Download Workshop on imaging science development for cancer prevention

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Cancer Biomarkers 3 (2007) 1–33
IOS Press
Workshop on imaging science development
for cancer prevention and preemption
Gary J. Kelloffa,∗ , Daniel C. Sullivana, Houston Bakera, Lawrence P. Clarke a , Robert Nordstroma ,
James L. Tatuma , Gary S. Dorfmana , Paula Jacobs b, Christine D. Bergc , Martin G. Pomperd ,
Michael J. Birrere , Margaret Temperof , Howard R. Higleyg , Brenda Gumbs Petty g ,
Caroline C. Sigmang , Carlo Maleyh , Prateek Sharmai , Adam Waxj , Gregory G. Ginsbergk ,
Andrew J. Dannenberg l, Ernest T. Hawkm, Edward M. Messingn , H. Barton Grossmano,
Mukesh Harisinghani p , Irving J. Bigioq , Donna Griebelr , Donald E. Henson s, Carol J. Fabiant,
Katherine Ferrarau , Sergio Fantiniv , Mitchell D. Schnallw , Jo Anne Zujewski x , Wendy Hayes y ,
Eric A. Kleinz , Angelo DeMarzoaa , Iclal Ocakbb , Jeffrey A. Ketterlingcc , Clare Tempanydd,
Faina Shternee , Howard L. Parnes ff , Jorge Gomezgg , Sudhir Srivastavahh , Eva Szabo ii, Stephen Lamjj ,
Eric J. Seibelkk , Pierre Massionll, Geoffrey McLennan mm, Kevin Clearynn , Robert Suhoo ,
Randall W. Burtpp , Ruth M. Pfeifferqq , John M. Hoffmanoo , Hemant K. Royrr, Thomas Wang ss,
Paul J. Limburgtt , Wafik S. El-Deiryuu , Vali Papadimitrakopoulouvv, Walter N. Hittelmanww ,
Calum MacAulayxx, Robert W. Veltriyy , Diane Solomonzz , Jose Jeronimo aaa ,
Rebecca Richards-Kortum bbb , Karen A. Johnson ccc, Jaye L. Vinerm , Steven P. Strattonccc ,
Milind Rajadhyaksha ddd and Atam Dhawan eee
a
NIH/NCI/DCTD, Cancer Imaging Program, Bethesda, MD, USA
NIH/NCI/DCTD, Cancer Imaging Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, USA
c
NIH/NCI/DCP, Early Detection Research Group, Bethesda, MD, USA
d
The Johns Hopkins University School of Medicine, Departments of Radiology, Pharmacology and Oncology,
Division of Neuroradiology, Baltimore, MD, USA
e
NIH/NCI/CCR, Cell and Cancer Biology Branch, Bethesda, MD, USA
f
University of California, San Francisco, Department of Medicine, Division of Medical Oncology, San Francisco,
CA, USA
g
CCS Associates, Inc., Mountain View, CA, USA
h
Wistar Institute, Molecular and Cellular Oncogenesis Program, Philadelphia, PA, USA
i
University of Kansas School of Medicine, VA Hospital, Kansas City, MO, USA
j
Duke University, Department of Biomedical Engineering, Medical Physics Program, Durham, NC, USA
k
University of Pennsylvania School of Medicine, Department of Gastroenterology, Philadelphia, PA, USA
l
New York Presbyterian Hospital/Weill Medical College of Cornell University, New York, NY, USA
m
NIH/NCI/OD, Office of Centers for Training and Resources, Bethesda, MD, USA
n
University of Rochester Medical Center, Department of Urology, Rochester, NY, USA
o
University of Texas MD Anderson Cancer Center, Department of Urology, Houston, TX, USA
p
Massachusetts General Hospital, Abdominal Imaging/Interventional Radiology, Boston, MA, USA
q
Boston University, Biomedical Engineering, Electrical and Computer Engineering, and Physics, Boston, MA, USA
r
NIH/NCI/DCP, Gastrointestinal and Other Cancers Research Group, Bethesda, MD, USA
s
The George Washington University Cancer Institute, Office of Cancer Prevention and Control, Washington, DC,
USA
b
∗ Corresponding author: Gary J. Kelloff, MD, NIH/NCI/DCTD,
Cancer Imaging Program, 6130 Executive Blvd., EPN, Rm 6058,
Rockville, MD 20852, USA. Tel.: +1 301 594 0423; Fax: +1 301
480 3507; E-mail: [email protected].
ISSN 1574-0153/07/$17.00  2007 – IOS Press and the authors. All rights reserved
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t
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
University of Kansas Cancer Center, Clinical Oncology, Kansas City, KS, USA
University of California, Davis, Department of Biomedical Engineering, Davis, CA, USA
v
Tufts University, Department of Biomedical Engineering, Medford, MA, USA
w
University of Pennsylvania, Department of Radiology, Philadelphia, PA, USA
x
NIH/NCI, Clinical Investigations Branch, Bethesda, MD, USA
y
Novartis Institutes for BioMedical Research, Division of Imaging, Bethesda, MD, USA
z
The Cleveland Clinic, Department of Urologic Oncology, Cleveland, OH, USA
aa
The Johns Hopkins University School of Medicine, Departments of Pathology, Oncology, Urology, Baltimore, MD,
USA
bb
NIH/NCI/DBS, Molecular Imaging Program, Bethesda, MD, USA
cc
Riverside Research Institute, Frederick L. Lizzi Center for Biomedical Engineering, New York, NY, USA
dd
Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
ee
AdMeTech Foundation, Department of Radiology, Boston, MA, USA
ff
NIH/NCI/DCP, Prostate and Urologic Cancer Research Group, Bethesda, MD, USA
gg
NIH/NCI/OD, Organ Systems Branch, Office of Centers Training and Resources, Bethesda, MD, USA
hh
NIH/NCI/DCP, Cancer Biomarkers Research Group, Bethesda, MD, USA
ii
NIH/NCI/DCP, Lung and Upper Aerodigestive Cancer Research Group, Bethesda, MD, USA
jj
British Columbia Cancer Agency, University of British Columbia, Vancouver Hospital, Vancouver, BC, Canada
kk
University of Washington, Technology Development, Seattle, WA, USA
ll
Vanderbilt-Ingram Cancer Center, Cancer Biology, Nashville, TN, USA
mm
University of Iowa Health Care, Internal Medicine, Iowa City, IA, USA
nn
Georgetown University Medical Center, Imaging Science and Information Systems (ISIS) Center, Department of
Radiology, Washington, DC, USA
oo
University of California, Los Angeles, David Geffen School of Medicine, Thoracic Imaging and Intervention, Los
Angeles, CA, USA
pp
University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA
qq
NIH/NCI, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
rr
Evanston-Northwestern Healthcare, Division of Gastroenterology, Evanston, IL, USA
ss
Stanford University, Department of Medicine, Division of Gastroenterology, Stanford, CA, USA
tt
Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN, USA
uu
University of Pennsylvania School of Medicine, Abramson Comprehensive Cancer Center, Philadelphia, PA, USA
vv
University of Texas MD Anderson Cancer Center, Thoracic/Health and Neck Medical Oncology, Houston, TX,
USA
ww
University of Texas MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA
xx
British Columbia Cancer Research Centre, Research Arm of the British Columbia Cancer Agency, Vancouver, BC,
Canada
yy
The Johns Hopkins Hospital, Brady Urological Research Institute, Department of Urology, Baltimore, MD, USA
zz
NIH/NCI/DCP, Breast and Gynecologic Cancer Research Group, Bethesda, MD, USA
aaa
NIH/NCI/DCEG, Environmental Epidemiology Branch, Rockville, MD, USA
bbb
University of Texas, Austin, Biomedical Engineering Program, Austin, TX, USA
ccc
University of Arizona, Arizona Cancer Center, Tucson, AZ, USA
ddd
Memorial Sloan-Kettering Cancer Center, Department of Medicine, Dermatology Service, New York, NY, USA
eee
New Jersey Institute of Technology, Department of Electrical and Computer Engineering, Newark, NJ, USA
u
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
Workshop Program Committee:
Gary J. Kelloff, MD, (Chair), NIH/NCI/DCTD/Cancer Imaging Program, Bethesda, MD, USA
Jeffrey Abrams, MD, NIH/NCI/DCTD/CTEP, Clinical Investigations Branch, Bethesda, MD, USA
Houston Baker, PhD, NIH/NCI/DCTD/Cancer
Imaging Program, Bethesda, MD, USA
Rachel Ballard-Barbash, MD, MPH, NIH/NCI, Applied Research Program, Bethesda, MD, USA
Christine D. Berg, MD, NIH/NCI/DCP, Early Detection Research Group, Bethesda, MD, USA
