+--------------------------------+------------+--------+---------------+
| Monitoriong menstrual cycle    | 15         | 7      | UCI           |
| functional variations in DOS   |            |        |               |
+--------------------------------+------------+--------+---------------+
| Measurement of Breast Tissue   | 50         | 14     | UCSF          |
| Optical Properties             |            |        |               |
+--------------------------------+------------+--------+---------------+
| Tomographic optical breast     | 150        | 91     | MGH           |
| imaging (TOBI)                 |            |        |               |
+--------------------------------+------------+--------+---------------+
| Optical properties during      | 120        | 83     | MGH           |
| dynamic breast compression     |            |        |               |
+--------------------------------+------------+--------+---------------+
| Parallel Detection and         | 300        | 174    | U Penn        |
| Computation for Diffuse        |            |        |               |
| Optical Tomography of Breast   |            |        |               |
+--------------------------------+------------+--------+---------------+
| In vivo diffuse optical        | 100        | 32     | U Penn        |
| tomography of the human breast |            |        |               |
| with MRI                       |            |        |               |
+--------------------------------+------------+--------+---------------+
| Fast optical imager for tumor  | 50         | 11     | U Penn        |
| detection                      |            |        |               |
+--------------------------------+------------+--------+---------------+
| Alternative breast imaging     | 330        | 49     | Dartmouth     |
| modalities                     |            |        |               |
+--------------------------------+------------+--------+---------------+
| Optical discrimination of      | 300        | 240    | Univ. College |
| dysplasia in Barrett's         |            |        | London        |
| esophagus                      |            |        |               |
+--------------------------------+------------+--------+---------------+
| Optical detection of           | 300        | 331    | Univ. College |
| metastasis in breast sentinel  |            |        | London        |
| nodes                          |            |        |               |
+--------------------------------+------------+--------+---------------+
| ESS-guided biopsy of colonic   | 150        | 150    | Univ. College |
| polyps                         |            |        | London        |
+--------------------------------+------------+--------+---------------+
| ESS sensing of dysplasia in    | 20         | 5      | Erasmus       |
| Barrett's esophagus            |            |        | Medical       |
|                                |            |        | Center,       |
|                                |            |        | Rotterdam     |
+--------------------------------+------------+--------+---------------+
| ESS sensing of breast cancer   | 20         | 0      | Erasmus       |
| intraoperatively               |            |        | Medical       |
|                                |            |        | Center,       |
|                                |            |        | Rotterdam     |
+--------------------------------+------------+--------+---------------+
| Optical monitoring of PDT      | 15         | 0      | Lund          |
| dosage in prostate cancer      |            |        | University    |
|                                |            |        | Hospital,     |
|                                |            |        | Sweden        |
+--------------------------------+------------+--------+---------------+
| ESS sensing of cancer in       | 30         | 31     | BUMC          |
| excised prostate glands        |            |        |               |
+--------------------------------+------------+--------+---------------+
| Testing of optically-guided    | 50         | 55     | BUMC          |
| polyp forceps during           |            |        |               |
| colonoscopy                    |            |        |               |
+--------------------------------+------------+--------+---------------+
| Testing of optically-guided    | 50         | 75     | Boston VA     |
| polyp forceps during           |            |        | Hospital      |
| colonoscopy                    |            |        |               |
+--------------------------------+------------+--------+---------------+
| Testing of optically-guided    | 50         | 0      | BUMC          |
| polyp snares during            |            |        |               |
| colonoscopy                    |            |        |               |
+--------------------------------+------------+--------+---------------+
| Testing of optically-guided    | 50         | 0      | Boston VA     |
| polyp snares during            |            |        | Hospital      |
| colonoscopy                    |            |        |               |
+--------------------------------+------------+--------+---------------+
| Optical monitoring of PDT      | 30         | 5      | U.Pitt.       |
| dosage in cervical cancer      |            |        | Cancer Inst.  |
| treatment                      |            |        |               |
+--------------------------------+------------+--------+---------------+
| Scattering spectroscopy probe  | 12         | 2      | UCSF          |
| for detecting brain tumor      |            |        |               |
| margins during surgery         |            |        |               |
+--------------------------------+------------+--------+---------------+
| Human Colon Cancer             |            |        | U Penn        |
| Susceptibility                 |            |        |               |
+--------------------------------+------------+--------+---------------+
| High Resolution Endoscopic     | 100        | 256    | Stanford/Palo |
| Imaging                        |            |        | Alto VA       |
+--------------------------------+------------+--------+---------------+
| Infrared Spectroscopy for *Ex  | 100        | 93     | Stanford/Palo |
| Vivo* Histopathology of        |            |        | Alto VA       |
| Gastrointestinal Mucosa        |            |        |               |
+--------------------------------+------------+--------+---------------+
| Detection of Neoplasia in the  | 100        | 32     | Stanford/Palo |
| Digestive Tract                |            |        | Alto VA       |
+--------------------------------+------------+--------+---------------+
| Novel Confocal Microscope for  | 100        | 30     | Stanford/Palo |
| Molecular/Cellular Imaging     |            |        | Alto VA       |
+--------------------------------+------------+--------+---------------+

**C.1.2.** [Clinical Protocols Under Development.]{.underline} In
addition to the approved protocols listed in table 1 the NTROI is
developing 10 new additional protocols that are aimed expand the breadth
and depth of the clinical studies, as well as providing standardization
across clinical sites that are testing the same tools or reagents. Team
1 is currently developing 2 standardized protocols, based on existing
protocols and acquired expertise, that will serve all clinical sites.
There are two protocols at BU under development for testing of biopsy
forceps incorporating optical probes for guidance to dysplasia. Team 3
has 4 protocols under development. (1) Phase I/II TRAIL/Sorafenib
combination therapy in solid malignancies. Optical imaging was used to
accelerate development of the protocol through the use of visible animal
models where luciferase is used to mark the therapeutic target. This
protocol includes PET/CT imaging of therapeutic response in the clinical
study. (2) PARISS hyperspectral imaging of cutaneous lesions in patients
with metastatic melanoma receiving systemic chemotherapy. (3) Imaging
B-Raf mutations in preneoplastic lesions using a mutant B-Raf molecular
beacon. (4) Multiplex quantitative histologic analysis of human breast
cancer cell signaling and cell fate. As Team 4 is transitioning into the
study of diseases outside of the GI tract three additional protocols are
being developed in the areas of detecting tumor margins in glioblastoma,
medulloblastoma and melanoma. Animal protocols have been approved to
perform the preclinical studies on these new cancer models for Team
4---see preclinical section below---and data generated as part of these
protocols have been used to support the translation to clinical studies.

**[C.2. Advances in the Field]{.smallcaps}**

**C.2.1**. [Instrumentation and technology]{.underline}. Technology
development within the NTROI has been over a range of modalities.
Devices and methods that are representative of the field include:

C.2.1.1. Clinical instrumentation for diagnostic spectroscopy for
measurements in a variety of organs for disease detection and monitoring
drug levels in the target tissues of the esophagus, breast, brain and
colon.

C.2.1.2. Endoscopic biopsy tools that incorporate optical fibers for
diagnostic guidance. These tools integrate well with the intra-vital
microscopy capabilities listed below.

C.2.1.3. Tests of a microendoscope for early detection of colon cancer

C.2.1.3.1. Targeted imaging agents based on peptides for the early
detection of colon cancer.

C.2.1.4. Miniature microscope based on a dual axes design that provides
a long working distance with X, Y and Z scanning capabilities and rapid
data acquisition. The instrument can work in reflectance and
fluorescence modes and thus acquire both micro-anatomic and functional
data.

C.2.1.5.Two new instrument prototypes for preclinical imaging for
improved animal studies of novel therapies. These enable hyperspectral
imaging, one macroscopically and the other microscopically.

C.2.1.6. Multidimensional spectroscopy, imaging, and tomography
technologies for molecular imaging of tumors, risk, and therapeutic
response in thick tissues

C.2.1.7. Multimodality methods that co-register optical images with MRI,
mammography, and ultrasound.

**C.2.2.** [Development of new reagents, and molecular
probes]{.underline}. Molecular probes with optically detectable
signatures will be key advances in the field of molecular imaging and
are the focus of intense development in nanotechnology. NTROI
investigators **i**. develop new molecular probes, **ii.** advance the
technologies for detecting novel probes created by other investigators
as part of the National efforts in nanotechnology, and **iii.** advance
the preclinical and clinical evaluation of these new reagents for early
detection and measures of outcome. The breadth of this activity is
evident in the list below of new reagents and models that have been
developed within the NTROI.

B.1.2.1. Several novel molecular beacons have been developed for
improved preclinical studies with potential for clinical application.

B.1.2.2. NTROI-funded investigators have developed 4 new
molecularly-targeted drug screens using optical readouts and have
coupled these to new animal models to provide a bridge from in vitro to
in vivo, which accelerates drug development.

B.1.2.3. Three new peptide probes have been developed to enhance early
diagnosis of colon cancer and tested in more than 20 patients as a phase
I clinical trial.

B.1.2.4. Four peptide probes have been developed for glioblastoma to
enable detection of tumor margins during surgical resection. These are
in animal models now and will be made available to clinicians as soon as
the instruments become available for clinical use and the probes are
approved by the IRB for detection of tumor margins.

**C.2.3.** [Preclinical Studies]{.underline}. The NTROI is unique in its
breadth of new technology developments of devices and probes, their
integration with animal model development and preclinical testing,
validations, and clinical studies. This strength is demonstrated by the
contribution of new animal models to national efforts in cancer
detection, prevention, therapy, and monitoring of early therapeutic
response. NTROI has a number of approved preclinical studies (Table 2)
that address the needs of the Network and support translational studies.
Within the NTROI here is extensive work in preclinical development of
new drugs, identification of new targets and evaluation of novel
therapies in addition to the preclinical testing of new technologies.

**Table 2. Preclinical Studies**

+------------------------------------------+------+-------------------+
| **Approved IACUC Protocol**              | **S  | **Institution**   |
|                                          | peci |                   |
|                                          | es** |                   |
+------------------------------------------+------+-------------------+
| Applications of DOS/imaging to monitor   | Rat  | UC Irvine         |
| Tumor Angiogenesis and Cancer Therapy    |      |                   |
| Effects on Rat Breast Tumor: A           |      |                   |
| Comparison Study with Tumor              |      |                   |
+------------------------------------------+------+-------------------+
| Online Measurements and Model-Based      | M    | Dartmouth         |
| Dosimetry in Photodynamic Therapy        | ouse |                   |
|                                          | /rat |                   |
+------------------------------------------+------+-------------------+
| Optical Pharmacokinetics Measurement of  | Rat  | Univ College      |
| Photosensitising Drug Concentrations for |      | London/Boston     |
| Photodynamic Therapy                     |      | Univ.             |
+------------------------------------------+------+-------------------+
| OP measurement of Lu and Gd-texaohyrins  | M    | Boston U./ U.     |
| in vivo                                  | ouse | Pitt.             |
+------------------------------------------+------+-------------------+
| Optical measurement of PDT drug          | M    | BU/Lund           |
| concentrations in animal tumor models    | ouse | University        |
+------------------------------------------+------+-------------------+
| Optical assessment of microvessel        | Rat  | BU/Beth Israel    |
| permeability in angiogenesis             |      | Deaconess         |
+------------------------------------------+------+-------------------+
| OP measurement of IA administered        | Ra   | BU/Columbia       |
| chemotherapy agents in brain tissue      | bbit | University        |
+------------------------------------------+------+-------------------+
| Imaging cancer therapeutic response      | M    | U Penn            |
|                                          | ouse |                   |
+------------------------------------------+------+-------------------+
| Imaging the transformation of human      | M    | U Penn            |
| mammary epithelial cells                 | ouse |                   |
+------------------------------------------+------+-------------------+
| Multifunctional low-density lipoprotein  | M    | U Penn            |
| nanoplatforms                            | ouse |                   |
+------------------------------------------+------+-------------------+
| Use of LDLr and GLUT for cancer imaging  | M    | U Penn            |
| and treatment                            | ouse |                   |
+------------------------------------------+------+-------------------+
| NMR and NIR detection of phospholipase   | M    | U Penn            |
| activity in vivo                         | ouse |                   |
+------------------------------------------+------+-------------------+
| Mechanism of antitumor response elicited | M    | U Penn            |
| by anti-angiogenic agents                | ouse |                   |
+------------------------------------------+------+-------------------+
| Imaging the role of p53 in sensitization | M    | U Penn            |
| of Bax-null cells to TRAIL plus CPT11    | ouse |                   |
+------------------------------------------+------+-------------------+
| Imaging the Mitotic Cascade              | M    | U Penn            |
|                                          | ouse |                   |
+------------------------------------------+------+-------------------+
| Novel Methods of Imaging Cancer          | M    | U Penn            |
| Metastasis                               | ouse |                   |
+------------------------------------------+------+-------------------+
| Determining the optimal therapeutic      | M    | U Penn            |
| combination of temozolomide, taxol, and  | ouse |                   |
| radiation in the glioblastoma multiforme |      |                   |
| brain tumor model                        |      |                   |
+------------------------------------------+------+-------------------+
| Imaging the role of p53 target genes in  | M    | U Penn            |
| tumorigenesis and chemosensitivity       | ouse |                   |
+------------------------------------------+------+-------------------+
| Imaging the transformation of human      | M    | U Penn            |
| mammary epithelial cells                 | ouse |                   |
+------------------------------------------+------+-------------------+
| Tissue/genetic determinants of           | M    | U Penn            |
| radiosensitivity                         | ouse |                   |
+------------------------------------------+------+-------------------+
| The effect of tumor hypoxia on           | M    | U Penn            |
| therapeutic responsiveness to TRAIL      | ouse |                   |
| ligand and                               |      |                   |
|                                          |      |                   |
| Tirapazamine                             |      |                   |
+------------------------------------------+------+-------------------+
| Esophageal tumorigenesis induced by      | M    | U Penn            |
| overexpression of oncogenes              | ouse |                   |
+------------------------------------------+------+-------------------+
| Optical imaging of tumor physiologic and | M    | U Penn            |
| metabolic changes with antiangiogenic    | ouse |                   |
| therapy                                  |      |                   |
+------------------------------------------+------+-------------------+
| Oncogene mRNA Imaging with               | M    | Jefferson         |
| Radionuclide-PNA Peptides                | ouse | University        |
+------------------------------------------+------+-------------------+
| The use of vaccinia virus in cancer      | M    | Stanford          |
| therapy                                  | ouse | University        |
+------------------------------------------+------+-------------------+
| Imaging effects of lasers on tissues     | M    | Stanford          |
|                                          | ouse | University        |
+------------------------------------------+------+-------------------+
| Visible Animal Models of Human Cancer    | M    | Stanford          |
|                                          | ouse | University        |
+------------------------------------------+------+-------------------+
| The Use of Attenuated *Salmonella        | M    | Stanford          |
| typhimurium* in Cancer Therapy           | ouse | University        |
+------------------------------------------+------+-------------------+
| Gene Delivery to Skin                    | M    | Stanford          |
|                                          | ouse | University        |
+------------------------------------------+------+-------------------+
| Miniature Confocal Theta Microscope for  | M    | Stanford          |
| Small Animal Imaging                     | ouse | University        |
+------------------------------------------+------+-------------------+
| Detection of Neoplasia in the Esophagus  | Rat  | Stanford          |
|                                          |      | University        |
+------------------------------------------+------+-------------------+
| Novel Confocal Microscope for            | M    | Stanford          |
| Molecular/Cellular Imaging               | ouse | University        |
+------------------------------------------+------+-------------------+
| Imaging of Glioblastoma Tumor Margins    | M    | Stanford          |
| with Confocal Microendoscopy             | ouse | University        |
+------------------------------------------+------+-------------------+

C.1.5.1. Drug Development. There are presently 20+ new small molecule
anti-cancer drugs in preclinical development with the NTROI. In
addition, preclinical imaging is being applied to the study of
immunotherapies and oncolytic viral therapy with the intent of
optimizing combination biotherapies for the elimination of residual
disease that persists after treatment with conventional therapies.

**C.2.4.** [Pathology]{.underline}. Since diagnosis and prognosis are
traditionally made through histopathology and the pathologist, the NTROI
has established a team of pathologists to help interpret data obtained
by in vivo optical measures and to help set common standards for
quantitative pathology methods as reliable benchmarks for optical
measurements. This team is establishing standards and providing
assessment of clinical samples for cross validation. Since optical tools
can provide macro and microscopic measures in the body, this team of
pathologists is developing groundwork to establish and build the new
field of in vivo pathology to exploit the molecular sensitivity and
cellular level resolution of optical techniques diagnosis and prognosis
in situ to immediately inform the attending physician. The Network is
having a significant impact because it provides an environment where
several modalities and approaches can be validated and cross-validated
by a team of pathologists well trained in optical measures and all using
standard approaches they developed to maximize effectiveness.
Over-and-above their specific involvement with NTROI projects, these
pathologists also are emissaries to the field of diagnostic pathology.
In essence, the Optical Imaging advances provide a challenge to
Pathologists: i) to keep pace with the field of Optical Imaging so that
Pathology maintains its pre-eminence as the source of diagnostic
'standards'; and ii) to take advantage of advances in Optical Imaging
(e.g., spectroscopic modalities, biomarkers) for analysis of tissues ex
vivo. The NTROI intends to serve as catalyst for recruiting Pathologists
as participants in the Optical Imaging field, essential to hastening the
translation of Optical technologies to the clinical setting. In each
instance, the pathologists participating in the NTROI have made
progress, including such symbolic events as publicizing Optical
Imaging-relevant technologies as cover articles in a major Pathology
journal (*Lab Invest*, Dec. 2005 and Dec. 2006 issues).

**C.2.5.** [Information Technologies]{.underline}. The NTROI has made
advances in standardization of data collection and management through
the development of two new software platforms called OMIRAD and SciPort.
This is an excellent example of how a Network of academic and industrial
collaborators together are able to accomplish a task otherwise out of
reach of each, and how the synergistic interaction among teams and
researchers can establish a standard approach within the field.

C.2.5.1 OMIRAD is designed to register/fuse/combine multi-dimensional
diffuse optical imaging (MD-DOI) with MR and X-ray mammography to drive
and improve:

-   optical reconstruction algorithms and diagnostic information,

-   specificity of MR and X-ray modalities in diagnosis,

-   standardization of all data processing elements

C.2.5.2. SciPort is a web-based software platform to manage the
experimental data of the NTROI to enable and provide:

-   close collaboration between universities by sharing data and
    protocols

-   an internet accessible, integrated, searchable database across the
    NTROI

-   Informatics Technology infrastructure to support clinical trials in
    years 4 and 5 of the NTROI.

-   

**[C.3. Publications and Presentations.]{.smallcaps}**

An important measure of program success is the number of publications
produced by the funded investigators, and by this criterion the NTROI
has been productive both clinically and technically. The publications
represent technology development as well as translation of novel
technologies to the clinic. The NTROI serves as a cornerstone of the
translational work and as a hub from which many of these publications
reach into other areas of support and experimentation. The investigators
in the NTROI were

active in the area of optical imaging prior to NTROI funding and
produced 32 publications during the first year of funding (Fig. 1). This
number increased in years two and three, with over 70 publications in
the most recent year for a total of about 170 peer-reviewed publications
for the three years of funding. A complete list is included in Appendix
A.

Another measure of NTROI success is the number of presentations and high
profile invited seminars. By this criterion the NTROI is also very
successful with over 150 presentations at national/international
meetings and symposia. These forms of dissemination are particularly
significant because NTROI concepts and research have been presented at
conferences that span across disciplines, from Optical Technology and
Imaging to Cancer Biology and Medical Oncology. Some of the more
important venues have been: the American Gastroenterology Association
Annual Meeting, The American College of Gastroenterology Annual
Scientific Meeting, The NIH Workshop in Diagnostic Imaging: From
Bench-to-Bedside, The Optical Society of America Conference on
Biomedical Optics, The International Photodynamic Association World
Congress, The International Conference on Tumor Progression and
Therapeutic Resistance, The Annual SPORE Investigator\'s Workshop, The
Gordon Research Conferences: Molecular Therapeutics of Cancer, Lasers in
Medicine and Biology, The Keystone Symposia: Mouse models of human
cancer, Federation of Immunology Societies, The AACR Annual Meeting, The
American Academy of Nanomedicine Annual Meeting, The World Congress on
Medical Physics and Biomedical Engineering, The San Antonio Breast
Cancer Symposium, The California Breast Cancer Res Symposium, The
International Biomedical Optics Society Meeting, The International
Society for Molecular Imaging Annual Meeting, SPIE---International
Society for Optical Engineering, Photonics West---Biomedical Optics
Symposium and Exhibition, Imaging in 2020: A Conference on Molecular
Imaging, The Radiological Society of North America (RSNA) Annual
Meeting, The European Conference in Biomedical Optics, and The American
Society for Photobiology Annual
Meeting![](media/image1.wmf){width="3.2694444444444444in"
height="2.3916666666666666in"}

**[C.4. Corporate Collaborators and Partners.]{.smallcaps}**

Effective translation of any technology requires the enthusiastic
engagement of industry. The NTROI established a tremendous (and growing)
group of corporate partners to accomplish the task of translating new
optical technologies. The corporate partners span multiple instrument
and drug companies large and small, well-established and start-ups
(Table 3). There was valuable discussion among all of the participants
at the workshop and key issues were emphasized in presentations. There
has been strong consensus within the Industrial Working Group that the
ultimate aim of the combined efforts with industrial partners is to
achieve delivery of clinically relevant instrumentation and reagents.
The industrial partners work with clinicians to ensure that instrument
designs are based on clinical needs.

**Table 3 Corporate Partners listed by team and type of collaboration.**

  ---------------------- ------------------------------------- ---------------
  **Corporation**        **Area of Collaboration**             **Team
                                                               Affiliation**

  Siemens Corporation    Information Technologies              Team 1

  GE Corporations        Instrumentation/molecular probes      Team 1

  ISS, Inc.              Instrumentation                       Team 1

  Hamamastu              Instrumentation/ components           Team 1

  ART Inc.               Instrumentation/clinical studies      Team 1

  Philips                Instrumentation/clinical studies      Team 1

  Praevium               Instrumentation/light sources         Team 1

  Modulated Imaging      Instrumentation/imaging               Team 1

  Centice                Instrumentation/spectroscopy          Team 1

  Newport Corporation    Instrumentation/components            Team 1

  Spectros Inc.          Instrumentation/clinical studies      Team 1

  Semicoa                Instrumentation/technologies          Team 1

  Imaging Diagnostic     Clinical studies                      Team 1
  Systems, Inc.                                                

  NIRx Medical           Clinical data analysis/visualization  Team 1
  Technologies                                                 

  Optimum Technologies,  Instrumentation                       Team 2
  Inc.                                                         

  Scientific Solutions,  Instrumentation                       Team 2
  Inc.                                                         

  Pharmacyclics, Inc.    Imaging and therapy                   Team 2

  LightForm              Optical Technologies                  Team 3

  Morphotek              Imaging agents                        Team 3

  Novartus               Therapeutic targets                   Team 3

  LiCOR                  Imaging agents                        Team 3

  Philips Medical        Instrumentation/clinical studies      Team 4

  STI                    Instrumentation, image processing and Team 4
                         data management                       

  Mauna Kea Technologies Clinical trials/                      Team 4
                         instrumentation/imaging technologies  
  ---------------------- ------------------------------------- ---------------

**[D. Working Groups:]{.smallcaps}**

During the first three years we have been developing the working groups
and establishing their identities, seeking the commonalities among the
teams and charting out the goals and mission. The value of the working
groups is being realized, and that value will dramatically increase in
the next year, even without any redirection of resources. A new WG,
Clinical Studies, met for the first time at the Workshop, and it was a
pleasant surprise to find keen interest in it. The initial discussions
by themselves were already of value in terms of shared experiences and
advice regarding regulatory matters and IRB issues. The Working Groups
are making progress and enhancing interactions between Teams to solve
problems faced by the field of optical imaging . The WGs provide an
excellent example of inter-Team collaboration in the NTROI program that
can serve as a model for other large NCI and NIH translational programs.

**[D.1. Pathology Working Group, Chair: James Crawford]{.smallcaps}**

This working group was initiated in the first year of the NTROI and has
been led by Wendy Wells and James Crawford, who are funded as parts of
Teams 1 and 4, respectively. The 2004 commission to the Pathology
Working Group (PWG) was 'To establish "Pathology Standards" in support
of "Optical Imaging". This translated into the following mission
statement: To work with the NTROI and the National Institute of
Standards and Technology (NIST) to establish conceptual and, if
possible, physical standards for validation of Optical Imaging
technologies for assessment and diagnosis of premalignant and malignant
lesions in humans. In the intervening two years, the respective members
of the PWG have been working both as 'reference pathologists' for their
NTROI teams (Wells, Crawford, Marco Novelli -- team 2), and as
independent pathologists advancing the spectroscopic (Peter Barker,
Richard Levenson) and morphometric (Calum MacAulay) frontiers of
diagnostic pathology. In these capacities, the following metrics for
2005 and 2006 pertain:

  ---------------------------------------------- ------------------------
  PWG member Authorship                          Publications

  First author                                   4

  Senior author                                  16

  Contributing author                            26

  *Total*                                        *46*

  Tasks specific to PWG                          35
  ---------------------------------------------- ------------------------

In their capacity as 'reference pathologists', they providedvalidation
of optical findings, adhering to rigorous standards for blinded case
review. As collaborating members of the NTROI, the pathologists provided
support for both experimental design and subsequent data analysis.

As lead investigators in their own right, these pathologists focused on
development of quantitative methods in pathology, to serve as objective
and consistent benchmark for optical methods. Towards this end,
publications specific to the objectives of the PWG specifically
addressed the following:

-   Immunohistochemistry: quantification; statistical analysis of
    morphometric data

-   Morphometric analysis: texture analysis (especially of nuclear
    morphology)

-   Artificial intelligence: segmentation and interpretation of
    morphologic images

-   Cytomics: multispectral imaging

-   In vivo imaging: fluorescence; quantum dots; spectroscopy

> confocal imaging in situ; light scattering in situ

-   Ex vivo imaging: multispectral analysis; Mie scattering; Near IR

-   Calibration standards: fluorescence; quantum dots

Ongoing areas of endeavor include attention to the following parameters
obtained by Optical Imaging instrumentation which may influence the
ability of Pathology to provide corroborative data:

-   physical performance of the instrumentation in obtaining optical
    data

-   instrument interaction with the examined object, including
    degradation of specimen quality

-   limits of resolution: morphologic; spectroscopic

-   processing of data, both by the Optical instrumentation and by
    Pathology instrumentation

-   use of Biomarkers: molecular design; access to relevant tissue
    compartments; limits of detection

-   quantifying pathology variables relevant to Optical Imaging:
    morphometry; spectroscopy

-   data management

Support of NTROI primary projects as 'reference pathologists' remain a
mainstay activity.

A key 'added value' of the Pathology Working Group is incorporation of
this team of physicians into the NTROI, whose specific professional
activity is diagnosis of human disease through analysis of tissue
samples. To the extent that Optical Imaging seeks to obtain
tissue-derived optical information which may be used independent of
pathology 'diagnosis' for patient care management and outcomes, it is
critically important that principles of diagnosis are always kept in
mind: protect the patient; preserve chain-of-custody and integrity of
diagnostic data; place the optical data in the context of the individual
patient; and establish the utility of optical testing. The ultimate goal
of such endeavor is to determine whether patients undergoing the
'optical diagnostic test' obtain better clinical outcomes than those not
being evaluated by optical testing. Specifically, the ultimate
determinant of the value of Optical Imaging is to successfully manage
patients on the basis of information so obtained. The involvement of
pathologists in essentially every stage of optical technology
development, testing, and implementation, optimizes the likelihood that
a sturdy evidence base can be established for use of non-invasive
Optical Imaging technologies.

**[D.2. Information Technologies Working Group, Chair: John
Pearson]{.smallcaps}**

Advances in this working group focused early and largely on support of
Team 1 and to a lesser extent Team 2, but with significant contributions
now to be made to the other teams. The software solutions are designed
to accommodate many different types of data sets and to integrate
clinical annotations with image and spectral data. Team 3 through the
efforts of Mike Feldman has been working towards developing and
integrating databases that include animal models, probes, and
achievements of the NTROI including indexing of publications. In Team 4
there are efforts being made in image archiving for in vivo microscopy
and in spectral analyses in the FTIR projects.

This working group has developed two novel IT approaches for database
organization, SciPort, and scientific visualization, OmiRad. Workshop
participants saw these as major accomplishments, and expect them to have
major impact on future collaborative and independent research as they
mature and disseminate (under IT Working Group guidance) throughout the
NTROI and beyond to the wider community of researchers.

The database architecture, SciPort, was developed to integrate and query
multi-modality, multi-dimensional data. The basic architecture is
derived from Radiological Society of North America (RSNA) standardized
approaches. Methods are integrated into the database for 3D analysis and
visualization. This project originated from the Dartmouth/Siemens
Corporate Research Software Core of Team 1 to facilitate data sharing
among Team 1 laboratories, and is being enhanced to accomplish similar
tasks throughout the NTROI under direction of the IT Working Group.

The special visualization engine, OmiRad, originated as a Team 1
Developmental Project, and was developed to support data analysis across
platforms. A unique function of OmiRad supports integration,
co-registration, and analysis of multi-dimensional data sets from
diffuse optical spectroscopy and imaging (DOS/DOI) and MRI, mammography,
and ultrasound. Additional important IT solutions developed and
disseminated by Team 1 include sophisticated software for quantitative
3D image reconstruction of diffuse optical tomography data, and
cross-correlation techniques for extracting unique information from
spectral and temporal fluctuations. These methods are important for
measuring physical parameters of tumors, such as blood flow, and show
promise in distinguishing between "malignant" and "benign" tumors. The
OmiRad approach is fairly general and is being adapted to answer needs
across the NTROI.