Laurence P. Clarke, PhD, NIH/NCI/DCTD, Cancer
Imaging Program, Bethesda, MD, USA
Andrew J. Dannenberg, MD, New York Presbyterian
Hospital/Weill Medical College of Cornell University,
New York, NY, USA
Gary S. Dorfman, MD, NIH/NCI/DCTD, Cancer
Imaging Program, Bethesda, MD, USA
Wafik S. El-Deiry, MD, PhD, University of Pennsylvania School of Medicine, Abramson Comprehensive
Cancer Center, Philadelphia, PA, USA
Jorge Gomez, MD, PhD, NIH/NCI/OD, Organ Systems Branch, Office of Centers Training and Resources,
Bethesda, MD, USA
Donna Griebel, MD, NIH/NCI/DCP, Gastrointestinal and Other Cancers Research Group, Bethesda, MD,
USA
Elisa Harvey, DVM, PhD, FDA/CDRH, Office of
Device Evaluation, Rockville, MD, USA
Ernest T. Hawk, MD, MPH, NIH/NCI/OD, Office
of Centers for Training and Resources, Bethesda, MD,
USA
Wendy Hayes, Novartis Institutes for BioMedical
Research, Division of Imaging, Bethesda, MD, USA
Donald E. Henson, MD, The George Washington
University Cancer Institute, Office of Cancer Prevention and Control, Washington, DC, USA
Paula Jacobs, PhD, NIH/NCI/DCTD, Cancer Imaging Program, SAIC-Frederick, Inc., NCI-Frederick,
Frederick, MD, USA
James W. Jacobson, PhD, NCI/DCTD, Diagnostic
Biomarkers and Technology Branch, Cancer Diagnostics Program, Bethesda, MD, USA
Karen A. Johnson, MD, PhD, MPH, NIH/NCI/DCP,
Breast and Gynecologic Cancer Research Group,
Bethesda, MD, USA
Paul J. Limburg, MD, MPH, Mayo Clinic College of
Medicine, Division of Gastroenterology and Hepatology, Rochester, MN, USA
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Timothy McCarthy, PhD, Pfizer, Inc., Global Research and Development, Groton, CT, USA
George Q. Mills, MD, MBA, FDA/CDER/OND/
OODP, Division of Medical Imaging and Radiopharmaceutical Drug Products, Silver Spring, MD, USA
Suresh Mohla, PhD, NIH/NCI/DCB, Division of
Cancer Biology, Tumor Biology and Metastasis Branch,
Bethesda, MD, USA
Howard L. Parnes, MD, NIH/NCI/DCP, Prostate and
Urologic Cancer Research Group, Bethesda, MD, USA
Robert A. Phillips, PhD, Ontario Cancer Research
Network, Toronto, ON, Canada
Sudhir Srivastava, PhD, MPH, NIH/NCI/DCP, Cancer Biomarkers Research Group, Bethesda, MD, USA
Daniel C. Sullivan, MD, NIH/NCI/DCTD/Cancer
Imaging Program (Chair), Bethesda, MD, USA
Eva Szabo, MD, NIH/NCI/DCP, Lung and Upper
Aerodigestive Cancer Research Group, Bethesda, MD,
USA
James L. Tatum, MD, NIH/NCI/DCTD, Cancer
Imaging Program, Bethesda, MD, USA
Robert W. Veltri, PhD, The Johns Hopkins Hospital,
Brady Urological Research Institute, Department of
Urology, Baltimore, MD, USA
Jaye L. Viner, MD, MPH, NIH/NCI/OD, Office of
Centers for Training and Resources, Bethesda, MD,
USA
Jo Anne Zujewski, MD, NIH/NCI, Clinical Investigations Branch, Bethesda, MD, USA
Abstract. The concept of intraepithelial neoplasm
(IEN) as a near-obligate precursor of cancers has generated opportunities to examine drug or device intervention strategies that may reverse or retard the
sometimes lengthy process of carcinogenesis [92,93,
144,189]. Chemopreventive agents with high therapeutic indices, well-monitored for efficacy and safety,
are greatly needed, as is development of less invasive
or minimally disruptive visualization and assessment
methods to safely screen nominally healthy but at-risk
patients, often for extended periods of time and at repeated intervals. Imaging devices, alone or in combination with anticancer drugs, may also provide novel
interventions to treat or prevent precancer.
1. Introduction
Current advances in molecular imaging [40,91,176,
196] and biomarker discovery for various cancers [124]
enable earlier detection and diagnosis of recognizable
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
Fig. 1. Examples of various imaging modalities employed to diagnose cancer and preneoplastic disease and to guide therapeutic intervention.
A) White-light optical endoscopy view of Barrett’s esophageal margin; B) Optical mammography near-infrared spectral image, tumor oxygenation
index view (with permission from [72]); C) Midband ultrasound image of the prostate [44]; D) Focal FDG-PET uptake in the ascending colon
revealed as a high-grade adenoma on colonoscopy and resected (used with permission [227]); E) Transverse contrast-enhanced CT scan images
of patient with lung nodule before, shortly after, and on three-month post-precutaneous RF ablation therapy (with permission [195]).
precancerous lesions (e.g., papillomas, nodules, etc.),
possibly even differentiating fields of transformed cells
from their normal tissue surroundings (Fig. 1). Indeed,
increasing numbers of available imaging modalities and
visualization tools (Fig. 2) have generated real questions regarding which instruments and image-driven
interventions produce the most significant and costeffective patient outcomes for the widest variety of cancer modalities.
Adopting specific imaging technologies as standards
for oncologists, radiologists, and nuclear medicine
specialists requires evidence-based demonstrations of
sensitivity/specificity and predictive value with clinical precision for each instrument design. Significant
competition is expected among imaging devices and
biomarker assessment methodologies as each developer negotiates the hurdles and challenges along various
engineering, clinical, and regulatory routes to the marketplace.
A workshop convened by the National Cancer Institute (NCI) Cancer Imaging Program in Gaithersburg,
MD, provided an overview of these convergent issues
and processes and facilitated discussion on the state of
imaging science development for cancer prevention and
preemption. Presentations by more than 50 researchers
and translation scientists focused on instruments and
techniques for evaluation of early cancer and imageguided intervention (IGI) in clinical settings. Keynote
speakers presented introductions to issues surrounding
the application of imaging techniques, including dis-
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
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Fig. 2. Spectral sensitivities/resolution of various imaging modalities; examples of imaging probes and agents; and principal applications/uses in
cancer treatment, diagnosis, and research investigations (adapted with permission from M. Pomper). FMT = fluorescence-mediated tomography;
BLI = bioluminescence imaging; GFP = green fluorescent protein; RFP = red fluorescent protein; NIRF = near-infrared fluorescence probes;
SPECT = single photon emission computed tomography; PET = positron emission tomography; 11 C-RAC = raclopride; 124 I-FIAU = I-labeled
2’-fluoro-2’-deoxy-5’-iodo-1β-d-arabinofuranosyluracil; 64 CU-ATSM = copper-diacetyl-bis(N 4-methylthiosemicarbazone); NAA = N -acetyl
aspartate; Cr = creatinine; Cho = choline; Glx = glutamate + glutamine; mI = myoinositol; MION = monocrystalline iron oxide nanoparticle.
ease incidence and prevalence, pathology and mechanism of lesion development, epidemiology, risk factors
and models, clinical presentation of disease, standard
of care, ongoing and new clinical protocols, screening
and early detection procedures, treatment interventions
(drugs, surgery, IGI), biomarkers, and currently used
imaging modalities. The keynote talks were followed
by presentations on imaging research and roundtable
discussions with experts from industry, academia, and
government who considered priorities for further research and development efforts needed to qualify investigational devices or methods for clinical use.
Progress in endoscopic or other optical assessment
methods and complementary approaches to biopsy and
ablation of suspicious lesions were highlighted in several sessions on hollow organ or surface epithelial neoplasias (e.g., Barrett’s esophagus, superficial bladder
cancer). Advances in instrumentation and development
of biomarkers for precancer detection in solid organs
(e.g., breast, prostate) were necessarily focused on remote or indirect imaging modalities such as computed
tomography (CT), magnetic resonance imaging (MRI),
positron emission tomography (PET), and ultrasound
or thermal spectroscopy.
2. Summary of presentations
2.1. Barrett’s esophagus
Dr. Carlo Maley, Wistar Institute, described the evolution of Barrett’s esophagus or esophageal intestinal metaplasia and its association with chronic gastroesophageal reflux disease (GERD) [121]. Barrett’s
esophagus has a risk of progression to esophageal adenocarcinoma ranging from 0.5–1%/year [21]; its incidence is increasing faster than any other cancer in the
Western world, perhaps related to the epidemic of obesity and attendant GERD seen in many developed countries. Current intervention standards include proton
pump inhibitor therapy for reflux and esophagectomy
if frank carcinoma is identified. Aberrant clones within the pre-malignant Barrett’s mucosa may cover complex concave shapes on the surface of the distal esophagus. Diagnosis and surveillance is based on extensive
random biopsy sampling methods, typically performed
every 2 cm down the Barrett’s segment under direct
endoscopic visualization. Careful prospective analysis
of biopsy material has found a correlation between risk
of progression to cancer and extent of aneuploidy and
loss of heterozygosity (LOH) of various tumor suppres-
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sor genes, describing a risk pathway predictive of patient outcomes [120,163]. Genetic heterogeneity within Barrett’s mucosa can be ranked in time and space
from an initial lesion showing p16 LOH with a relatively low-risk ratio progressing to p53 LOH (which has
the highest risk ratio for development of carcinoma),
then aneuploidy. Better methods to image proliferative or mutant clones would permit less onerous biopsy
sampling, a better understanding of how clones expand,
as well as the potential to intervene before higher-risk
lesions progress.
Dr. Prateek Sharma, University of Kansas, has applied just such a series of innovations to Barrett’s
esophagus assessment, using in vivo chromoendoscopic tissue staining, magnification and high-definition endoscopy, and narrow-band imaging (NBI) filters, to better define regions of dysplasia. Conventional whitelight inspection of Barrett’s segments can be enhanced
by applying Lugol’s iodine, indigo carmine, or methylene blue spray to the esophageal surface to distinguish complex and often subtle patterns of intestinal
metaplasia at its junction with normal squamous surface
epithelium. Videoendoscopes equipped with a chargecoupled device (CCD) chip use high pixel densities to
produce high image resolution. Furthermore, with a
movable higher magnification lens (35–115X power),
endoscopists can evaluate microscopic mucosal features within the regions of Barrett’s metaplasia, such
as raised villiform or tubular patterns, well correlated
with risk of progression [41,179,180]. Higher-intensity
blue-light illumination with special NBI spectral filters
enables imaging of both superficial epithelial and deeper tissue features such as capillary vascular patterns
within regions of interest. NBI can be used without
tissue dye augmentation with the detection of bloodvessel hemoglobin as the primary chromophore; it has
high sensitivity and specificity in distinguishing highgrade dysplasia (HGD) in Barrett’s disease [87,177].
Novel imaging techniques can potentially help identify
neoplastic areas in Barrett’s endoscopy; a banding suction device then can be used to resect suspicious areas
of dysplasia under direct narrow-band visualization.
Real-time optical biopsy of Barrett’s lesions would
avoid the trauma and delay associated with current conventional histopathologic analysis. Dr. Adam Wax,
Duke University, described several proof-of-concept
approaches to this problem, which involve diagnosing
disease while evaluating intact living tissue at the cellular level. Low-coherence interferometry (LCI) combined with oblique angle detection of scattered light
(a/LCI) detects precancerous changes based upon ep-
ithelial nuclear size and texture at various tissue depths
without sectioning, fixation, or applying exogenous
contrast agents. Signal discrimination parameters for
a/LCI have been worked out for various nuclear characteristics of both cancer and precancer cell lines in vitro [220] as well as in an in vivo animal carcinogenesis
model [221], where reversal of precancerous epithelial
changes with an apoptosis-inducing chemopreventive
agent impacted a/LCI-detected nuclear features. Ex vivo evaluation of resected Barrett’s specimens by a/LCI
scanning of up to 20 × 10 cm areas of mucosa showed a
marked correlation between tissue nuclear atypia classified as diseased or normal by a/LCI, and tissue dysplasia grades assigned by histopathology. Measurements
of large tissue surface areas that once took 30 minutes
to perform can now be performed in 40 milliseconds
due to the rapidity and sensitivity of current a/LCI fiber
optic probes with a laser scanning spectrometer and improved processing power [159]. A portable instrument
system with these new design features has the potential to become a clinically relevant measurement and
diagnostic tool.
Dr. Gregory Ginsburg, University of Pennsylvania,
reviewed current clinical standards for observational
management of Barrett’s esophagus and the variety of
endoluminal therapies now available as alternatives to
surgery. Individuals with long-segment disease (1–7%
of Barrett’s population) have greater risk for progression to cancer compared to those with short-segment
disease (6–17%) [57,75]. If HGD is detected during
surveillance biopsy, 30% of patients typically show an
intramucosal cancer if esophagectomy is performed,
and 16–60% develop cancer from 5–7 years after diagnosis and without further management [24,164,173].
However, 40–80% of Barrett’s patients with HGD don’t
progress, with ∼50% remaining stable and ∼25% regressing to lower-grade disease. Because of this wide
variability in outcomes and current lack of precision in
risk stratification, endoscopic ablation or mucosal resection therapies may be preferable to esophagectomy.
Before considering superficial ablative therapies, it is
advisable to evaluate the esophagus by methods such as
endoscopic ultrasound in order to rule out disruptions
in the mucosal wall or submucosal adenopathy that
might indicate more invasive disease [175]. Ablative
endoluminal therapies include thermal and cryotherapy approaches and cytotoxic approaches such as photodynamic therapy with photofrin/aminolevulinic acid
(ALA). Thermal ablation instruments include directcontact electrocautery probes or circumferential radiofrequency (RF) balloon electrodes (e.g., HALO 360
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
from BARRx, Inc.), and non-contact systems such as
laser or argon plasma beam coagulators. These instruments are relatively safe and unlikely to cause perforations, but carry the risk of leaving residual “buried
Barrett’s” under regenerating mucosa [136]. PDT with
photofrin or ALA taken up preferentially by dividing
cells provides a potentially more specific method of
delayed necroinflammatory ablation. A pivotal trial
that resulted in FDA approval showed the PDT technique to be highly efficacious in eliminating circumferential long-segment Barrett’s disease with multi-focal
HGD, thereby reducing progression to cancer during
2–5 years follow-up [146]. Complications such as postoperative stricture were not markedly different than
those seen for other thermal ablative methods; however, some skin photosensitization by the dyes, and areas of PDT “skip” requiring multiple treatment sessions, were noted. All ablative methods have the disadvantage of destroying mucosa that might provide valuable histopathologic diagnostic information. Because
of this, focal or short-segment Barrett’s is often better managed with instruments that permit endoluminal
mucosal resection (EMR) [3], such as the suction/snare
device described by Dr. Sharma. Dr. Ginsburg’s unpublished research indicates that multimodal endoluminal
therapeutic approaches combining techniques such as
PDT with EMR may be optimal in complex cases.
2.2. Bladder cancer
The bladder is another hollow organ prone to develop
superficial tumors within a readily accessible mucosa.
Dr. Edward Messing, University of Rochester, provided an overview of suspected disease etiology (smoking, chemical/industrial exposures) and some demographic risk factors (> 2:1 male/female ratio, median
age of 70 at presentation). Currently, no well-accepted
urine biomarker exists for the earliest forms of bladder
carcinogenesis, usually detected through patient selfreporting of hematuria or irritative voiding [133,139].