**[D.3. Imaging and Drug Development Working Group (IDDWG), Chair: Wafik
El-Deiry]{.smallcaps}**

The goals of this working group include (1) exploring obstacles to drug
development from discovery to clinical use and how imaging can
facilitate the process, (2) integration of imaging approaches into the
drug development process, (3) development of strategies to increase
support in academia, (4) outreach to cancer societies and clinicians to
promote development and use of optical imaging, and (5) to develop
better models of academia-industry interactions for use of imaging in
the drug development process. In 2006, steps were taken to reach out to
the cancer community through a review published in the J Clin Oncol.
entitled "Imaging and Oncologic Drug Development," and an educational
session presentation at the AACR entitled "The Promise of Optical
Technologies for Measuring Tumor Response in Cancer Therapy Trials." The
Imaging in Drug Development Working group met at the 2006 Workshop to
discuss issues relevant to its mission. Recommendations for
consideration include (1) development of a national Probe Discovery
Program that may rely on some existing resources of Drug Discovery
program. (2) Development of databases for probes and models with help
from IT-WG. (3) Development of "Master Agreements" to facilitate
interactions between academic institutions and industry. (4) Encourage
NCI to consider developing a larger program to fund optical imaging
agents for animals to assist with drug development. (5) Work on
demonstration projects that show the use and value of imaging at all
phases of drug development. (6) Continue outreach to cancer societies
and clinicians to promote development and use of optical imaging for
drug development. (7) The Imaging in Drug Development Working group
through communication, databases, meetings, and publications can help
accelerate academia-industry interactions for use of imaging in the drug
development process.

**[D.4. Clinical Studies Working Group, Acting Chair: Anson
Lowe]{.smallcaps}**

The Clinical Studies working group met for the first time at this
workshop and discussed ways in which it could be of value to each of the
NTROI teams. The NTROI has begun to interfaces with ACRIN in the testing
of new approaches in the transition from single center trials to
multicenter clinical trials for evaluation of optimized methods.
Participants discussed the contributions that this working could make to
the overall objectives. They concluded early that a working group in the
area of clinical studies could have an impact on patient recruitment for
clinical studies that are part of the program. Although there appears to
be significant collaboration among members within the same team, few
collaborative clinical studies exist between NTROI teams. They suggested
that the Clinical Studies working group could facilitate such
interaction. Between-Team clinical studies would help identify optimal
approaches and would serve to refine the tools that are being developed
as part of the NTROI. As a means toward engaging clinicians in NTROI
projects, the group strongly suggested that more of the clinicians
involved in the NTROI sponsored clinical trials should be encouraged to
attend the annual NTROI meetings. Their presence would provide valuable
clinical perspective to the discussions and serve to refine and optimize
the clinical studies. The Clinical Studies working group also discussed
a potential role of this working group in establishing standards with
respect to patients and instrumentation. Such standards currently exist
within specific teams, but must be established across teams if
collaborations are to succeed. Lastly, the group discussed whether it
could serve a role in providing input on which projects and technologies
to develop and support for collaborative clinical studies between
institutions and teams. The participants felt that a working group aimed
at refining and integrating clinical studies would benefit the NTROI and
agreed to work toward developing a mission statement that defines the
role of the working group and moves this agenda forward.

**[D.5. Industry Working Group, Chair: Tom Baer]{.smallcaps}**

The Industry Working Group (IWG) of the Network for Translational
Research in Optical Imaging (NTROI) became active in September 2004 when
they undertook to develop clear policies on intellectual property (IP)
to facilitate early and sustained University-Industrial collaboration
and otherwise help accelerate movement of optical technologies and
methods from the laboratory into self-sustaining clinical use. One of
the prime objectives of this working group is to set the stage for
Public Private partnerships that will advance the technologies into
mainstream use through both device companies and large pharmaceutical
corporations. One of the possible directions being investigated in the
trans NIH Biomarker consortium and this is being explored due to the
investment in probe development within the NTROI. Their operating
premise was that early, continual industrial participation is essential
for efficient technology transitions. They identified related early
tasks. First was to develop ground rules for protection of intellectual
property (IP). They developed a sample IP agreement document. They
concluded that most relevant IP is protected ab initio or closely held
for later disclosure only after the developers protect it. They
concluded that IP is neither a significant issue nor impediment to the
NTROI. Second was to identify several NTROI opportunities for clinical
translation and help them achieve earliest translation into marketable
products. They quickly realized that highly specific requirements for
each opportunity made it the responsibility of the originators, not the
NTROI generally. Third was recognition that validation would require
test objects, and that each Team's requirements differed. Efforts were
turned to development of appropriate phantoms and other means for
quality assurance, standards, and the ability to compare results between
subsequent models of devices, multiple copies of each device, and
between imaging modalities.

After a period of quiescence, the Industry WG reactivated and met at the
October 2006 NTROI Workshop. Roughly two thirds of them attended the IWG
meeting. They adopted a mission statement that consisted of two parts:

-   Develop and assess economic models for clinical applications of
    optical imaging.

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-   Evaluate NTROI technology programs for clinical feasibility and
    their evolutionary stage, and identify barriers to
    commercialization.

The group formed two sections to focus on providing specific
recommendations on each part to the NTROI principal investigators, which
fell within the scope of the IWG mission statement. These
recommendations included:

-   Perform an economic impact analysis of individual NTROI programs

    -   How do these programs impact patients, physicians, providers and
        the US Healthcare system?

    -   Address the question: Is there an ***ROI*** at the end of
        NT***ROI***? (that is a return on investment For the US
        taxpayer.)

    -   Work with Industry WG members, business schools affiliated with
        the university institutions, and NIH health policy analysts to
        develop working economic models for commercial embodiments of
        NTROI technology

-   Determine a methodology for evaluating the clinical feasibility of
    NTROI technology and the evolutionary stage of each program

    -   Identify any technical barriers to commercialization.

These suggestions were presented to the NTROI group and a lively
discussion ensued.

**[E. PROGRESS AND FUTURE AIMS FOR INDIVIDUAL TEAMS]{.smallcaps}**

**[E.1. TEAM 1: University of California, Irvine
(]{.smallcaps}**<http://www.bli.uci.edu/ntroi>).

The Team 1 presentation reiterated the following broad goals of our
program as defined 3 years ago:

**[E.1.]{.smallcaps}1.** Define the clinical role of optics in breast
cancer detection and clinical management

**[E.1.]{.smallcaps}2.** Accelerate the development of a standardized
technology platform as a stand-alone device or in conjunction with MRI
and mammography.

**[E.1.]{.smallcaps}3.** Impact breast cancer detection, clinical
management, and quality of life for breast cancer patients within 5
years. In order to satisfy these broad goals we proposed the following 5
specific aims:

> **[E.1.]{.smallcaps}3.1.** Develop a common instrument platform with
> multiple, user selective modes of operation: spectral/spatial/temporal
>
> **[E.1.]{.smallcaps}3.2.** Optimize compatibility of optical imaging
> with MRI and Mammography
>
> **[E.1.]{.smallcaps}3.3.** Validate performance and test functional
> sensitivity
>
> **[E.1.]{.smallcaps}3.4.** Establish "tissue optical indices" (TOI)
> that report on functional parameters (e.g. metabolism, angiogenesis,
> E/S density...)
>
> **[E.1.]{.smallcaps}3.5.** Deliver instruments to clinical sites for
> translational studies that assess optical imaging as a stand-alone
> and/or integrated approach (MRI/mammography)

**[E.1.4. Team 1 Achievements and Highlights.]{.smallcaps}** Team 1
(<http://www.bli.uci.edu/ntroi>) presented a comprehensive status report
updating accomplishments for each specific aim. Significant progress has
been made in each area and the current intense focus is on aim #5. We
have identified the poor performance of x-ray mammography in
radiographically dense breast tissue as a major clinical problem. This
has significant impact on cancer detection in pre- and peri-menopausal
women and high risk subjects. In addition, there are major challenges to
clinical decision-making in assessing the efficacy of neoadjuvant
chemotherapy and identifying margins during surgery. Team 1 technologies
are expected to make significant contributions to each of these areas by
providing rapid, quantitative measurements of tumor biochemical
composition and metabolism.

**[E.1.4.1. Validated Platforms:]{.smallcaps}** Team 1 has developed
both diffuse optical imaging (DOI) and diffuse optical spectroscopy
(DOS) platforms for breast cancer detection, tumor characterization,
chemotherapy monitoring, and risk assessment. These platforms have been
validated in clinical studies of approximately 500 total patients at all
Team 1 sites. NTROI-standardized photon migration technologies have been
developed and currently function as stand-alone and integrated systems
in MRI and mammography. Several comprehensive studies using conventional
imaging approaches (MRI, MRS, DCE-MRI, mammography, ultrasound) and
histopathology have been performed to validate the performance and
information content of DOS and DOI in tissue phantoms and patients.
Standard tissue phantoms have been developed as imaging tools and have
been shared with NTROI sites in order to **cross validate** methods and
probes. DOS and DOI have been shown in clinical studies to provide
unique, quantitative information on tumor biochemical composition that
cannot be derived from other methods. Preliminary clinical studies show
sensitivity and specificity for malignant tumor detection in younger
(\<45 yr olds) that exceed the performance expected of mammography for
young, radiographically dense breast.

**[E.1.4.2. Use of Working Groups.]{.smallcaps}**

**[E.1.4.2.1. IT solutions:]{.smallcaps}** Team 1 has developed 2 novel
IT approaches for database organization and scientific visualization
designed to lead to a common IT platform for medical optical imaging.
The database architecture, SciPort, is designed to integrate and query
multi-modality, multi-dimensional data. The basic architecture is
derived from RSNA standardized approaches. Methods are integrated into
the database for 3D analysis and visualization. A special visualization
engine, OmiRad, has been developed for data analysis across platforms. A
unique function of OmiRad supports integration, co-registration, and
analysis of multi-dimensional data sets from DOS/DOI and MRI,
mammography, and ultrasound. Additional important IT solutions developed
and disseminated by Team 1 include sophisticated software for
quantitative 3D image reconstruction of diffuse optical tomography data,
and cross-correlation techniques for extracting unique information from
spectral and temporal fluctuations. These methods are important in
measuring physical parameters of tumors, such as blood flow, and have
shown promise in distinguishing between "malignant" and "benign" tumors.

**[E.1.4.3. Drug response:]{.smallcaps}** A significant emphasis of Team
1 has been on the utilization of DOS and DOI in clinical studies to
monitor and predict the efficacy of pre-surgical neoadjuvant
chemotherapy. Team 1 technologies track structural and functional tumor
response and have been validated by MRI, ultrasound, and histopathology.
Early functional changes measured by DOS/DOI precede tumor size
(structural) changes seen with conventional imaging. Preliminary results
in a limited patient population demonstrate that DOS can predict outcome
(responder vs. non-responder) within the first week of therapy, and
perhaps prior to therapy, based on intrinsic optical signatures.

**[E.1.4.4. Standardized systems:]{.smallcaps}** A standardized, bedside
platform based on quantitative broadband diffuse optical spectroscopy
(DOS) has been tested and validated in a 58 patient study. Quantitative
DOS measurements of complete NIR absorption and scattering spectra (600
nm-1000 nm) are obtained using a non-invasive handheld probe in
approximately 6 seconds. Standard mapping patterns are performed on each
subject. Physiological parameters are calculated from DOS measurements
and displayed in image maps. A standard operating manual has been
developed to facilitate multi-center operation of the DOS device. DOS
instruments are under construction for placement of identical devices in
5 NTROI clinical sites to facilitate a multi-center clinical trial.
Standard protocols for monitoring neoadjuvant chemotherapy and
differential diagnosis are in development and these clinical studies
will be conducted in a multi-center trial at each of 5 Team 1 sites.

**[E.1.5. Team 1 Objectives for next two years:]{.smallcaps}** Team 1
objectives for the next 2 years are focused primarily on establishing a
coordinated multi-center clinical study that combines DOS/DOI with MRI
in 5 participating clinical sites (UCI, UCSF, UPENN, MGH, Dartmouth).
Our goal is to link with ACRIN and initiate the first ACRIN-sponsored
trial that utilizes optics and MRI. Our specific tasks are to:

1)  Complete construction of 5 identical standard Laser Breast Scanner
    (LBS) platforms, standard operating manuals, and breast tissue
    simulating phantoms, and deliver to team 1 sites.

2)  Initiate a multi-center pilot study to work out standardization of
    instruments, protocols, database, and analysis tools.

3)  Integrate data into NTROI-established database (SciPort), analysis
    tools (OmiRad) and clinical infrastructure of 5 NCI comprehensive
    cancer centers for data and protocol sharing.

4)  Continue to engage corporate partners, the medical community, and
    patient advocates to optimize impact and acceptance of new optical
    technology, build consensus on validation of optical methods, and
    create a knowledge/database for accelerating FDA approval of breast
    optical imaging.

5)  Design more extensive prospective trials based on pilot experience
    in 2 areas: a) early prediction of chemotherapy response and b)
    tumor detection/diagnosis in dense breast tissue.

6)  Leverage NTROI infrastructure and ACRIN for initiating Phase II/III
    studies that would allow validation of clinical endpoints.

**[E.1.6. Team 1 Collaborations with other NTROI teams:]{.smallcaps}**
Team 1 is collaborating with Team 2 to introduce probe- and
intra-operative based imaging methods to breast cancer margin and node
characterization. Interactions with Team 3 include efforts to
quantitatively measure tissue oxygen tension and consumption in small
animal models to assess chemo- and radiation therapy efficacy.
Interactions with Team 4 involve identifying potential molecular targets
that would correlate upstream gene expression with downstream physiology
measurements in order to predict individual patient response to
chemotherapy. Team 1 is also working with all teams to develop
customized IT tools for clinical data analysis and management, as well
as multi-modality co-registration methods for image quantification,
fusion, and visualization. These activities are expected to facilitate
the development of a fully optimized platform for multi-modality imaging
of breast cancer in humans and small animals using endogenous signals
and exogenous molecular probes.

**[E.1.7. Team 1 New opportunities for Team Members and Other
Collaborators.]{.smallcaps}** Team 1 has leveraged the resources of 5
P30 comprehensive cancer centers (UCI, UCSF, UPenn, Dartmouth, and MGH),
4 P41 Research Resource Centers (2 at UCI, MGH, UPenn), and 2 NCI
program projects (Dartmouth, UPenn) in order to accomplish these aims.
In addition, Team 1 has formed a network of several academic and
industry associate members around the world who are working towards
these common goals. Associate members participate extensively in Team 1
dissemination and training activities, including annual retreats,
conferences, panels, and the special Team 1 IT workshop. There are
opportunities to interact with Team 3 in the use of animal models of
breast cancer, in the use of probes that sense intravascular and
interstitial hypoxia and through exploratory studies of the prototype
macro PARISS imager being developed by Team 3 to obtain hyperspectral
signatures from lesions using a stage platform and fiberoptic format.