Confirmatory diagnosis of transitional cell carcinoma (TCC) is then made by cytoscopic examination of
the bladder. TCC is staged through pathologic assessment of papillary tumors recovered by transurethral
resection (TURBT) or biopsy of more extensive areas of TCC in situ (TIS). Single low-grade superficial
(Ta, T1) TCC, with a low rate of progression to muscle invasion (5–10%), but a high rate of recurrence,
is typically managed by surveillance cystoscopy every
three months with TURBT as needed. Higher-grade
lesions (stage Ta, T1, TIS) have a 20–70% progression
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rate requiring intravesical therapy with antimitotics or
immunomodulatory agents such as Bacillus CalmetteGuerin (BCG) as an adjunct or alternative to TURBT.
Muscle-invasive disease is usually treated by cystectomy. Using intraoperative near-infrared imaging to trace
infusions of fluorescent dyes such as indocyanin green
that are taken up by the cavernous nerves in the pelvic
plexus may be able to spare the complication of nerve
damage-induced impotence often associated with this
procedure.
Application of optical fluorescence to improve detection and outcome of TCC was presented by Dr. H.
Barton Grossman, MD Anderson Cancer Center. Although current standard white-light cystoscopy is highly reliable in detecting bladder cancer, certain TIS lesions are visually difficult to detect and residual tumors
may often remain after TURBT. Intravesical infusion
of dyes such as ALA that make TCC more visible when
illuminated by blue light have the potential to improve
the diagnostic sensitivity of cystoscopy. Several clinical trials comparing ALA fluorescence to white-light
cystoscopy found a reduced risk of recurrence or progression when TURBT was performed with ALA [9,
48]. Recent development of a hexyl ester of ALA,
HAL (Hexvix ), has made adoption of fluorescence
microscopy even more practical. HAL instillation reduces the amount of time required for dye uptake by
a bladder tumor to one hour. In several clinical studies [85,171], HAL increased TCC detection sensitivity
to 96% compared to 77% for white-light cystoscopy.
False-positive regions of normal mucosa, noted with
HAL as well as ALA, were produced by non-specific
fluorescence seen with areas of post-BCG inflammation. Increasing the interval after intravesical therapy should permit resolution of this inflammation and
increase specificity of the fluorescence technique.
Bladder cancer that has advanced to invade muscle requires radical cystectomy (described above) as
well as extensive dissection of the surrounding pelvis,
including removal of draining lymph nodes. Successful identification and resection of nodes has a direct survival benefit for these patients [73]. Standard imaging modalities like CT and MRI rely primarily on node size to detect metastasis, despite the
considerable overlap in size between benign and malignant nodes. Attempting to distinguish between involved and uninvolved nodes using MRI contrast enhancement agents such as gadolinium, and metabolic imaging methods such as 18 fluoro-2-deoxyglucose
positron emission tomography (FDG-PET), are usually confounded by urinary concentration of tracer in
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the adjacent bladder. Dr. Mukesh Harisinghani, Massachusetts General Hospital, reviewed his experience
with a novel MRI nanoparticle contrast agent to delineate and stage nodal involvement in bladder cancer.
These ultrasmall (21 nm) dextran-coated supermagnetic iron oxide particles (ferumoxtran-Combidex) show
contrast uptake and decreased signal intensity on T2weighted MRI images as a result of their uptake by normal lymph node macrophages (i.e., “black is benign”).
In contrast, areas of lymph node infiltrated with tumor cells show space-filling regions without nanoparticle uptake and retain their high-signal-intensity MRI
density. An initial clinical trial of 48 patients scheduled for cystectomy [35] recovered 172 lymph nodes
after ferumoxtran infusion imaging; this MRI contrastenhancement method yielded sensitivity and specificity
of 95% and 95% when compared to routine histopathologic diagnosis, resulting in a negative predictive value for patient outcome of 100% and a positive predictive value of 90%. Whether this contrast agent clears
rapidly enough from uninvolved nodes to permit accurate follow-up of response monitoring is still questionable, as is whether its initial uptake is confounded by
lymph node fibrosis, produced by chemo- or radiotherapy, which may be more routinely observed for cancers
in other organ systems. At present, the agent has not
been approved by FDA.
Dr. Irving Bigio, Boston University, reviewed the
concept of noninvasive optical tissue biopsy and described various spectroscopic methods applicable to
bladder cancer; most common are UV-induced fluorescence of exogenous agents and autofluorescence spectroscopy, along with Raman and infrared reflectance
techniques. Dr. Bigio and his colleagues are currently working on elastic scattering spectroscopic (ESS)
approaches which, when performed using appropriate
fiberoptic instruments, are point-sensitive to morphologic tissue architectural variations at cellular and subcellular levels. Although not directly applicable to construction of tissue images, ESS can provide a backscatter signal spectrum that differentiates between tissue
histomorphometry characteristics of benign, canceradjacent, and malignant bladder mucosa after appropriate computational image analysis [137]. Complex
spectra generated by ESS relate to the spatial variations of the indices of refraction displayed by all
cellular components, including water, proteins, lipids,
and DNA, when comprising higher-order structures
such as membrane bilayers and cytoplasm that include
cell organelles and nuclei. Morphological changes in
these cellular structures during carcinogenesis, includ-
ing shifts in nucleus-to-cytoplasm ratio, nuclear shapefactors, chromatin distribution, and organelle and inclusion arrangement are characteristic of all pathologic
processes and generate variations in photon-scattering
spectra that, collected in a sufficient database, enable
identification of disease margins and can improve accuracy when selecting regions of transformed bladder
mucosa for resection or ablation.
2.3. Breast cancer
Dr. Carol Fabian, University of Kansas, summarized
the current state of the art for risk assessment and breast
cancer early detection. Screening mammography has
now become routine for women in the US; breast density pattern analysis using breast imaging, reporting, and
data systems (BIRADS) can add additional discriminatory power to the score derived from the common Gail
risk assessment tool [53,205] used to advise women regarding their risk of cancer development. Components
of the Gail risk formula (age, reproductive history, familial risk, atypical biopsy results, etc.) that result in
a calculation of 1.67% estimate of cancer development within five years cause an assessment of high risk.
Similarly, > 75% breast density (BIRADS 4) indicates
a greater than five-fold increase in five-year risk relative to those with the lowest BIRADS score. Additional cytomorphologic monitoring may be indicated for
these high-risk individuals, including nipple aspirate
fluid and ductal lavage sampling, or random fine-needle
aspiration (FNA) [43,178,225]. New molecular or tissue histomorphometric biomarker methods (e.g., immunocytochemical staining for proliferative antigens
or hormone receptors, automated quantitative nuclear
morphometry) are being examined to reduce the interpretive variance seen with standard cytology index
scoring systems (Masood score). Risk assessment formulae, breast density measurements, and cytomorphologic screening procedures have all been incorporated
into cancer prevention trial designs to provide highrisk cohort selection and monitor effects of intervention
with cancer-preventive drugs. For example, tamoxifen
substantially reduced mammographic density at least in
younger women, most likely reflecting epithelial stroma content of breast tissue and impact of the antiestrogen on glandular and ductal epithelial structures at
risk. More recently, newer selective estrogen receptor
modulators (SERMSs) such as arzoxifene, and estrogen synthesis inhibitors such as aromatase inhibitors
(letrozole, etc.), are under evaluation as cancer preventive agents using breast density, cytomorphologic,
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
and other molecular biomarker measurement methods
(e.g., insulin-like growth factor (IGF)-1/IGF-BP3 ratio)
to assess safety and efficacy [42,97]. However, standard CT methods to determine breast density are not
optimal for risk assessment and treatment monitoring
in every setting. Younger, very high-risk women (e.g.,
those with BRCA1/2 mutations), who opt for screening
rather than prophylactic surgery, would benefit from a
modality that does not use radiation, which may in itself
increase the risk of transformation events in the breast.
MRI and ultrasound approaches appear fruitful. Older and post-menopausal women with low breast density due to adipose tissue replacing stroma may still be
at considerable risk for cancer development; imaging
modalities such as thermal or transillumination (TLM)
spectroscopy [181] may better predict vascular changes
associated with incipient tumor formation.
Dr. Katherine Ferrara, University of California at
Davis, described the role of ultrasound in breast tumor
imaging, the prospects for enhancing its sensitivity and
specificity by addition of contrast agents, and its potential in IGI. Specifically, the addition of “microbubble” contrast agents to current standard ultrasound techniques used in differential diagnosis of suspicious lesions and in guiding biopsy needle placement could
improve tumor resolution and capacity to identify tumor vascular volume and flow [47]. These gas-filled
(lipid-encapsulated) ultrasound-detectable microbubbles show enhanced regions of viable tumor with high
integrated blood flow and an increased extent of perfusion that is well correlated with CT-based estimates and
confirmed with histology. Decreased tumor flow parameters document microbubble-enhanced ultrasound
imaging response to treatment with antiangiogenic
agents. The promise of this innovative technology was
illustrated by a series of experiments providing proofof-concept for molecular imaging and drug delivery
applications. Ligand-specific targeting of liposomeencapsulated fluorocarbon gas microbubbles provided
a two- to three-fold increase in tumor vascular localization identifiable by ultrasound when compared to control microbubble treatments. When ultrasound is applied, labeled microbubbles are concentrated up to 30fold in targeted vessels in vitro and up to six-fold in vivo. Deflection of the ligand-bearing bubble away from
the vascular flow onto the vessel wall by the ultrasound
force pulse is thought to be the mechanism behind this
concentration phenomenon. By further increasing the
ultrasound force, drug- or gene-loaded nanoparticles or
multiplayer liposome shells could undergo enhanced
extravasation into the tumor parenchyma rather than
9
passive infiltration/diffusion from the tumor vascular
bed. This insonification technique is thought to deliver
more drug, and, therefore, potentiate cell death within the region of ultrasound treatment. In a preclinical model, rats with bilateral subcutaneous tumor implants infused with paclitaxel-containing nanoparticles
showed decreased tumor growth rate on their insonated
side. Development of new, high-power, multi-modality
ultrasound transducer probe arrays to permit simultaneous or sequential imaging, radiation force, or fragmentative operation modes, will be important in bringing
this new technology to the clinic.
Dr. Sergio Fantini, Tufts University, discussed nearinfrared spectral imaging for breast cancer. Optical
imaging has been used to identify and display the vascular network of the breast, usually by exploiting the
absorption spectrum of hemoglobin (690 nm) that provides spatial separation from other normal breast components such as lipids and water. This technology
makes increased vessel density at a tumor site apparent. Images can be enhanced by increasing density of
two-dimensional arrays of illumination sources and detectors, or by using a phased-array intensity approach
to achieve increased depth discrimination. In addition,
multiple wavelength information from this system can
potentially assess mammary tumor oxygenation [63]
by examining hemoglobin oxygen saturation spectra at
750–856 nm. Tumor hypoxia increases in more aggressive tumors that may be largely dependent on anaerobic
metabolism for growth. As a result of modeling the
optical spectral signal at various levels of hemoglobin
oxygenation, the next-generation instrument will image oximetry data largely independent of tumor size,
shape, and depth within the breast.
Dr. Mitchell Schnall, University of Pennsylvania, reviewed use of MRI to detect and direct appropriate
therapy in breast cancer, and compared its sensitivity to
that of ultrasound and mammography. As confirmed by
biopsy in several single and multicenter studies, MRI,
especially when used with contrast enhancement, is superior to other imaging methods in detecting multicentric and multifocal disease [13,101,108,218]. Instances
in which other modalities out-performed MRI included 12% of cancers that did not show contrast enhancement, typically DCIS lesions or invasive cancers identified through calcification. Lack of MRI enhancement
still had a 94% negative predictive value for the presence of invasive cancer [172]. MRI can improve identification of candidates for breast-conserving therapy by
eliminating those with multifocal lesions beyond the
primary tumor field [78] and providing guidance on un-
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
dertaking adjunctive chemohormonal or radiation therapy. Another application of MRI is in guiding treatment planning and targeting focal breast tumor ablation
therapy. Focused ultrasound (FUS) provides a noninvasive thermal ablation effect within breast tissue by
using sonication to raise tissue temperatures, creating
a circumscribed area of tumor necrosis while sparing
external and adjacent normal tissues. Real-time MRI
can monitor tissue-heating progress and follow-up MRI
can estimate the extent and success of FUS-induced
necrosis. In an initial clinical trial, results predicted by
MRI visualization were highly correlated with biopsy
findings from the ablation site [58,94].
2.4. Prostate cancer
Dr. Eric Klein, The Cleveland Clinic, provided an
overview of current incidence and prevalence data on
prostate cancer, shared some current concepts regarding risk factors and etiology of the disease, and detailed available or pending findings from recent large
screening and intervention trials with the potential to
influence standard of care and development of imaging
technology.
In the Western world, one in seven men older than 70
will develop prostate cancer. Though prostate-specific
antigen (PSA) screening means most men will now
be diagnosed with early disease (85% not palpable on
digital rectal exam (DRE), fewer grade 8–10 Gleason
score tumors, etc.), significant debate still exists regarding which tumors are biologically significant and
clinically relevant. Infection and/or inflammation are
hypothesized to be the basis for prostate carcinogenesis, whether driven by an infectious agent [209] or by
dietary or environmental exposure to substances that
cause oxidative stress and chronic inflammation [140].
A number of prostate cancer susceptibility genes control or regulate pathways associated with cellular defense; intervention with protective agents such as nonsteroidal antiinflammatory (NSAIDs) drugs or freeradical scavenging drugs hold promise for primary
prevention or as adjuncts to other therapies. Managing more advanced, extraglandular disease, or biochemical failure after radical prostatectomy or external beam radiation, remains problematic; challenges
remain in imaging disease stage and progression associated with these distinct classes of cases [99,187].
A wealth of fundamental data soon to be available
from large screening trials (e.g., European Organization of Research and Treatment of Cancer (EORTC),
or Prostate, Lung, Colorectal, and Ovarian Cancer
(PLCO)), and implications for prevention science from
recent findings of hormone antagonist studies such as
the Prostate Cancer Prevention Trial (PCPT) [204] and
toremifene [157,190], should stimulate new ways of
thinking about treatment and diagnosis in urology and
imaging communities.
Dr. Angelo De Marzo, Johns Hopkins University, detailed pathological considerations in establishing
prostate cancer diagnoses and the need for precision
imaging procedures in this process. More than a million trans-rectal ultrasound (TRUS)-guided biopsies are
performed in the US every year, typically as a result
of DRE and/or PSA elevation. Although sophisticated
prostate volumetric mapping tools can more accurately
direct placement of multiple-needle core biopsies into transitional, peripheral, and central prostate zones
(thought to have differential risks of tumor development), this blind sampling often misses known cancer lesions. Progression to adenocarcinoma is now believed to originate in precursor lesions such as proliferative inflammatory atrophy (PIA), proceeding through
high-grade prostatic intraepithelial neoplasia (HGPIN)
to higher and higher Gleason grade cancers [34,140].
Evidence for this progression model has been bolstered
by morphological mapping studies,immunohistochemical studies, and molecular biology studies [34]. All
stages of carcinogenesis may be seen in a single core
biopsy or a series of cores. A diagnosis of cancer
(∼10–30% of all biopsies) then requires determination
of features such as tumor type, Gleason score for each
positive core, number of positive cores, and percent of
core involvement before treatment strategies (hormonal
therapy, prostatectomy, radiation) can be recommended. Imaging modalities that could identify highly suspicious areas within the prostate would be very helpful for
directing the location in which the biopsy cores are taken. Additional quantitative tissue histomorphometry
and nuclear morphometry derived from image analysis
would improve the overall assessment of tumor presence/absence, extent, and Gleason grade [214]. Better
accuracy in determination of disease status and severity would allow for more informed choices regarding
treatment or watchful waiting and thus could reduce
unnecessary procedures and treatments caused by overdiagnosis.