**[E.1.7.1. Other Sources of Funding:]{.smallcaps}** Approximately 35
new grant proposals have been submitted by Team 1 investigators to
leverage NTROI funding. Major awards by team 1 investigators include:
Arjun Yodh (R01), "Multi-Spectral Parallel-Plate Diffuse Optical Breast
Tomography", Orhan Nalcioglu (R21/33) "Combined MR-Diffuse Optics for
Functional Imaging", Albert Cerussi (R44) with Praevium Corporation,
"Compact Multi-Wavelength Probe for Quantitative Tissues" and Keith
Paulsen (R01), "Frequency Domain Optical Imaging of Breast Cancer".

**[E.1.7.2. Developments Leading to New Opportunities:]{.smallcaps}**

> **[E.1.7.2.1. Industry collaboration:]{.smallcaps}** Team 1 has
> developed extensive industry collaborations with large and small
> companies in order to accelerate translation and commercialization of
> DOS/DOI technologies. Team 1 research and standardized approaches have
> played a significant role in efforts at Philips, GE, ART, and Siemens.
> More than \$400,000 in support has been granted by industry for Team 1
> projects. FirstScan is a new start up company that has licensed
> approximately 40 NTROI patents with the goal of advancing a hand-held
> probe design. FirstScan is currently seeking FDA approval for its use
> in breast tumor characterization. The ART scanner is in Phase II
> clinical trials and is coordinating efforts with Team 1. Extensive
> interactions occur between Team 1 and several other companies. Many
> have resulted in submission and funding of SBIR grants.
>
> **[E.1.7.2.2. Training, Dissemination, Communication:]{.smallcaps}**
> In order to facilitate communication and outreach, interactive
> net-tools have been established and integrated into a website
> (<http://www.bli.uci.edu/ntroi>). Team 1 holds monthly conference
> calls and 3 face-face meetings/year. Team 1 research has appeared in
> approximately 80 peer-reviewed publications and a total of 55
> presentations at major scientific sessions have been organized by Team
> 1, including: NIH workshops, optics meetings (SPIE, OSA), cancer
> meetings (SPORE, San Antonio Breast Cancer), and RSNA. More than 15
> students, faculty, and fellows have travelled between Team 1 sites to
> facilitate technology transfer, training, and collaboration.

**[E.2. TEAM 2: Boston University
(]{.smallcaps}**<http://www.bu.edu/osc/index.html>)

Team 2 has particularly strong clinical input, especially from
participants in London and Boston. An example of future opportunities
includes: The Team 2 work on breast cancer (in particular, assessment of
sentinel nodes) attractive for clinical collaboration with Team 1, who
are scientifically superb and doing complementary diagnostic studies of
breast tissue.

**[E.2.1. Team 2 Achievements and Highlights:]{.smallcaps}**

**[D.2]{.smallcaps}.1.1.** Tested prototypes of endoscopic biopsy
forceps that incorporate an elastic-scattering spectroscopy (ESS) fiber
probe, for reliable co-registration of optical measurements and biopsy
site. They work with a commercial partner for product development. This
will be necessary for clinical implementation of optically-guided biopsy
applications.

**[E.2]{.smallcaps}.1.2.** Novel signal processing/statistical methods
under development at BU are demonstrating better results than
traditional Principle Component Analysis and Linear Discriminant
analysismethods for spectral classification and correlation with
pathology. These novel developments, based on Support Vector Machines
and AdaBoost classifiers, with Sequential Floating Forward Selection for
feature selection, preserve the underlying biological information and
offer the clinically-important option of error rejection, which is
critical for real clinical applications and doing complementary
diagnostic studies of breast tissue.

**[E.2.]{.smallcaps}1.3.** Our growing database of clinical studies for
esophageal and colonic cancers is yielding good values for sensitivities
and specificities and, more importantly, negative predictive values.
Training sets have mostly become large enough that prospective testing
on new patients can soon begin.

**[E.2.]{.smallcaps}1.4.** New user-interface software is under
development at UCL for collecting esophagus ESS data -- a much more user
friendly than the prior version, for real clinical end-users. It is
essential to have software designers and clinicians working side by
side. This software will be of value to Team 4, who are also pursuing
esophageal cancer detection.

**[E.2.]{.smallcaps}1.5.** Instrument standardization has been improved,
improving confidence that results from different sites will be
compatible. Standard calibration fixtures have been delivered to the
different sites.

**[E.2.]{.smallcaps}1.6.** Preliminary work has been done at UCL on
developing a pseudo-image of the esophagus by taking multiple point
measurements. Numerous point measurements are made on an array of sites,
and the resulting optical diagnoses are assembled computationally to
provide a diagnostic "map" of areas of mild and severe dysplasia. This
constructed image can then serve as a reference for future surveillance
procedures to quickly guide the clinician to higher risk areas. This
would greatly improve the clinical value for surveillance. Our
Industrial Partner, Optimum Technologies, is working on an esophageal
scanner with Lev Perelman, who is a member of our External Scientific
Advisory Committee -- this constitutes another opportunity to
collaborate with UCL, and provide cross-validation, one of the key
intents of the NTROI.

**[E.2.]{.smallcaps}1.7.** First demonstration of correlation between
in-vivo ESS measurements and quantitative laboratory determination of
the extent of aneuploidy in tissue has been done at UC London. These
exciting results provide novel diagnostic information relevant to
prognosis in Barrett's.

**[E.2.]{.smallcaps}1.8.** Animal studies of PDT pharmacokinetics in
Pittsburgh have yielded excellent agreement between Optical
Pharmacokinetics (OP) measurements and HPLC assays, an important step
toward validation of OP as an in vivo analytical method. Animal work in
both Pittsburgh and London have set the stage for human studies. A
clinical study is imminent in Pittsburgh for monitoring the dosage of
Lutrin during PDT treatment of cervical cancer patients.

**[E.2.2. Team 2 Objectives for next two years:]{.smallcaps}**

**[E.2.2.1.]{.smallcaps}** Provide biopsy forceps and polyp snares
equipped with ESS-fiber optics to Team 2 clinical teams at London,
Boston and Pittsburgh, and for collaborative studies with Team 4 at
Stanford.

**[E.2.2.2.]{.smallcaps}** Collaborate with industrial partner (Optimum
Technologies) to develop next-generation clinically-ready,
commercializable versions of ESS and OP instruments suitable for the
rigors of clinical use.

**[E.2.2.3.]{.smallcaps}** Prepare and perform a prospective clinical
study for detection of dysplasia in Barrett's esophagus in preparation
for multi-site studies combined for greater statistical power. We will
collaborate with Team 4 on this objective.

**[E.2.2.4.]{.smallcaps}** Clinical study of ESS to monitor tissue
response to PDT in the esophagus, specifically to detect incomplete
mucosal "ablation" shortly after light delivery and detect buried glands
after healing--both essential for establishing long term efficacy of
treatment. (Animal studies started.)

**[E.2.2.5.]{.smallcaps}** Test the hypothesis that ESS detects high
risk cases (dysplasia, HGD or both) more accurately than we thought.
Current algorithms were not designed to distinguish dysplasia from
aneuploidy in Barrett's, but an evaluation of false positives from prior
studies looking for dysplasia in Barrett's may disclose that the false
positives may represent a new diagnostic opportunity: those patients
with aneuploidy. A collaboration with Team 4 will augment this project.

**[E.2.2.6.]{.smallcaps}** Answer question of whether it is possible to
correlate optical assessment of archived tissues with in-vivo
measurements, and correlate both to dysplasia and aneuploidy. This would
enable development of prognosis from ESS data.

**[E.2.2.7.]{.smallcaps}** Complete clinical studies of use of OP for
management of PDT dosage for cervical cancer patients.

**[E.2.2.8.]{.smallcaps}** Complete the development of our novel signal
analysis/statistical methods and implement them as diagnostic algorithms
in the instruments for immediate diagnostic feedback.

**[E.2.2.9.]{.smallcaps}** Partner with industry to commercially develop
clinical applications.

**[E.2.2.10.]{.smallcaps}** See listings below about new collaborations.

**[E.2.3. Team 2 Collaborations with other NTROI teams:]{.smallcaps}**
Collaboration with Team 4 has begun, and a dedicated ESS instrument has
been acquired. The intent is to join in a combined clinical study of
Barrett's, wherein ESS measurements on specific epithelial sites can be
correlated with in-situ confocal microscope images of the same tissue
site. This will provide valuable information and cross validation for
both modalities as to underlying mechanisms.

**[E.2.3.1.]{.smallcaps}** Breast imaging. We plan to liaise with Team 1
on how our breast work at University College of London could correlate
with theirs and with another group at the University College of London
involved in optical imaging of the breast (Jem Hebden). This may be
particularly valuable for monitoring the effects of treatment of cancer
by chemotherapy, radiotherapy, local ablation (PDT, thermal ablation
etc) and benign conditions like fibroadenomas (thermal ablation).

**[E.2.3.2.]{.smallcaps}** Data analysis on line. This has been set up
by Team 2 (Bob Parker in Pittsburgh) -- initially for our optical
pharmacokinetic measurements, but it is clear that this is a service
that is being developed to serve all the NTROI teams.

**[E.2.3.3.]{.smallcaps}** Team 3 is developing optical probes for
angiogenesis and anti-angiogenesis factors -- this could link in with
the work of Team 2 on monitoring the results of PDT. We are thus
initiating collaborative interactions to follow up. Team 3 has been
working towards the development of therapeutic molecular beacons that
are activated by PDT and induce apoptosis in tumors where they are
specifically delivered. Team 3 has been developing molecular beacons
that may be very useful for Team 2 for the detection of mutations of the
Ras gene in Barrett's esophagus. Additionally, Team 3 has developed
animal models of human esophageal cancer that tie in nicely with efforts
in Team 2.

**[E.2.3.4.]{.smallcaps}** Technology being developed by Team 4 a mirror
scanning system usable through an endoscope for fluorescence detection -
that might be adaptable for ESS measurements in the esophagus, enabling
faster scanning of Barrett's epithelium. We will explore this
opportunity

**[E.2.4. Team 2 Collaborations with SPORES and other External
Collaborators]{.smallcaps}**

**[E.2.4.1.]{.smallcaps}** Collaboration has begun with UCSF, Dr.
Mitchel Berger (Chief of Neurosurgery), to test ESS for sensing tumor
margins during brain surgery. Under separate foundation funding a
dedicated ESS instrument has been acquired, and the first clinical tests
will happen this Fall (06).

**[E.2.4.2.]{.smallcaps}** Collaboration with Columbia University
Medical Center has begun (Dr. Shailendra Joshi) for the application of
optical pharmacokinetics for testing in animal models of a novel method
for intra-arterial drug delivery of chemotherapy agents for brain
tumors.

**[E.2.4.3.]{.smallcaps}** Extension of work to other organs. Work on
ESS for detecting cancer in excised axillary sentinel lymph nodes,
funded by DoD and Hamamatsu Corp., is an outgrowth of our NTROI
activities. We have developed a scanner (400 pixels/cm^2^) which gives
about 96% specificity for detection of cancer with 75% University
College of London

**[E.2.4.4.]{.smallcaps}** Collaborators at the University College of
London, we have a program in maxillo-facial surgery developing a series
of optical diagnostic techniques for detecting dysplasia and early
cancer -- this has grown from the NTROI program. Other collaborators at
the University College of London are developing a program for ESS in the
major airways to detect dysplasia and early cancer.

**[E.2.4.5.]{.smallcaps}** A collaboration with both the University
College of London and an industrial partner (Scientific Solutions, Inc.)
will use ESS to distinguish between benign pigmented skin lesions and
malignant melanomas.

**[E.2.4.5.]{.smallcaps}** A new collaboration with the University of
Rochester Medical Center (Dr. Edward Messing, Chief of Urology) will
test ESS for detection of bladder cancer in post-treatment surveillance
patients. A grant application has been submitted.

**[E.2.5. Team 2 New opportunities for Team Members and Other
Collaborators,]{.smallcaps}**

**[E.2.5.1. Other Sources of Funding]{.smallcaps}**

> [E.2.5.1.1. **Funded:**]{.smallcaps}
>
> \* DOD Breast Cancer Initiative funded grant at the University College
> of London for the sentinel node studies.
>
> \* Leveraged funding from Hamamatsu Corp. to the University College of
> London for technology development for clinical implementation of
> sentinel node assessment method.
>
> \* Coulter Foundation grant to BU for development and
> commercialization of the optically-guided endoscopic snares for colon
> polyps (based on ESS to distinguish adenomatous from hyperplastic
> polyps).
>
> \* Seed funding from BU Photonics Center to develop optical method to
> monitor apoptosis.
>
> \* Industrial partner (Optimum Technologies) has received SBIR Phase I
> and Phase II funding to develop the next generation ESS/OP systems and
> polarized ESS optical fiber probes.
>
> \* Industrial collaborator, Scientific Solutions, Inc., received SBIR
> Phase I funding for development of hand-held ESS tool for detection of
> melanoma.
>
> [E.2.5.1.2. **Pending Review:**]{.smallcaps}
>
> \* Columbia University Medical Center -- R01 application for using
> Optical Pharmacokinetics to demonstrate improved intra-arterial
> delivery of chemotherapy agents to brain tumors.
>
> \* University of Rochester Medical Center -- R21 application for using
> elastic-scattering spectroscopy for minimally-invasive surveillance of
> bladder cancer patients.

**[E.2.6. Developments in the NTROI Leading to New
Opportunities]{.smallcaps}**

**[E.2.6.1. Spin-off Clinical Translational Studies in Other
Areas]{.smallcaps}**

\* Breast cancer -- sentinel node assessment, and assessment of surgical
margins

\* Breast cancer -- ductoscopy, potentially coupled with ESS

\* Studies of Pc4 PDT treatment of dermal metastases. (In collaboration
with Nancy Oleinik, Case Western Reserve.)

\* Skin cancer -- ESS differentiation of melanoma from benign nevi.

\* Oral cancer, bronchial cancer

\* Prostate cancer -

**[E.2.6.2. Potential industrial development and commercialization
opportunities (specific application interests omitted due to
confidentiality agreements):]{.smallcaps}**

\* Braintree Laboratories

\* Cook Endoscopy

\* Bard Medical

\* Optimum Technologies

\* Scientific Solutions, Inc.

**[E.2.7. Interaction with Working groups.]{.smallcaps}**

It is Dr. Bigio's impression that it will be difficult to extract value
from the Industrial WG, because of the fact that each Team deals with a
different class of companies with different product lines and different
IP issues. It may be best to allow each team to develop its own
industrial partners and let the individual institutions deal with their
IP issues. Otherwise, I think we can end bogging ourselves down in legal
matters, with minimal benefit for the Network.

**E.3. TEAM 3: [University of Pennsylvania]{.smallcaps}**

**[E.3.1. Overview]{.smallcaps}**

[**E.3.1.1**.T]{.smallcaps}he focus of Team 3 has been to image tumor
progression and therapeutic responses in animal models using
bioluminescence and fluorescence as well as near-IR imaging. Efforts on
molecular pathways and molecular imaging have been directed at
apoptosis, angiogenesis, and imaging molecular changes associated with
prognosis or therapeutic response.