Among imaging methods, dynamic contrast-enhanced (DCE) MRI with 3 Tesla scanners has potential for improving diagnosis and prognostic accuracy
in prostate cancer. Dr. Iclal Ocak of the NCI Molecular Imaging Program discussed the use of MRI techniques in evaluating disease, noting that the hetero-
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
geneity of disease ranging from very indolent to highly aggressive presents a quandary for therapy selection
that may be addressed with improved imaging methods. Addition of the endorectal coil to the 3 Tesla scanner imaging protocol increases the signal available, reduces noise from other anatomical sites, and most patients tolerate it well. These new generation 3 Tesla MR scanners, used with dynamic contrast material
injection have increased sensitivity and specificity of
the T2-weighted image with improved signal to noise
ratios [32]. Prostate and other tumor vasculature often has an altered morphology and increased permeability relative to surrounding normal tissue parenchyma [128]. As a result, tumor area shows early wash-in
and early wash-out of contrast agent due to increased
permeability and leakiness of pathologic tumor vessels.
DCE-MRI with the current SENSE (sensitivity encoding) protocol [210] correlated with biopsy or prostatectomy data holds promise for developing a tool to distinguish tumor foci by detection of early enhancement
and early clearance of contrast agent from the extravascular extracellular tumor microenvironment. Magnetic
resonance spectroscopy (MRS) has also shown great
potential in the localization, staging, and assessment of
aggressiveness of prostate cancer, which is characterized by reduced levels of citrate and polyamines, and
increased level of choline in proton MRSI (magnetic resonance spectroscopy imaging). The differences
in concentration of metabolites have been attributed
to increased phospholipid turnover associated with increased tumor cell proliferation and increased cellularity within the tumor foci [31]. The higher field scanners
also have advantages for MRSI in prostate cancer detection due to higher spectral/spatial resolution and decreased temporal resolution compared with lower field
scanners. The increase in spectral resolution at 3 Tesla using an endorectal coil may offer better separation
of choline, polyamine, and creatine peaks that overlap
considerably at lower Tesla. Thus, MRSI has the potential to significantly improve metabolic assessment
of prostate cancer. MRI with an endorectal coil at 3
Tesla remains to be the most promising tool for stratification of patients toward “watchful waiting,” standard
therapy, or more aggressive treatment.
Because ultrasound and MRS approaches sense fundamentally different properties within prostate tissue
(mechanical and chemical), combining the two techniques could be synergistic for improving classification
of prostate cancer risk. Dr. Jeffery Ketterling discussed
collaboration between groups at Riverside Research Institute in New York City and Virginia Mason Medical
11
Center in Seattle. Using a clinical ultrasound data acquisition system, they are building a database of images
to be correlated with clinical case data and histologic
“truth” from biopsy and resection specimen archives.
Serving as a teaching set, their neural-network computer system incorporates data from 617 biopsies (83%
negative and 17% positive) derived from 64 patients
(64% benign diagnosis and 36% cancer), along with
relevant clinical data (age, PSA, etc.) and baseline
B-mode ultrasound scans. Subtle differences in tissue
histology microarchitecture displayed as unique scattering properties on ultrasound are believed to be correlated with and predictive of biopsy outcome. Incorporation of these factors in the current teaching set has
enhanced discrimination between cancerous and noncancerous tissue with a receiver operating characteristic (ROC) curve area of 0.84 compared to 0.64 obtained by ultrasound assessment alone. Similar ROC
curve areas have been obtained for tumor area classification with citrate/choline MRS [86]. Current efforts attempt to register ultrasound and MRS data into three-dimensional data sets and correlate combined
tissue-type profiles with prostatectomy histology.
Dr. Clare Tempany, Harvard Medical School, spoke
on evolution of MRI-guided diagnosis and therapy from brachytherapy seed placement developed in
the late 1990s [33] to current state-of-the-art techniques. Real-time intraoperative image fusion and
open-interventional magnet designs (e.g., GE Healthcare) with MRI-compatible needles and anesthesia now
guide robot-assisted prostate biopsy that is more accurate and reliable than TRUS procedures. This system allows for biopsies with MR guidance from multiparametric images such as H1 Proton spectroscopy or
DCE-MRI. As in breast cancer ablative therapy, FUS
is also seen as a non-invasive treatment alternative to
prostate cancer radiotherapy and surgical treatments.
MR-guided FUS approaches to prostate cancer follow
many of the same design principles learned from earlier studies on ultrasound surgery for uterine leiomyomas [203], where beam paths need to be calculated
to avoid bowel and bone, and staged rounds of sonication are used to obtain optimal heating using MR
thermometry to guide and directly monitor in real-time
the effective thermal ablation. Research is underway to
develop an MR-guided FUS device for prostate cancer
ablation. Trials have been performed in Europe with
over 460 men with low-risk localized prostate cancer
to be enrolled in the Ablatherm multicenter trial, which
will build on preceding successful early-phase investigations [55,119,207] as evidence needed for regulato-
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
ry approval for the Ablatherm instrument system and
procedure. Dr. Tempany concluded her presentation
by describing the advanced multi-modal image-guided
operating room with 3T MRI, PET/CT, and procedure
room (AMIGO GEHC) soon to be installed at Brigham
and Women’s Hospital.
2.5. Ovarian and pancreatic cancer
Drs. Michael Birrer, NCI Center for Cancer Research, and Margaret Tempero, University of California at San Francisco, reviewed cancers of the ovary
and pancreas, some of the most deadly and difficult
to detect. The occult nature and late-stage presentation of these cancers, and their lack of response to
most current forms of intervention, are in part due
to a dearth of reliable systemic biomarkers and good
imaging alternatives for early detection. In ovarian
cancer, five-year survival for stage I disease is 90%,
yet 70% of diagnoses occur at later stages of disease
where survival drops precipitously. Although certain
high-risk groups of women (those with family history
or BRCA 1/2 mutations) have been identified, vague
symptoms and no identifiable ovarian cancer precursor lesion confront public health practitioners and oncologists with the daunting prospect of mass population screening for a disease with low prevalence. The
best available imaging approach to date, transvaginal ultrasound/sonography (TVS), still lacks sensitivity
and specificity, though it can be somewhat improved
by adding CA125 serum marker to the screen [182].
Among 22,000 postmenopausal women randomized to
observation or annual CA125 testing followed by TVS
for abnormal serum results, comparable numbers of
ovarian cancers were detected in the observation (20)
and screening groups (16) at five-year follow-up [82].
However, while cancers detected with the screening
procedures were found at a significantly early stage,and
surgical intervention improved overall survival in the
screening group to 73 months, compared to 42 months
in observation controls (p = 0.0112), the number of
deaths from an index cancer did not differ significantly
between groups (p = 0.083; 95% CI 0.78–5.13). In
addition, incorporating the CA125 test into the already
insensitive TVS screen creates difficulties due to false
positive serum elevations also seen with other cancers
and gynecologic conditions (e.g., breast, pancreatic,
and endometrial cancer; pelvic inflammatory disease;
uterine leiomyomata; endometriosis; menstrual variance; pregnancy). When CA125 was coupled to TVS
as a first screen in ∼14,500 postmenopausal women,
1.2% of participants (180) were referred to surgery, but
only 17 ovarian cancers were found (though most were
early-stage disease) [212]. This 10:1 ratio of surgical
risks incurred per cancer detected suggests that routine
screening of low-risk women in this manner should
not be recommended. Currently, results of a definitive large group trial of CA125 and TVS screening in
77,000 women is pending as part of the NCI, PLCO
study.
Several incremental improvements and alternatives
to these standard methods for imaging adnexal masses
in women have also been evaluated. Adding Doppler
imaging to TVS has been explored for its ability to detect tumor-specific angiogenesis and increased blood
flow. A meta-analysis of a large number of studies
found that TVS morphology combined with Doppler
imaging is significantly better at differentiating ovarian cancer from benign conditions (e.g., dermoid cyst,
endometriosis, cystoma, pelvic inflammatory disease)
than TVS alone [98]. Three-dimensional (3D) reconstruction and multiplanar volume-rendering displays of
ultrasound data improve definition of adnexal masses
and their relationship to internal anatomical structures.
Data also support increasing specificity by confirmatory use of other imaging modalities such as CT or MRI
after initial TVS/Doppler screening [102]. PET and
SPECT scanning methods with metabolic ( 18 -FDG),
proliferative ( 18 -F-fluorothymidine), or hypoxia (misonidazole) tracers have also been assessed for identifying ovarian cancer in both clinical and preclinical
studies [69,112,131,194].
A similar lack of early symptoms, early invasion and
metastasis, and chemoresistance characterize pancreatic cancer; more than 80% of patients are diagnosed with
advanced or unresectable disease. With a cure rate of
only 4–5%, and a median survival of only about three
months for patients without treatment, pancreatic cancer was described by Dr. Tempero as the Mount Everest of cancer diagnosis and treatment problems. Some
hints for screening strategies have come from epidemiologic associations shown for smoking, diabetes, and
obesity, and genetic factors such as hereditary pancreatitis, BRCA2, HNPCC, and Li-Fraumeni syndromes.
Due to significant advances in understanding the molecular pathogenesis of pancreatic cancer, a candidate pancreatic intraepithelial neoplastic (PanIN) precursor has
been proposed [80]. Various oncogene activation or
overexpression events (e.g., K-ras, epidermal growth
factor receptor (EGFR)), tumor suppressor pathway
mutations or derangements (p53, p16, SMAD), and
other processes in the microenvironment affecting in-
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
vasion and metastasis (angiogenesis, desmoplasia, inflammation, etc.) in pancreatic cancer provide opportunities to apply these discoveries to improve early detection and treatment. Using appropriate risk stratification, it might be possible to deploy endoscopic ultrasound for early surveillance, followed by endoscopic retrograde cholangiopancreatography. As we identify more cases of early stage disease, we can build
a biorepository of serum and normal DNA, pancreatic
duct juice, and preinvasive and invasive tumor tissue
for molecular and proteomic analysis. The uniquely
hypoxic microenvironment of pancreatic cancer also
suggests ways to exploit this phenomenon to develop
imaging probes. New and better animal models of pancreatic cancer [2,74] provide test environments to evaluate these rationally designed diagnostic and treatment
candidates.
2.6. Lung cancer
Dr. Stephen Lam, British Columbia Cancer Agency, introduced an examination of lung cancer by describing sequential histological stages seen during lung
carcinogenesis, characterized by variations in nuclear
size, shape, and staining properties of epithelial cells.
Pathologically, lesions are graded as squamous metaplasia, mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ, and cancer; dysplasia level
correlates with malignant potential. Numerous genetic
changes occur in addition to histopathological changes.
Studies have shown that 1.2–3.5% of moderate dysplasia, 8–50% of severe dysplasia, and 25–100% of carcinoma in situ will progress to invasive cancer within
two years [18,20,79,83,104,135,170,215].
The epithelial surface of the lung is complex, consisting of a branching system of airways leading to gas
exchange units with surface area the size of a tennis
court. Lung cancer consists of several cell types that are
preferentially located in different parts of the bronchial
tree. No imaging modalities can visualize the whole
surface of the lung and allow tissue sampling for pathological diagnosis and molecular profiling. Autofluorescence bronchoscopy has provided the first good method
for detecting high-grade intraepithelial neoplasia (IEN)
and obtaining biopsies in the central airways. However, biopsy may completely remove small lesions, giving the false impression that drug intervention has regressed IEN or that the majority of IEN lesions regress
spontaneously.
Progress has been made in developing other optical
imaging methods to characterize these lesions without
13
removing them. Confocal microendoscopy, a highspeed scanning system with an ultra-sensitive detector
and near-video frame rate, can be combined with autofluorescence to allow visual differentiation of the border between normal and abnormal epithelium [18]. Reflectance confocal microendoscopy allows cell-by-cell
delineation [118]. Finally, large surfaces of epithelia
can be scanned simultaneously using optical coherence
tomography (OCT) [206] (see also under Skin Cancer).
Important challenges still exist in detecting and preventing neoplastic lung lesions, including identifying
and managing peripheral adenocarcinoma. CT of the
chest is a sensitive method to detect peripheral IEN lesions beyond the visual range of current fiberoptic bronchoscopes. Recently developed external navigational
systems make it feasible to biopsy the peripheral airway
under CT guidance, resulting in a better understanding of progression pathways of non-squamous lesions.
Coupling microendoscopy with CT imaging may also
be useful for following peripheral lesion progression
non-invasively.
Twenty-five percent of cured lung cancer patients
will get a second cancer in five years. Detection of
early lesions does not necessarily discriminate which
are premalignant. A possible solution would find nodules in at-risk patients, determine which are malignant
versus benign using optical techniques, and ablate malignant nodules. The process would be repeated every
few years.
Potential advances in lung cancer treatment include
use of inhalational chemotherapy, possibly combined
with imaging techniques to determine if treatment has
reached target lesions.
Dr. Eric J. Seibel, University of Washington, described two new instruments under development that
use current technologies for in vitro lung cancer screening and IGIs: optical projection tomography microscopy (OPTM) and scanning fiber endoscopy (SFE).
OPTM generates 3D images with submicron and isometric resolution of cells and nuclei from cell suspensions injected into a rotating capillary tube. This multiperspective image collection allows automated detection of nuclear abnormalities based on 3D tomographic
reconstruction. The technology is similar to CT, using
optics instead of x-rays. Ultimately, this instrument
approach will be applied to image whole cells isolated
from sputum samples and FNA.
SFE generates images in vivo using an ultra-thin
and flexible catheter-like probe. Red, green, and blue
(RGB) laser light (635, 532, and 442 nm) are combined
into a single-mode optical fiber, the distal tip of which
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
is driven at mechanical resonance of 5 kHz. The fiber
scanner generates 500-line images at 15 Hz by scanning the RGB laser light in a spiral pattern from the
distal tip. The backscattered light is collected from the
80◦ scanned field by a ring of 12 plastic optical fibers
that surround the fiber scanner. The current prototype
probe is 1.6 mm in diameter. By using alternative lightcollection methods, future prototypes will be as small
as 1.0 mm in diameter.
A custom guidance system being tested in pigs introduces SFE through the working channel of a standard
bronchoscope while being directed by a guide wire.
The interactive 3D user interface has been developed to
perform five functions: Automated segmentation and
virtual rendering of airways from a chest CT scan; virtual bronchoscopic navigation of airway anatomy and
path-planning for biopsy; real-time tracking and display of the endoscope tip using an electromagnetic sensor; cell sampling in the more peripheral lung under
direct video imaging; and automated annotation of procedural events, including 3D path, optical diagnoses,
and biopsy locations. SFE probe components are low
in cost, allowing high-volume manufacturing and disposability.
Dr. Pierre Massion, Vanderbilt University, discussed
approaches to solving one of the biggest problems in
lung cancer research: Why do only 10–15% of smokers, and only 8% of patients with lung dysplasia, go on
to develop lung cancer? Genomic and proteomic technologies may improve our understanding of this disease
by allowing rapid and complete analysis of genome
and proteome expressed in a given cell or tissue type.
For cancer, differential profiling can determine if the
genomic and/or proteomic profile of a set of cancers
differs from a set of normal tissues or from one another.
In addition, genome and proteome expression profiles
have the potential to improve clinical management of
lung cancer by improving classification or providing
data to develop a diagnostic classifier or identify new
molecular diagnostic and therapeutic targets [64].
Matrix-assisted laser desorption ionization mass
spectrometry (MALDI-MS) creates molecular weightannotated patterns keyed to tissue location, providing proteomic profiles that allow clear delineation of
high-grade versus low-grade dysplasia, and preinvasive
versus invasive neoplasia [160,191,226]. MALDI-MS
profiling may help determine which preinvasive lesions
are likely to develop into lung cancer. Potential clinical
applications include biomarker discovery, tumor biology, and validation of targets found using other imaging
technologies.
Areas of further development include increasing the
number of proteins analyzed and pixel-to-pixel cycle
time, integrating bioinformatic tools and image processing, and developing sample protocols targeted at
specific tissues/diseases. Further bioinformatics development is also needed to improve rapid protein identification protocols, create a test pattern recognition algorithm to classify samples, and validate biomarker
candidates prospectively in case-cohort studies.