**[E.3.]{.smallcaps}1.2.** Progress has been made in the area of
molecularly targeted drug screening using cell-based assays and
non-invasive live cell imaging as a read-out.

**[E.3.]{.smallcaps}1.3.** Team 3 has developed interactions with the
SPORE in skin cancer at the Wistar Institute to develop molecular
beacons and diagnostic methods for pre-neoplastic skin lesions as well
as optical methods for therapeutic monitoring.

**[E.3.]{.smallcaps}1.4.** Team 3 has developed interactions with
industry including LightForm with whom they have been developing the
PARISS hyperspectral imager. Progress was made in microscopic imaging
and development of algorithms for data standardization at different
sites.

**[E.3.]{.smallcaps}1.5.** A recently built prototype Macro PARISS
imager is currently being tested in the laboratory prior to use in
clinical protocols for endoscopic and fiberoptic spectroscopic data
acquisition in humans. Team 3 has been developing an interaction with
Morphotek to image in vivo therapeutic antibodies developed through
genetic evolution.

**[E.3.]{.smallcaps}1.6.** Additional efforts are underway to develop
relationships with Novartis for collaboration in drug screening and
development using optical imaging.

**[E.3.]{.smallcaps}1.7.** Finally, through the direction of the NTROI
Steering Committee, Team 3 has initiated efforts in the area of probe
development for optical imaging of apoptosis, oncogene expression,
oxygen sensing, and tumor targeting.

**[E.3.2. Team 3 Achievements and Highlights:]{.smallcaps}**

**[E.3.]{.smallcaps}2.1.** Animal models: Significant progress has been
made in the area of animal model development for monitoring of
therapeutic response.

**[E.3.]{.smallcaps}2.1.1.** Starting with primary human esophageal
epithelial cells and introduction of selected combinations of oncogenes
and reporter genes, it has been possible to monitor variable kinetics of
tumor growth in mouse models driven by various oncogenes including
H-Ras, Akt, EGFR and c-Myc/Bcl-XL. Microarray experiments have provided
evidence that some oncogene-driven tumors may be good models of squamous
esophageal cancer whereas others better model adenocarcinomas. These
models provide an outstanding opportunity to test the impact of
oncogenes on tumor metabolism, FDG uptake, and therapeutic response.
5.2.1.2. Significant progress has been made in the development of animal
models of breast cancer starting with human mammary epithelial cells
followed by targeting the BRCA1 tumor suppressor gene and driving tumor
progression with selected oncogenes relevant to human breast cancer. The
resulting models are being used to test therapeutics and to monitor
spectral signatures and optical probes during therapeutic response.

**[E.3.]{.smallcaps}2.1.2.** Team 3 has introduced gene silencing in
vivo coupled with optical imaging in animal models. This approach has
been used to target death receptor expression as well as tumor
suppressor gene expression to monitor the relevance and importance of
candidate tumor suppressors both for tumor growth as well as therapeutic
response.

**[E.3.]{.smallcaps}2.2**. Molecular Beacons. Progress has been made in
the development of molecular beacons.

> **[E.3.]{.smallcaps}2.2.1.** Molecular beacons have been developed to
> detect the V600E B-Raf mutation commonly found in melanoma. This
> beacon is being optimized for eventual use in therapeutic monitoring.
>
> **[E.3.]{.smallcaps}2.2.2.** Molecular beacons have been generated to
> detect Ras gene mutations in pancreatic cancers. Work by Eric
> Wickstrom is comparing optical and radioisotopic methods of use in
> pancreatic cancer xenografts.
>
> **[E.3.]{.smallcaps}2.2.3.** Progress has been made in the generation
> of a therapeutic beacon through a developmental project to Gang Zheng.
> A beacon that is activated by PDT has been made that is selectively
> delivered to tumors that express the folate receptor. The beacon
> accumulates in folate receptor positive tumors which undergo apoptosis
> following delivery of light to the accumulated beacon.
>
> **[E.3.]{.smallcaps}2.2.4.** PEptide beacons have been used to monitor
> apoptosis in resected freshly explanted human colon treated with
> different chemotherapeutic agents, as a prelude to endoscopic
> apprtoaches to detect toxicity and therapeutic response.
>
> **[E.3.]{.smallcaps}2.2.5.** A peptide with the sequence, DEVD, has
> been linked to Aminoluciferin and adapted for use in high throughput
> screening of drugs that can restore apoptosis in hypoxic tumors.
>
> **[E.3.]{.smallcaps}2.2.6.** Progress has been made in the area of
> standardization by Andrew Tsourkas by coupling quantum dots to
> molecular beacons to standardize beacon uptake across different cells
> and tumors.

**[E.3.]{.smallcaps}2.3** Oxygen sensing: Progress has been made by
Sergei Vinogradov in developing oxygen microscopy by 2-photon excited
phosphorescence. These designed phosphorescent sensors for oxygen are
intended for use to image oxygen distributions in vivo with sub-micron
spatial resolution.

**[E.3.2.4 Drug Development:]{.smallcaps}**

> **[E.3.]{.smallcaps}2.4.1.** Progress has been made in the area of
> optical imaging using cell-based screening for new drugs that can
> restore molecular responses in tumors that lead to tumor apoptosis.
>
> **[E.3.]{.smallcaps}2.4.2.** Progress has been made in the
> identification of lead compounds, and in demonstration of use of
> animal models and imaging for drug target validation. Small molecules
> wirth anti-tumor effects have been isolated that appear to target p73
> in tumors with p53 mutations.
>
> **[E.3.]{.smallcaps}2.4.3.** New screens have been designed to
> identify new drugs that sensitize tumors that have become resistant
> during hypoxia.
>
> **[E.3.]{.smallcaps}2.4.4.** Imaging has been used to examine the
> schedule dependence of administration of fractionated radiotherapy
> with a mutiple kinase inhibitor in preparation for introduction into
> the clinic.
>
> **[E.3.]{.smallcaps}2.4.5.** Progress has been made with the
> identification of TRAIL plus Sorafenib as a particularly powerful new
> therapeutic combination for therapy-resistant tumors. Optical imaging
> was used to document anti-tumor effects and the development of a
> compelling rationale for a Phase I/II therapy trial in cancer
> patients.

**[E.3.]{.smallcaps}2.5**. Imaging tumor microenvironment: Progress has
been made in developing models to allow the viusualization of
therapeutic response in vivo through 3D 2-photon microscopy. Efforts are
underway to introduce probes for hypoxia and other markers of tumor
microenvironment including the presence of stem cells and angiogenesis.

**[E.3.]{.smallcaps}2.6.** Progress has been made by Dr. Bill Lee in the
development and use of oxyphor G2 probes to image intravascular hypoxia
in animal models being treated with anti-vascular agents including
combretastatin.

**[E.3.3. Team 3 Objectives for next two years:]{.smallcaps}**

**[E.3.]{.smallcaps}3.1.** Develop imaging application to improve
therapy:

> **[E.3.]{.smallcaps}3.1.1.** Efforts will continue to build
> infrastructure for imaging including animal models, cell-based drug
> screening, preclinical validation of drug targets and efficacy.
>
> **[E.3.]{.smallcaps}3.1.2.** Efforts will continue to develop
> collaboration with industry to accelerate progress in drug
> development. This includes collaboration to access larger chemical
> libraries and efforts to develop clinical trials with pharmaceutical
> companies.

**[E.3.]{.smallcaps}3.2** Mature SPORE collaborations:

> **[E.3.]{.smallcaps}3.2.1.** Develop use of molecular beacons to
> detect oncogene mutations in skin and other cancers.
>
> **[E.3.]{.smallcaps}3.2.2** Develop use of Macro PARISS imager in
> preclinical studies with the goal of developing a clinical protocol
> for early detection as well as a protocol for therapy monitoring.

**[E.3.]{.smallcaps}3.3.** 3D imaging of tumor microenvironment:

**[E.3.]{.smallcaps}3.3.1.** Continue to develop use of 2-photon
microscopy to image aspects of the tumor microenvironment that are
relevant to therapeutic response

**[E.3.]{.smallcaps}3.3.2.** Image tumor microenvironment through whole
animal imaging and multiple probes of molecular events and compare
various platforms to help the field learn which technologies can be used
for what applications.

**[E.3.]{.smallcaps}3.4. [Drug discovery]{.smallcaps}:**

**[E.3.]{.smallcaps}3.4.1.** Continue to develop cell-based assays using
optical imaging to identify novel therapeutic agents and combinations.

**[E.3.]{.smallcaps}3.5**. Increase collaborations with other teams in
the area of use of probes and animal models as well as with new
instrumentation such as the PARISS system.

**[E.3.]{.smallcaps}3.6.** Increase efforts to develop new imaging
probes and work with Imaging and Drug Development Working Group to
develop databases of imaging probes and models.

**[E.3.3. Team 3 Collaborations with other NTROI teams:]{.smallcaps}**

Work with Team 1 in use of DOI for detection of changes associated with
tumor response in animal models we have developed that include
aggressive breast cancers created through silencing the BRCA1 gene and
expression of mutant Ras. Work with Team 2 to explore opportunities for
use of animal models of esophageal cancer and molecular beacons
including PDT beacons. Share beacons when possible including the Ras
beacon that may be applied as a molecular tool in Barrett's esophagus.
Work with Team 4 in efforts to bring molecular beacons into clinical
studies using in vivo microscopy and endoscopy.

**E.4. TEAM 4: [Stanford University
(]{.smallcaps}http://ntroi.stanford.edu/)**

The objective of team 4 is to develop an integrated optical molecular
imaging strategy for the early detection of cancer in hollow organs,
such as esophagus and colon. This approach combines dual axes confocal
microendoscopy for sub-cellular imaging with deep tissue penetration and
mesoscopic fluorescence imaging to scan centimeter sized surface areas
using preferential binding peptide reagents to target antigens unique to
transformed mucosa. Significant progress has been made at each step in
process for engineering to clinical studies. We have **i.** developed
miniature microscopes with tremendous flexibility and number
capabilities for cancer detection, **ii.** developed probes to be used
in macro- and microscopic detection of cancer, and **iii.** tested
hardware and probes in the clinic for their ability to detect and
evaluate malignant lesions. It was recognized early that this could lead
to the development of the emerging field of *in vivo* pathology and for
this reason a significant investment has been made in the Pathology
Working Group through the funding of Dr. Crawford and his team at the
University of Florida.

**E.4.[1. Team 4 Achievements and Highlights:]{.smallcaps}**

**E.4.1.1.** [Clinical studies of existing and new probes]{.underline}.
We have begun the clinical evaluation of fluorescein tagged peptides for
the purpose of enhancing the detection of dysplasia in human esophagus
and colon. IRB approvals have been obtained, and over 30 patients have
been recruited for these studies, using the CellviZio-GI, a commercially
available confocal imaging system from Mauna Kea Technologies, Inc that
uses a 488 nm laser source. In addition, we have observed the dynamic
and steady state uptake of fluorescein by colonic crypts, demonstrating
the ability to study tissue physiology *in vivo*. These studies provide
a better understanding of transport mechanisms in colon, help target
biopsy of pre-malignant mucosa, and demonstrate identification and
localization of tumor margins in colon. We have studied 300 patients
with the non-specific agent, fluorescein, and these data are under
review for publication.

**E.4.1.2.** [Hardware development]{.underline}. Dual axes confocal
prototypes operating at 488, 780 and 1300 nm have been developed and
scaled down to a 10 mm package diameter. The 1300 nm prototype was
developed first, and provides reflectance images of tissue
microarchitecture with the deepest tissue penetration up to 1 mm. The
488 nm instrument was designed to collect fluorescence (FITC and GFP),
and has the best transverse and axial resolution of 1 and 2 microns,
respectively. The 780 nm system provides an optimal tradeoff between
tissue penetration and resolution, and is compatible with near-infrared
dyes, such as Cy 7, Alexa Fluor 780, Li-Cor 800, and indocyanine green.
We plan to further scale down the 780 nm instrument first to 5 mm and
then to 3.2 mm diameter for compatibility with standard medical
endoscopes used in community practice.

**E.4.1.3.** [Development of probes for new targets.]{.underline}
Through our effective collaboration with Drs. Marnett and Piston at
Vanderbilt University, we have demonstrated binding of Cox2
inhibitor-based probes to cancer cells in pre-clinical models. At
Stanford we have demonstrated binding of peptide probes to dysplastic
lesions in the human colon.

**E.4.[2. Team 4 Objectives for next two years:]{.smallcaps}**

**E.4.2.1**. We plan to develop preferential binding peptide reagents
for identifying dysplasia in Barrett's esophagus, and optimize the
peptide sequence used to detect dysplasia in colon. For these purposes,
we will:

**E.4.2.1.1.** Increase the avidity of peptide probes in colon that have
already been developed within the program. There were several
investigators at the 2006 workshop who have experience with
multimerization of peptide reagents and we will work with Dr. Sam
Achelifu, in a collaboration initiated at the 2006 workshop, to create
peptide multimers labeled with a fluorophore that excites at 780nm for
use with our new dual axes system. We will consult with Callum McCauly
and Adrian Nunn on these peptide multimer designs---they both offered
advice and help at the 2006 NTROI Workshop

> **•** We will develop and test peptide multimers for selected peptides
> to increase signal. This will first be attempted with
> biotin-facilitated tetramers and then with other designs.
>
> **•** We will evaluate selected designs and synthesis for clinical
> use.
>
> **•** We will seek a corporate partner for development of these
> reagents.

**E.4.2.1.2.** Develop preferential binding peptides for esophagus using
phage display using transformed Barrett's cells in culture (e.g. SEG-1
and hTERT) for panning followed by excised biopsy specimens collected
during screening endoscopy. These peptides will be conjugated to
fluorescein and their performance will be evaluated *in vivo*.

**E.4.2.1.3** Once the 5 mm dual axes confocal microendoscope is
completed we will evaluate the clinical performance of this instrument
with colonic and esophageal dysplasia.

**E.4.2.1.4.** We feel that we have a good set of peptides for the
detection of dysplasia, but we will also continue to evaluate additional
peptides as potential probes for dysplasia detection in the esophagus
and colon. Specifically we will attempt to stain excised tissues with
these reagents as a means of screening and further developing peptide
probes. We have extended this approach to cancers of both the skin and
brain.

**E.4.2.2.** Implement the 5 mm dual axes microscope and the new
packaging designs.

**E.4.2.2.1.** We will use custom made collimators to repackage the
optical components that are currently in the 10 mm microscope into a 5mm
package and then characterize system performance.

**E.4.2.2.2.** The microscope in the new packaging design will be tested
by obtaining *ex vivo* and *in vivo* images

**E.4.2.1.4.** A key feature of the dual axes instrument is the z-scan
micromotor that will enable us to interrogate a half of cubic mm of
tissue at 3 to 4 um resolution, and generate 3D images. This will be
demonstrated first in the 10 mm and then in the 5 mm microscope.

**E.4.2.1.5.** Significantly larger surface areas can be achieved with
dual axes confocal by combining individual frames into a real time
mosaic image using advance image processing algorithms to be developed
with the Stanford Bio-Robotics program.

**E.4.2.3.** Instrument channels in conventional endoscope have a 3.7 mm
diameter, and thus we will redesign the MEMS mirror to further scale
down the form factor of the dual axes confocal to approximately 3 mm in
diameter. For this purpose we will:

> **•** Redesign the MEMS mirror using a new process that accommodates
> vertical scanning.
>
> **•** Model the frequency response of the mirrors with Coventorware
> software
>
> **•** Fabricate and test prototype mirrors over a 12-18 month period.
>
> **•** Optimize mirror deflection angles for ±5 degrees optical.
>
> **•** Integrate system architecture with micro-optics design for large
> field of view.
>
> **•** Redesign packaging in 3 mm form factor.

**E.4.2.4.** The program is currently focusing on early detection of
dysplasia in Barrett's esophagus and colon, and we will use the
strengths of the dual axes system that have been revealed in GI cancers
to address issues in other clinical diseases.

**E.4.2.4.1.** We will continue to evaluate Barrett's esophagus using
the MKT CellviZio-GI. This work will be conducted with Team 2. We will
extend the clinical studies on Barrett's esophagus in collaboration with
Team 2. As we move toward multi-center clinical trials collaborating
with a team with experience in emerging optical technologies will
benefit the study design and its execution. In addition, experience with
both Team 2 and Team 4 technologies will facilitate development of an
integrated instrument.

**E.4.2.4.2.** We will look into the issues involved in building an
instrument combined with the technologies being developed by Team 2.

**E.4.2.4.3.** We have already begun to investigate colon cancer and
will work toward early detection of sporadic cancer and that associated
with ulcerative colitis using the MKT Cellvizio GI.

> **•** Working with the Informatics WG and the Pathology WG, we will
> developed pattern recognition for the diseases of the GI that are the
> current focus of this program.
>
> **•** In collaboration with Team 3 we will work on animal models for
> the preclinical validation of in vivo microscopy using the preclinical
> Cellvizio and the novel dual axes instruments.
>
> **•** We will extend the studies to glioblastoma and work with Mitch
> Berger of the UCSF SPORE and with Team 2 on this project. We have
> already developed peptides that bind with some specificity to human
> glioblastoma and will co-develop these with the instruments.

**E.4.2.4.4** The 10 mm diameter prototype will first be used in the
clinic as a handheld instrument to guide Moh's micrographic surgery of
basal and squamous cell carcinoma with Dr. Hayes Gladstone, a Stanford
dermatological surgeon.

**E.4.2.5.** We have begun work on another fiber-optic system for *in
vivo* diagnosis based on Fourier Transform Infrared (FTIR) with
Attenuated Total Reflectance (ATR) to interrogate differences in the
molecular bonds of biochemical functional groups between normal and
pre-malignant tissue. This is one of the development projects and the
aims are to develop an *in vivo* method that does not require the use of
an exogenous agent, a source of potential toxicicity. We will first
demonstrate the performance of this fiber optic instrument to
distinguish between normal colon mucosa and polyps within the next 6
months in collaboration with STI. Then we will develop this approach to
guide pinch biopsy for dysplasia in Barrett's esophagus and fine needle
aspiration for assessment of pancreatic cancer.

**E.4.2.5.1**. Examine molecular fingerprint of spectra in the next 6
months. We will work with Allen Poirson and John Hargrove of STI and
Robert Parker of the Informatics WG on algorithm development and
spectral analyses. This is linked to efforts underway with Team 2 in
spectral analyses

**E.4.2.5.2**. Perform *in situ* tissue evaluation over the next 12
months

> **•** We will refine the preparation of tissue
> surface---dehydration---for FTIR analyses.
>
> **•** We will work with Team 2 and STI Medical Systems on improving
> the spectral analyses.
>
> **•** We will begin to assemble a data base of tissue signatures along
> with John Pearson in Team 1 to create this database.

**E.4.2.6.** We will select 10 stromal and cancer markers from the
database of disregulated genes that has been generated as part of the
development project led by Dr. Anson Lowe (Stanford University)

> **•** We will identify existing reagents---if possible---for these
> selected markers and ectopically express markers in cell lines for the
> purpose of developing reagents for *in vivo* detection using the
> fiber-optic systems that are the focus of this program.
>
> **•** In the event that we can not use existing reagents, we will
> screen phage display libraries for 7 and 12 amino acid peptides that
> bind to the selected targets that are expressed on cell lines.
>
> **•** We will develop and test these reagents on excised tissues and
> *in vivo.*

**E.4.2.7.** We have a number of projects involving animal models and
these will be further developed with Team 3 and co-developed for use
with instruments being developed as part of Team 2's program.

**E.4.2.7.1.** We will develop reagents of glioblastoma using the U87
xenograft model

> **•** The current set of peptides have been developed using the U87
> cell line as well as with primary human brain tissues (normal and
> GBM). These will be tested using the fiber-based systems.
>
> **•** The purpose of these studies will be to developed methods for
> tumor margin detection.

**E.4.2.7.2.** Team 3 has developed a set of cell lines with a number of
oncogenes expressed in these cells. These will serve as screens for the
effects of oncogenes on the immunological targets of NKG2D ligands. We
have evidence that oncogenes upregulate these ligands leading to
improved recognition of tumor targets by NK T cells and other immune
cells. Specifically we will determine if oncogene expression changes the
recognition of tumor targets by cytokine induced killer (CIK) cells, and
then evaluate the ability of CIK cells to deliver oncolytic vaccinia
viruses to tumor cells as a dual biotherapy.

**E.4.2.7.3.** We have recently become part of the Children's Brain
Cancer Consortium and this group at Stanford has proposed to use \$2M in
philanthropic dollars to develop better methods for early diagnosis of
medulloblastoma and improved therapies.

> **•** We will evaluate a comprehensive gene expression profile---a
> consortium objective is to generate this profile---and the intent is
> to use these as markers for new diagnostics that can be used with
> fiber-based microscopes.
>
> **•** We will look for peptides that identify specific disease states
> and disease markers as identified by the gene expression data

**E.4.2.7.4.** We will evaluate the CIK-vv biotherapy for efficacy
against medulloblastoma.

**E.4.2.7.5.** We will continue to refine the rat anastomosis model of
Barrett's esophagus and begin to target p53, and p16 as early markers of
transformation using fluorescence peptides reagents and the small animal
imaging version of the CellviZio.

**E.4.[4. Team 4 New opportunities for Team Members and Other
Collaborators, ]{.smallcaps}**

**E.4.[4.1. Other Sources of Funding\--]{.smallcaps}**NIH Grants

> • Dual Axes confocal microscope for small animal imaging, NIH/NCI
>
> R33 EB001864 (Principal Investigators: T.D. Wang and C. H. Contag)

**Appendix A:** Total NTROI publications.

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167. 

Rozan, L.M. and W.S. El-Deiry, *p53 downstream target genes and tumor
suppression: a classical view in evolution.* Cell Death and Diff 2007.
14(1): p. 3-9.Zeiser, R., V.H. Nguyen, J.Z. Hou, A. Beilhack, E.A.
Zambricki, M. Buess, C.H. Contag, and R.S. Negrin, *Early CD30 signaling
is critical for adoptively transferred CD4+CD25+ regulatory T cells in
prevention of acute graft versus host disease.* Nat. Immunol.
2007.Zeiser, R., V.H. Nguyen, A. Beilhack, M. Buess, S. Schulz, J.
Baker, C.H. Contag, and R.S. Negrin, *Inhibition of CD4+CD25+ regulatory
T-cell function by calcineurin-dependent interleukin-2 production.*
Blood, 2006. 108(1): p. 390-9.Yang, W., L.M. Rozan, E.R. McDonald, 3rd,
A. Navaraj, J.J. Liu, E.M. Matthew, W. Wang, D.T. Dicker, and W.S.
El-Deiry, *Carps are ubiquitin ligases that promote MDM2-independent P53
and phospho-P53ser20 degradation.* J. Biol. Chem 2007Wells, W. A., G. N.
Schwartz, P. M. Morganelli, B. F. Cole, J. J. Gibson, and W. B. Kinlaw,
*Expression of \"Spot 14\" (THRSP) predicts disease free survival in
invasive breast cancer: immunohistochemical analysis of a new molecular
marker*, Breast Cancer Res. Treat. 98, 231-240 (2006). Wang, W., S.H.
Kim, and W.S. El-Deiry, *Small-molecule modulators of p53 family
signaling and antitumor effects in p53-deficient human colon tumor
xenografts.* PNAS, USA, 2006. 103(29): p. 11003-8.Wang, S. and W.S.
El-Deiry, *p73 or p53 directly regulates human p53 transcription to
maintain cell cycle checkpoints.* Cancer Research, 2006. 66(14): p.
6982-9.Wang, Q., C.H. Contag, H. Ilves, Y.A. Cao, B.H. Johnston, and
R.L. Kaspar, *CMR 2005: 12.05: Use of in vivo imaging to follow
siRNA-mediated reporter gene inhibition in a transgenic mouse skin
model.* Contrast Media & Molecular Imaging, 2006. 1(2): p. 85.Wang X.,
B. W. Pogue, S. Jiang, H. Dehghani, X. Song, S. Srinivasan, B. A.
Brooksby, K. D. Paulsen, C. Kogel, S. P. Poplack, and W. A. Wells,
*Image reconstruction of effective Mie scattering parameters of breast
tissue in vivo with near-infrared tomography*, J. Biomed. Opt. 11,
041106 (2006). Thorne, S.H., R.S. Negrin, and C.H. Contag, *Synergistic
antitumor effects of immune cell-viral biotherapy.* Science, 2006.
311(5768): p. 1780-4.Thompson, H.G., J.D. Mih, T.B. Krasieva, B.J.
Tromberg, and S.C. George, *Epithelial-derived TGF-beta2 modulates basal
and wound-healing subepithelial matrix homeostasis.* Am. J physiol,
2006. 291(6): p. L1277-85.Tang, S., T.B. Krasieva, Z. Chen, and B.J.
Tromberg, *Combined multiphoton microscopy and optical coherence
tomography using a 12-fs broadband source.* J Biomed Optics, 2006.
11(2): p. 020502.Tang, S., T.B. Krasieva, Z. Chen, G. Tempea, and B.J.
Tromberg, *Effect of pulse duration on two-photon excited fluorescence
and second harmonic generation in nonlinear optical microscopy.* J
Biomed Optics, 2006. 11(2): p. 020501.Tang, J., L.K. Qu, J. Zhang, W.
Wang, J.S. Michaelson, Y.Y. Degenhardt, W.S. El-Deiry, and X. Yang,
*Critical role for Daxx in regulating Mdm2.* Nat Cell Biol., 2006. 8(8):
p. 855-62.Takaoka, M., C.E. Smith, M.K. Mashiba, T. Okawa, C.D. Andl,
W.S. El-Deiry, and H. Nakagawa, *EGF-mediated regulation of IGFBP-3
determines esophageal epithelial cellular response to IGF-I.* Am. J
physiol, 2006. 290(2): p. G404-16.Sharwani, A., W. Jerjes, V. Salih, B.
Swinson, I.J. Bigio, M. El-Maaytah, and C. Hopper, *Assessment of oral
premalignancy using elastic scattering spectroscopy.* Oral Oncology,
2006. 42(4): p. 343-9.Scata, K.A. and W.S. El-Deiry, *Taming NEMO to
slay cancer cells.* Cancer Biol & Ther, 2006. 5(9): p. 1096-7.Rozan,
L.M. and W.S. El-Deiry, *Identification and characterization of proteins
interacting with Traf4, an enigmatic p53 target.* Cancer Biol & Ther,
2006. 5(9): p. 1228-35.RaubOncogene, C.B., V. Suresh, T. Krasieva, J.
Lyubovitsky, J.D. Mih, A.J. Putnam, B.J. Tromberg, and S.C. George,
*Noninvasive Assessment of Collagen Gel Microstructure and Mechanics
Using Multiphoton Microscopy.* Biophys. J. 2007 92: 2212-2222.Oyama, K.,
T. Okawa, H. Nakagawa, M. Takaoka, C.D. Andl, S.H. Kim, A. Klein-Szanto,
J.A. Diehl, M. Herlyn, W.S. El-Deiry, and A.K. Rustgi, *AKT induces
senescence in primary esophageal epithelial cells but is permissive for
differentiation as revealed in organotypic culture.* Oncogene
2007.Nguyen, V.H., R. Zeiser, D.L. Dasilva, D.S. Chang, A. Beilhack,
C.H. Contag, and R.S. Negrin, *In vivo dynamics of regulatory T cell
trafficking and survival predict effective strategies to control
graft-versus-host disease following allogeneic transplantation.* Nat
Immunol. 2006.Morioka, I., R.J. Wong, A. Abate, H.J. Vreman, C.H.
Contag, and D.K. Stevenson, *Systemic effects of orally-administered
zinc and tin (IV) metalloporphyrins on heme oxygenase expression in
mice.* Ped.Research, 2006. 59(5): p. 667-72.Mayes, P.A. and W.S.
El-Deiry, *The complementary roles of the extrinsic and intrinsic
apoptotic pathways in promoting the death of cancer cells.* Cancer
Journal (Sudbury, Mass, 2006. 12(4): p. 247-9.Madsen, S.J., C.H. Sun,
B.J. Tromberg, V. Cristini, N. De Magalhaes, and H. Hirschberg,
*Multicell tumor spheroids in photodynamic therapy.* Lasers Surg Med,
2006. 38(5): p. 555-64.Lyubovitsky, J.G., J.A. Spencer, T.B. Krasieva,
B. Andersen, and B.J. Tromberg, *Imaging corneal pathology in a
transgenic mouse model using nonlinear microscopy.* J Biomed Optics,
2006. 11(1): p. 014013.Lovat, L.B., K. Johnson, G.D. Mackenzie, B.R.
Clark, M.R. Novelli, S. Davies, M. O\'Donovan, C. Selvasekar, S.M.
Thorpe, D. Pickard, R. Fitzgerald, T. Fearn, I.J. Bigio, and S.G. Bown,
*Elastic scattering spectroscopy accurately detects high grade dysplasia
and cancer in Barrett\'s oesophagus.* Gut, 2006. 55(8): p. 1078-83.Liu,
J.T., M.J. Mandella, S. Friedland, R. Soetikno, J.M. Crawford, C.H.
Contag, G.S. Kino, and T.D. Wang, *Dual-axes confocal reflectance
microscope for distinguishing colonic neoplasia.* J Biomed Optics, 2006.
11(5): p. 054019.Lee, J., D.J. Saltzman, A.E. Cerussi, D.V. Gelfand, J.
Milliken, T. Waddington, B.J. Tromberg, and M. Brenner, *Broadband
diffuse optical spectroscopy measurement of hemoglobin concentration
during hypovolemia in rabbits.* PhysiMeasure 2006. 27(8): p. 757-67.Lee,
J., N. El-Abaddi, A. Duke, A.E. Cerussi, M. Brenner, and B.J. Tromberg,
*Noninvasive in vivo monitoring of methemoglobin formation and reduction
with broadband diffuse optical spectroscopy.* J AAppl Physiol 2006.
100(2): p. 615-22.Kuribayashi, K., P.A. Mayes, and W.S. El-Deiry, *What
are caspases 3 and 7 doing upstream of the mitochondria?* Cancer Biol &
Ther, 2006. 5(7): p. 763-5.Kim, S.H., H. Nakagawa, A. Navaraj, Y.
Naomoto, A.J. Klein-Szanto, A.K. Rustgi, and W.S. El-Deiry, *Tumorigenic
conversion of primary human esophageal epithelial cells using oncogene
combinations in the absence of exogenous Ras.* Cancer Res, 2006. 66(21):
p. 10415-24.Jin, Z. and W.S. El-Deiry, *Distinct signaling pathways in
TRAIL- versus tumor necrosis factor-induced apoptosis.* Molec Cell Biol,
2006. 26(21): p. 8136-48.Ilves, H., R.L. Kaspar, Q. Wang, A.A. Seyhan,
A.V. Vlassov, C.H. Contag, D. Leake, and B.H. Johnston, *Inhibition of
Hepatitis C IRES-Mediated Gene Expression by Small Hairpin RNAs in Human
Hepatocytes and Mice.* Annals of the New York Academy of Sciences, 2006.
1082: p. 52-5.Hirschberg, H., D.R. Sorensen, E. Angell-Petersen, Q.
Peng, BJ. Tromberg, C.H. Sun, S. Spetalen, and S. Madsen, *Repetitive
photodynamic therapy of malignant brain tumors.* J Env Path Tox Oncol,
2006. 25(1-2): p. 261-79.Helms, M.W., B.H. Brandt, and C.H. Contag,
*Options for visualizing metastatic disease in the living body.*
Contributions to microbiology, 2006. 13: p. 209-31.Grimberg, A., C.M.
Coleman, Z. Shi, T.F. Burns, T.K. Maclachlan, W. Wang, and W.S.
El-Deiry, *Insulin-Like Growth Factor Factor Binding Protein-2 is a
Novel Mediator of p53 Inhibition of Insulin-Like Growth Factor
Signaling.* Cancer Biol & Ther, 2006. 5(10): p. 1408-14.Goun, E.A., R.
Shinde, K.W. Dehnert, A. Adams-Bond, P.A. Wender, C.H. Contag, and B.L.
Franc, *Intracellular cargo delivery by an octaarginine transporter
adapted to target prostate cancer cells through cell surface protease
activation.* Bioconjugate chemistry, 2006. 17(3): p. 787-96.Frieboes,
H.B., X. Zheng, C.H. Sun, B. Tromberg, R. Gatenby, and V. Cristini, *An
integrated computational/experimental model of tumor invasion.* Cancer
Res, 2006. 66(3): p. 1597-604.Fong, Y., L. Wagman, M. Gonen, J.
Crawford, W. Reed, R. Swanson, C. Pan, J. Ritchey, A. Stewart, and M.
Choti, *Evidence-based gallbladder cancer staging: changing cancer
staging by analysis of data from the National Cancer Database.* Annals
of surgery, 2006. 243(6): p. 767-71; discussion 771-4.Finnberg, N. and
W.S. El-Deiry, *Selective TRAIL-induced apoptosis in dysplastic
neoplasia of the colon may lead to new neoadjuvant or adjuvant
therapies.* Clinical Cancer Res, 2006. 12(14 Pt 1): p. 4132-6.Johansson
A, Svensson J, Andersson-Engels S, Bendsoe N, Svanberg K, Bigio IJ,
Alexandratou E, Kyriazi M, Yova D, Gräfe S. Trebst T. *mTHPC*
pharmacokinetics following topical administration. SPIE 2006; 6094:
60940c-1-60940c-8.Fanucchi, M.P., F.V. Fossella, R. Belt, R. Natale, P.
Fidias, D.P. Carbone, R. Govindan, L.E. Raez, F. Robert, M. Ribeiro, W.
Akerley, K. Kelly, S.A. Limentani, J. Crawford, H.J. Reimers, R.
Axelrod, O. Kashala, S. Sheng, and J.H. Schiller, *Randomized phase II
study of bortezomib alone and bortezomib in combination with docetaxel
in previously treated advanced non-small-cell lung cancer.* J Clin
Oncol., 2006. 24(31): p. 5025-33.El-Deiry, W.S., C.C. Sigman, and G.J.
Kelloff, *Imaging and oncologic drug development.* J Clin Oncol., 2006.
24(20): p. 3261-73.El-Deiry, W.S. and A.K. Rustgi, *Cancer biology: a
new discipline with required reading.* Cancer Biol & Ther, 2006. 5(10):
p. 1415.El-Deiry, W.S., *Lobbying Congress to make cancer funding a
priority: what scientists can do.* Cancer Biol & Ther, 2006. 5(5): p.
467-9.Dicker, D.T., J. Lerner, P. Van Belle, S.F. Barth, D.t. Guerry, M.
Herlyn, D.E. Elder, and W.S. El-Deiry, *Differentiation of normal skin
and melanoma using high resolution hyperspectral imaging.* Cancer Biol &
Ther, 2006. 5(8): p. 1033-8.Dhar, A., K.S. Johnson, M.R. Novelli, S.G.
Bown, I.J. Bigio, L.B. Lovat, and S.L. Bloom, *Elastic scattering
spectroscopy for the diagnosis of colonic lesions: initial results of a
novel optical biopsy technique.* Gastrointestinal endoscopy, 2006.
63(2): p. 257-61.Contag, C.H., *Molecular imaging using visible light to
reveal biological changes in the brain.* Neuroimaging Clinics of North
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W.S. El-Deiry, *DR5 knockout mice are compromised in radiation-induced
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Kogel, John Weaver, Steven Poplack, Justin D Pearlman and Keith D
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properties using MRI-guided NIR tomography*, Proceedings of SPIE 5693,
2005 Brooksby, B. Shudong Jiang, Hamid Dehghani, Brian W. Pogue, Keith
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thymocyte development.* PNAS, USA, 2004. 101(11): p. 3898-902.Xu, Heng,
Hamid Dehghani, Brian W. Pogue, Keith D. Paulsen, Roger Springett, Jeff
F. Dunn, *Optical tomography system based on second-differential
spectroscopy for small animal brain study,* Proceedings of the Optical
Society of America Biomedical Optics Meeting, Advances in Optical
Imaging and Photon Migration Session, Miami Beach FL, April 14-17,
2004.Wang, W. and W.S. El-Deiry, *Targeting FOXO kills two birds with
one stone.* Chem & Biol, 2004. 11(1): p. 16-8.Wang, W. and W.S.
El-Deiry, *Targeting p53 by PTD-mediated transduction.* Trends in
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*Cytochrome c: a crosslink between the mitochondria and the endoplasmic
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the development of novel cancer therapeutics.* Cancer treatment and
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silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor
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clusterin, which inhibits their growth in vitro and carcinogenesis in
vivo.* Cancer Res, 2004. 64(9): p. 3126-36.Takaoka, M., H. Harada, C.D.
Andl, K. Oyama, Y. Naomoto, K.L. Dempsey, A.J. Klein-Szanto, W.S.
El-Deiry, A. Grimberg, and H. Nakagawa, *Epidermal growth factor
receptor regulates aberrant expression of insulin-like growth
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and W.S. El-Deiry, *p53-Dependent activation of a molecular beacon in
tumor cells following exposure to doxorubicin chemotherapy.* Cancer Biol
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Arvanitis, A. Karlsson, S. Beer, S. Mandl, M.H. Bachmann, A.D. Borowsky,
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M. Dews, D. Yu, A. Thomas-Tikhonenko, D.T. Dicker, and W.S. El-Deiry,
*Direct repression of FLIP expression by c-myc is a major determinant of
TRAIL sensitivity.* Molec Cell Biol, 2004. 24(19): p. 8541-55.Pogue,
B.W., B. Chen, S. Gibbs, X. Zhou, P.J. Hoopes, and T. Hasan,
*Mitochondrial targeting in photodynamic therapy with verteporfin and
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Photobiology, Seattle WA, July 10-14 (2004).McDonald, E.R., 3rd and W.S.
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results in sensitization to death ligands and inhibition of tumor cell
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Socinski, G. Sibley, A.W. Blackstock, J.E. Herndon, S. Zhou, T. Shafman,
A. Tisch, R. Clough, X. Yu, A. Turrisi, M. Anscher, J. Crawford, and J.
Rosenman, *Carboplatin/paclitaxel or carboplatin/vinorelbine followed by
accelerated hyperfractionated conformal radiation therapy: report of a
prospective phase I dose escalation trial from the Carolina Conformal
Therapy Consortium.* J Clin Oncol., 2004. 22(21): p. 4329-40.Lin, S.W.,
M. Cook, N. Finnberg, E. Bernhard, D. Baldwin, and W.S. El-Deiry,
*p53-dependent induction of serine proteases in irradiated mouse colon.*
Cancer Biol & Ther, 2004. 3(12): p. 1290-7.Kim, S.H., K. Kim, J.G.
Kwagh, D.T. Dicker, M. Herlyn, A.K. Rustgi, Y. Chen, and W.S. El-Deiry,
*Death induction by recombinant native TRAIL and its prevention by a
caspase 9 inhibitor in primary human esophageal epithelial cells.* J
Biol Chem, 2004. 279(38): p. 40044-52.Kim, K., H. Nakagawa, P. Fei, A.K.
Rustgi, and W.S. El-Deiry, *Targeting Bcl-xL in esophageal squamous
cancer to sensitize to chemotherapy plus TRAIL-induced apoptosis while
normal epithelial cells are protected by blockade of caspase 9.* Cell
Death Diff, 2004. 11(5): p. 583-7.Johnson, K.S., D.W. Chicken, D.C.
Pickard, A.C. Lee, G. Briggs, M. Falzon, I.J. Bigio, M.R. Keshtgar, and
S.G. Bown, *Elastic scattering spectroscopy for intraoperative
determination of sentinel lymph node status in the breast.*J Biomed.
Optics, 2004. 9(6): p. 1122-8.Jin, Z., E.R. McDonald, 3rd, D.T. Dicker,
and W.S. El-Deiry, *Deficient tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) death receptor transport to the cell
surface in human colon cancer cells selected for resistance to
TRAIL-induced apoptosis.* J Biol Chem 2004. 279(34): p.
35829-39.Jakubowski, D.B., A.E. Cerussi, F. Bevilacqua, N. Shah, D.
Hsiang, J. Butler, and B.J. Tromberg, *Monitoring neoadjuvant
chemotherapy in breast cancer using quantitative diffuse optical
spectroscopy: a case study.*J Biomed. Optics, 2004. 9(1): p.
230-8.Hirschberg, H., C.H. Sun, B.J. Tromberg, A.T. Yeh, and S.J.
Madsen, *Enhanced cytotoxic effects of 5-aminolevulinic acid-mediated
photodynamic therapy by concurrent hyperthermia in glioma spheroids.* J
Neuro-oncology, 2004. 70(3): p. 289-99.Hardy, J., K.P. Francis, M.
DeBoer, P. Chu, K. Gibbs, and C.H. Contag, *Extracellular replication of
Listeria monocytogenes in the murine gall bladder.* Science, 2004.
303(5659): p. 851-3.Gruber, P.J., Z. Li, H. Li, D. Worrad, B. Huang, I.
Abdullah, W. Wang, W. El-Deiry, V.A. Ferrari, and R. Zhou, *In vivo
imaging of MLC2v-luciferase, a cardiac-specific reporter gene expression
in mice.* Acad Rad, 2004. 11(9): p. 1022-8.Fong, K.D., H.M. Song, R.P.
Nacamuli, B.L. Franc, C. Mari, T.D. Fang, S.M. Warren, C.H. Contag, F.G.
Blankenberg, and M.T. Longaker, *Apoptosis in a rodent model of cranial
suture fusion: in situ imaging and gene expression analysis.* Plastic
Reconstruct Surg, 2004. 113(7): p. 2037-47.Finnberg, N. and W.S.
El-Deiry, *Activating FOXO3a, NF-kappaB and p53 by targeting IKKs: an
effective multi-faceted targeting of the tumor-cell phenotype?* Cancer
Biol & Ther, 2004. 3(7): p. 614-6.Fei, P., W. Wang, S.H. Kim, S. Wang,
T.F. Burns, J.K. Sax, M. Buzzai, D.T. Dicker, W.G. McKenna, E.J.
Bernhard, and W.S. El-Deiry, *Bnip3L is induced by p53 under hypoxia,
and its knockdown promotes tumor growth.* Cancer Cell, 2004. 6(6): p.
597-609.Dash, B.C. and W.S. El-Deiry, *Cell cycle checkpoint control
mechanisms that can be disrupted in cancer.* Meth Molec Biol (Clifton,
N.J, 2004. 280: p. 99-161.Blankenberg, F.G., S. Mandl, Y.A. Cao, C.
O\'Connell-Rodwell, CH. Contag, C. Mari, T.I. Gaynutdinov, J.L.
Vanderheyden, M.V. Backer, and J.M. Backer, *Tumor imaging using a
standardized radiolabeled adapter protein docked to vascular endothelial
growth factor.* J Nuc Med, 2004. 45(8): p. 1373-80.Bigio, I.J. and S.G.
Bown, *Spectroscopic sensing of cancer and cancer therapy: current
status of translational research.* Cancer Biol & Ther, 2004. 3(3): p.
259-67.Beckham, J.T., M.A. Mackanos, C. Crooke, T. Takahashi, C.
O\'Connell-Rodwell, C.H. Contag, and E.D. Jansen, *Assessment of
cellular response to thermal laser injury through bioluminescence
imaging of heat shock protein 70.* Photochem Photobiol, 2004. 79(1): p.
76-85.A\'Amar, O.M., R.D. Ley, and I.J. Bigio, *Comparison between
ultraviolet-visible and near-infrared elastic scattering spectroscopy of
chemically induced melanomas in an animal model.*J Biomed. Optics, 2004.
9(6): p. 1320-6. Stott, JJ, J.P. Culver, S.R. Arridge, and D.A. Boas,
*Optode Positional Calibration in Diffuse Optical Tomography*, Applied
Optics 42(16): 3154-3162. 2003.Pogue, B.W. Shudong Jiang, Xiaomei Song,
Subhadra Srinivasan, Hamid Dehghani, Keith D. Paulsen, Tor D. Tosteson,
Christine Kogel, Sandra Soho, and Steven P. Poplack, *Near-infrared
scattering spectrum differences between benign and malignant breast
tumors measured in vivo with diffuse tomography,* Proceedings of the
Optical Society of America Biomedical Optics Meeting, Advances in
Optical Imaging and Photon Migration Session, Miami Beach FL, April
14-17, 2004.Pogue, B. W., S. Jiang, S.P. Poplack, C. Kogel, H. Dehghani,
S. Soho, S. Srinivasan, X. Song, W. Wells, T.D. Tosteson, and K.D.
Paulsen, *Interpreting hemoglobin, oxygen saturation, water and
scattering properties of breast cancer tumors measured non-invasively
with near-infrared tomography,* Proceedings of the American Association
for Cancer Research, 95th Annual Meeting, Orlando FL, pp1218, #5282,
March 27-31 (2004).Merritt S., G. Gulsen, G. Chiou, Y. Chu, C. Deng,
A.E. Cerussi, A.J. Durkin, B.J. Tromberg, and O. Nalcioglu, *Comparison
of water and lipid content measurements using diffuse optical
spectroscopy and MRI in emulsion phantoms,* Technol Cancer Res Treat.
2003 Dec;2(6):563-9.Li, A. Q. Zhang, J.P. Culver, E.L. Miller, and D.A.
Boas, *Reconstructing chromosphere concentration images directly by
continuous-wave diffuse optical tomography,* Optics Letters 29(3):
256-258. 2004.Kilmer, M.E., E.L. Miller, A. Barbaro, and D.A Boas,
*Three-Dimensional Shape-Based Imaging of Absorption Perturbation for
Diffuse Optical Tomography*, Applied Optics 42(16): 3129-3144. 2003.Li,
A., E.L. Miller, M.E. Kilmer, T.J. Brukilacchio, T. Chaves, J. Stott, Q.
Zhang, T. Wu, M. Chorlton, R.H. Moore, D.B. Kopans, and D.A. Boas,
*Tomographic optical breast imaging guided by three-dimensional
mammography*, Applied Optics 42(25): 5181-5190. 2003.Corlu, A., T.
Durduran, R. Choe, M. Schweiger, E.M.C Hillman, S.R. Arridge, A.G. Yodh,
*Uniqueness and wavelength optimization in continuous-wave multispectral
diffuse optical tomography.* Optics Letters, 2003. 28: p. 2339-2341.

**[Appendix B: Agendas from Recent Annual Retreats]{.smallcaps}**

**Team 1 NTROI Retreat June 22-24, 2006, Hyatt Newporter, Newport Beach,
CA**

**Thursday June 22, 2006**

*Terrace Arbor/Terrace Ballroom*

2:00-5:30 pm Reception and Poster Viewing

5:30-6:30 pm Dinner

Introductory Comments: Bruce Tromberg

6:30-7:00 pm: **Optical Fluorescence Imaging of Breast Cancer**, Leon
Bakker, Philips Research

7:00-7:30 pm: **Spatial and spectral data in optical mammography,**
Sergio Fantini, Tufts University

**Friday June 23, 2006**

*Terrace Arbor/Terrace Ballroom*

7:30-8:00am: Continental breakfast

**Standardization and Software Post-processing**

***Chair: Fred Azar, Siemens Corporate Research***

8:00-8:15 am: **Introduction**, Bruce Tromberg and Fred Azar

8:15-8:30 am: **Dartmouth College Presentation**, Brian Pogue

8:30-8:45 am: **University of Pennsylvania, Yodh Group**, Kijoon Lee

8:45-9:00 am: **University of Pennsylvania, Chance Group**, TBN

9:00-9:15 am: **Massachusetts General Hospital**, Qianqian Fang

9:15-9:45 am: **University of California, Irvine and San Francisco**,
Catherine Klifa

Coffee Break and Poster Viewing 9:45 am to 10:00 am

10:00-10:30 am: **OMIRAD Platform: Latest Post-processing
Developments**, Fred Azar

10:30-11:00 am: **SciPort Platform: Managing experiment data,
State-of-the-Art**, John Pearson

Discussion 11:00 am to 11:30 am

Lunch and Poster Viewing 11:30 am to 12:30 pm

**Instrumentation**

***Chair: Albert Cerussi, University of California, Irvine***

12:30-1:00 pm: **Multi-Frequency Diffuse Optical Tomography (MF-DOT) &
MRI: A Hybrid System for Dynamic Imaging of Cancer**, Gultekin Gulsen

1:00-1:30 pm: **Implications of performing optical imaging under
mammographic compression -- changes in the physiological state of the
breast and potential novel optical cancer markers**, Stefan Carp

1:30-2:00 pm: **Recent progresses of combined X-ray/diffuse optical
tomographic breast imaging system and clinical data analysis at
Massachusetts General Hospital**, Qianqian Fang

2:00-2:30 pm: **Development of a non-contact optical scanning system for
frequency domain spectroscopy of tissues**, Enrico D'Amico

Coffee Break and Poster Viewing 2:30 pm to 3:00 pm

**Translational**

***Chair: Brian Pogue, Dartmouth College***

3:00-3:30 pm: **Intrinsic markers revealed by a novel analysis of
near-infrared spectra of breast tumors**, Shwayta Kukreti

3:30-4:00 pm: **Overview of the Neoadjuvant Chemotherapy Imaging at
Dartmouth**, Shudong Jiang

4:00 - 4:20 pm: **Breast Cancer Contrast from Diffuse Optical Tomography
and Correlation Spectroscopy in Characterization and Therapy
Monitoring**, Regine Choe

4:20 - 4:40 pm: **Recent Work in Diffuse Optical Tomography: Correlation
with PET and the Use of Large Data Sets**, Soren Konecky

4:40-5:10 pm: **Variations in Chemotherapy Response during the First
Week**, Albert Cerussi

Dinner 5:30 pm to 8:00 pm

7:00-9:00 pm: **Planning for Multi-Center Clinical Trial Meeting**

**Saturday June 24, 2006**

*Terrace Arbor/Terrace Ballroom*

8:30-10:00 am: Continental breakfast, wrap up and Poster Viewing

8:30-10:00 am: Executive Committee Meeting and Conference Call

Poster Breakdown

**2006 Team 1 NTROI Retreat Posters**

**1) Reconstruction of Tissue Dynamics in the Compressed Breast Using
Multiplexed Measurements and Temporal Basis Functions**

Gregory Boverman, Qianqian Fang, Stefan Carp, Juliette Selb, Eric L.
Miller, and David A. Boas

**2) Review of the clinical study at MGH: 20+ cases of co-registered
X-ray Tomosynthesis and**

**Tomographic Optical Breast Imaging (TOBI) on healthy breasts and
breasts presenting lesions.**

Juliette Selb, Qianqian Fang, Gregory Boverman, Stefan Carp, Richard
Moore, Dianne Georgian-Smith, Daniel B. Kopans, and David A. Boas.

**3) Effects of radiotherapy on rat breast tumor hemodynamics monitored
by near infrared**

**spectroscopy**

Jae G. Kim1,4, Vincent Bourke2, Cheng-Hui Chang3, Dawen Zhao2, Ralph P.
Mason2, Hanli Liu4

1 Beckman Laser Institute, University of California at Irvine

2 Department of Radiology, University of Texas Southwestern Medical
Center at Dallas

3 Department of Radiation Oncology, University of Texas Southwestern
Medical Center at Dallas

4 Joint Program of Biomedical Engineering, University of Texas at
Arlington and University of Texas

Southwestern Medical Center at Dallas

**4) A Comparison of Optical Reconstruction Methods Incorporating
Spectral and MR- Derived**

**Spatial Information**

Colin Carpenter, Subhadra Srinivasan, Brian Pogue, Hamid Dehghani and
Keith D. Paulsen

Thayer School of Engineering, Dartmouth College, Hanover NH 03755

**5) An Analysis of Patient Perspectives and Experience Using the Laser
Breast Scanner**

Debbi Gordon1, Natasha Shah1, Lari Wenzel2, Brian Hill1, Montana
Compton1, Amanda Durkin1, Tran Du1, Sara Siavoshi1, Albert Cerussi1,
David Hsiang3, and Bruce Tromberg1

1Beckman Laser Institute, University of California, Irvine

2 Center for Health Policy Research, University of California, Irvine

3Chao Comprehensive Cancer Center, University of California, Irvine

**6) Remission-mode Diffuse Tomography can Localize Absorber and
Fluorescent Objects but Image Sensitivity is Non-linear with Depth**

Dax Kepshire, Dartmouth College

**7) Spectral Evidence for the optical detection of the fast neuronal
signal as seen as a change due to scattering in the mammalian brain**

Kandice Tanner1, Rui Ma2, Joseph Malpeli2, William W. Mantulin1,3 and
Enrico Gratton1,3

1 Department of Physics, University of Illinois- Urbana- Champaign, 2
Neuroscience program and Department of Psychology, University of
Illinois- Urbana- Champaign, 3 Department of Biomedical Engineering,
University of California, Irvine

**8) MRI-Localized Region Spectroscopy with Near-Infrared Tomography:
Analysis of wavelengths, spatial prior false positives and experimental
feasibility**

Jia Wang1, Scott Davis2, Subhadra Srinivasan2, Shudong Jiang2, Brian W.
Pogue2, Keith D. Paulsen2

1Department of Physics and Astronomy, Dartmouth College, Hanover NH

2Thayer School of Engineering, Dartmouth College, Hanover NH

2006 NTROI Retreat Poster Abstracts

**9) Breast Tissue Microscopic Fluctuations in Refractive Index Studied
through Phase Contrast**

**Measurements**

Xin Wang, Dartmouth College

**10) Weighted Least--Squares for Diffuse Optical Tomography**

Phaneendra Yalavarthy, Brian Pogue, Hamid Dehghani, Shudong Jiang, and
Keith Paulsen

Thayer School of Engineering, Dartmouth College, Hanover, NH 03755

**11) Tissue Bound Water Studies on Breast Tumor using Diffuse Optical
Spectroscopy**

Sophie (So Hyun) Chung1, Albert Cerussi1, Sean Merritt, Natasha Shah1,
David Hsiang2, Rita Mehta2 and Bruce Tromberg1

1Beckman Laser Institute, Laser Medical and Microbeam Program,
University of California, Irvine

2Chao Comprehensive Cancer Center, University of California, Irvine

**12) A Novel Integrated Photonic System for DOT/MR Imaging**

Vishal Saxena (1), Ignacio Gonzalez-Gomez (3), Gevorg Karapetyan (1),
Vazgen Khankaldyyan (2), and Walter E. Laug (2) Departments of Radiology
(1), Pediatrics (2) and Pathology (3) Saban Research Institute,
University of Southern California

MS# 81, 4650 Sunset Blvd., Los Angeles CA 90027 Vsaxena@usc.edu

Industrial Collaborator: N-Wave CT, Hartford, Connecticut

**13) Mini-FDPM with Full Heterodyne: Improved Sensitivity and Fast,
Non-Invasive Detection of**

**Breast Cancer Detector Based on Frequency Domain Photon Migration**

Keun-Sik No, Qiang Xie, Richard Kwong, Amanda Durkin, Albert Cerussi,
Bruce Tromberg, Pai Chou

**14) Progress on Inhalational Differential Contrast for In Vivo Optical
Imaging**

Sanhita Dixit, Ken Kotz, Ashley Gibbs, Theresamai Le, Khalid Amin and
Gregory Faris SRI International

**15) Co-registration of Dynamic Contrast Enhanced MRI and Broadband
Diffuse Optical**

**Spectroscopy for Characterizing Breast Cancer**

Min-Ying Su, HJ Yu, N Shah, D. JB Hsiang, RS Mehta, A Cerussi, B
Tromberg, and O. Nalcioglu

**16) Method for Recovering Quantitative Broadband Diffuse Optical
Spectra from Layered Media**

Ang Li, Richard Kwong, Albert Cerussi, Sean Merritt, Carole Hayakawa and
Bruce Tromberg

Beckman Laser Institute and Medical Clinic, Univ. California Irvine

**17) Multi-Wafer Laser Diode for use in Diffuse Optical Spectroscopy**

Vijay Jayaraman1, Devin Leonard1, Richard Kwong2, Amanda F. Durkin2,
Albert E. Cerussi2, and Bruce Tromberg2 1Praevium Research, Santa
Barabara, CA 2Beckman Laser Institute, Laser Medical and Microbeam
Program, University of California, Irvine

**18) Qualitative Depth Sectioned Imaging with Diffuse Optical
Spectroscopy in Breast Phantoms**

Anu Kohli1, Richard Kwong2, Albert Cerussi2, and Bruce Tromberg2

1Harvey Mudd College, Claremont, CA

2Beckman Laser Institute and Medical Clinic, Univ. California Irvine,
1002 Health

**Annual Symposium of the National Translational Research Group**

**Into Optical Imaging (NTROI)**

University College London

Monday 18^th^ and Tuesday 19^th^ September 2006

**[Monday 18^th^ September 2006]{.underline}**

***Venue: Taviton (SEES Building) 345, 346 or 347***

8:15-8:30am Light refreshments (coffee and tea)

8:30-8:45am Welcoming remarks and Team 2 overview - Prof. Irving Bigio

**8:45am -1:00pm Presentations to External Scientific Advisory Committee
(ESAC):**

8:45-11:00 Primary Projects

08:45--09:30 Primary Project 2, UCL Dr Laurence Lovat, Ms. May Yong

09:30--10.15 Primary Project 1, UCL Prof Stephen Bown (incl. breast
results)

10:15--11:00 Primary Project 3, U. Pitt. Dr Julie Eiseman

11:00-11:15 Refreshment break

11:15am-1:00pm Developmental projects

11:15-11:30 UCL -- closeout of project Dr Laurence Lovat

> 11:30-12:00 Boston Medical Center Dr Satish Singh
>
> 12:00-12:30 Erasmus MC, Rotterdam Dr H J C M Sterenborg/Dr. Arjen
> Amelink
>
> 12:30-1:00 Lund University Dr Katarina Svanberg/Dr Stefan
> Andersson-Engels

**1.00-2:00pm Lunch (provided) - Working lunch for ESAC (separate,
closed session)**

**2:00-3:30pm Continued presentations to ESAC (open session)**

> 2:00- 2:45 Technical Support core Prof Irving Bigio/Prof Robert
> Parker/Mr Randal
>
> Chinnock

2:45-3:00 Administrative core Ms Jennifer Marron

3:00-3:15 Ancillary projects Prof. Irving Bigio

and future directions

**3:30 -- 4:30pm ESAC wrap-up (closed session)**

4:30 -- 5:30pm Report from the ESAC to the Team Leaders (closed - NCI
observers welcome)

3:30 -- 4:30pm Round table discussion regarding new directions for NTROI
Team #2 (technical needs, fiber design and development)

4:30-5:30 pm Poster Session begins

5:30pm ESAC and Team Leaders join poster session/Cocktail reception

***Venue: Wilkins Portico***

**\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\***

7:30pm Dinner at Somerset House

**[Tuesday 19^th^ September 2006]{.underline}**

***Venue: Taviton (SEES Building) 345, 346 or 347***

9:00 am Tour of endoscopy suite

Practical demonstrations (done via videoconference)

Hands on presentation of UCL ESS box with new software capabilities

11:00 am Discussions on in vivo dosimetry of PDT and clinical
implications of ESS

1:00 pm Working lunch to continue conversations and wrap up session

2:00 pm Formal end to conference

Visit the London Eye or the Tate Modern Museum

*or*

Hands on demonstration of animal studies in the Laser Centre

> *JAM/7Sept06*

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