Dr. Geoffrey McLennan,University of Iowa, reminded the audience that although biopsy is the gold standard for diagnosing lung cancer, information about a
patient’s lung cancer risk obtained from biopsy is often
incomplete. The paradox of lung cancer is that small
peripheral lung cancers can be found by multidetector computed tomography (MDCT), but not diagnosed
easily. The natural history of small peripheral lung
cancers remains uncertain and therapeutic options are
unsatisfactory. Most detected nodules suspicious for
lung cancer represent noncancerous disease. Unlike
other organs, the lung presents specific imaging problems because of motion associated with breathing and
cardiac oscillation in the left lower lung. A further
barrier to developing better imaging methods for lung
nodules is the current lack of understanding regarding
their pathological structure and function as related to
3D imaging [46]. Determining how much of a lung
nodule is cancer and how it is organized appears critical
for further development of more specific imaging and
treatment strategies.
External magnetic guidance allows access to nearly 100% of peripheral nodules using a combination of
technologies. Digital imaging allows rapid fine manipulation into a precise location within the lesion through
magnetic guidance. Device placement can also be verified through magnetic tracking, with secondary fluoroscopic verification. Confocal or other microscopy can
allow macro- or micro-optical sampling of the lesion.
Finally, if the lesion is considered possibly malignant,
ablation can be performed. Magnetic guidance can also stabilize a device for real-time microscopy. These
methods have all been developed, and some have been
tested in clinical research studies [68,174].
Dr. Kevin Cleary, Georgetown University, discussed
the challenges of biopsying the lung, including pneumothorax, cumbersome Z-frame and remote center of
motion (RCM), cardiac motion, and ribs in the path
of needle insertion. Robotic devices are capable of
tracking lesions and compensating for lung motion in
real time with lower radiation doses to physicians and
higher accuracy. In addition, robotic systems have the
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
potential to achieve the same reach and dexterity as the
human hand.
A collaboration between the Computer Aided Interventions and Medical Robotics (CAIMR) group at
Georgetown University, the Urology Robotics Laboratory at Johns Hopkins Bayview Medical Center, and the
Department of Radiology at the University of Maryland Medical Center, is developing a robotic system to
assist the physician in accurate CT fluoroscopy-guided
needle biopsy of lung nodules. Completed first-phase
testing focused on demonstrating the feasibility of using a joystick-controlled robotic “needle driver” to accurately hit simulated lesions in a phantom under CT
fluoroscopy guidance. Initial results showed feasibility
of motion tracking. However, current robotic technology is not capable of releasing the needle. The second phase involves developing an enhanced gripper and
new end-effector that spins and releases the needle to
minimize the force needed for needle placement. This
phase is currently under development and will be tested
first in phantom studies and then animal studies.
Dr. Robert Suh, University of California, Los Angeles, discussed the use of percutaneous transthoracic
needle biopsy (TNB) for diagnosing pulmonary nodules. It allows previously inaccessible lesions to be
sampled and tissue to be retrieved for histologic diagnosis [100]. Image guidance techniques, i.e., fluoroscopy, ultrasound, CT, and CT fluoroscopy, can be
combined with TNB to improve accuracy of biopsy and
treatment.
For example, only approximately 15% of patients
diagnosed with lung cancer are surgical candidates.
Though some patients have technically resectable disease, they cannot undergo surgical resection because of
co-morbid cardiopulmonary disease. This latter patient
population represents a suitable target for novel, minimally invasive “lung-sparing” therapies that could provide local control. Several minimally invasive imageguided thermal ablation techniques treat cancer by applying intense heat through a small probe inserted directly into the tumor.
Types of thermal energy include RF, microwave,
laser, and cryoablation. RF ablation has been the best
developed, secondary to the advent of bipolar, multielectrode, and internal tip-cooling RF electrodes [109].
Pulmonary RF ablation allows safe thermal ablation
of pulmonary metastases with a low complication rate
and acceptable tumor control rate [216]. Percutaneous
microwave therapy is also a safe new treatment for
lung cancer, achieving a marked effect with minimum
trauma [45]. Percutaneous cryoablation therapy for
15
metastatic lung tumors is feasible and minimally invasive, with satisfactory local control [90].
Further areas of development for thermal ablation
in lung cancer diagnosis and treatment include use of
neo-adjuvant and adjuvant therapies (e.g., radiotherapy, brachytherapy, and chemotherapy), generating additional data through prospective and randomized trials designed to improve patient selection, refining image guidance and energy delivery, and providing postthermal ablation follow-up.
Gene expression profiles of tumors may predict treatment response and outcome. A recent study was performed of molecular signatures in lung cancer biopsy
specimens obtained from 23 patients undergoing CTguided transthoracic biopsy or endobronchial brushing
for undiagnosed nodules [17]. It was hypothesized that
profiles derived from lung tumor biopsies would discriminate tumor-specific gene signatures and provide
predictive information about outcome. Class prediction models for lung cancer histology and for cancer
outcome produced a histology model that identified 99
genes differentially expressed by lung cancer subtypes
and an outcome model that identified 42 genes associated with high risk for cancer death within 12 months.
It was concluded that gene expression profiles of lung
cancer biopsy specimens identify unique tumoral signatures that provide information about tissue morphology and prognosis. Specimens acquired by imageguided lung biopsy, used to identify biomarkers of clinical outcome, may assist in managing care of lung cancer patients. Prospective clinical trials are needed to
determine efficacy and utility.
2.7. Colon cancer
Dr. Randall Burt, University of Utah, presented an
overview of colon cancer etiology and current opportunities for its detection and treatment. About one in
17 persons in the US will get colon cancer in their
lifetime. Risk factors include advanced age, ulcerative colitis, previous adenoma or cancer diagnosis,
a high red meat/high fat diet, pelvic irradiation, alcohol or cigarette use, obesity, tall stature, cholecystectomy, and high sucrose consumption [26,71,114,
156]. Colon cancer risk may be reduced 20–30% with
a high vegetable/fruit diet, a high-fiber diet, high folate/methionine intake, high calcium intake, or hormone replacement, but prospective intervention studies
with several of these agents have shown that vitamins
C and E, selenium, β-carotene, and high-fiber, low-fat,
optimal-nutrition diets provide no protection against
16
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
developing colon cancer [71]. However, calcium, aspirin, and cyclooxygenase (COX)-2 inhibitors provide
significant protection; risk reduction of at least 60%
is associated with physical activity or aspirin/NSAID
use [6,15,71,123].
Most colon cancers arise from adenomatous polyps.
Polyp-to-cancer evolution can take 10 to 20 years;
therefore, most colon cancer screening is actually colon
adenoma screening. The risk of an adenoma developing into cancer depends on polyp size, shape, and
histology.
While the majority of colon cancers arise sporadically, up to 33% may be inherited, but with less than 5%
associated with rare colon cancer syndromes [26,114].
Understanding the molecular pathogenesis of colon
cancer began with discovering the adenomatous polyposis coli (APC) gene, a tumor suppressor gene that
is mutated in familial adenomatous polyposis (FAP), a
rare inherited syndrome. Somatic APC mutations are
also found; > 80% of all colon cancer may result from
an initial APC gene mutation. Polyp-to-malignancy
progression involves mutation of multiple additional
genes, including K-ras, p53 and others [156]. Another
rare syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), arises from mutations of mismatch repair
(MMR) genes. Fifteen per cent of sporadic colon cancers also exhibit somatic inactivation of MMR genes.
Symptoms of colon cancer range from rectal bleeding and abdominal pain to changes in bowel habits,
weight loss, and decreased appetite. Symptoms are unusual in stage I or II cancer; but if detected in those
stages, chances of survival are > 80%. However, in
stage III or IV, symptoms are common and the chances
of survival are < 30%. Overall five-year survival is
now 64%, up from 50% in 1974.
Current screening guidelines for average-risk persons age 50 and older include annual fecal occult
blood testing (FOBT), flexible sigmoidoscopy every
five years, barium enema every five to 10 years, or
colonoscopy every 10 years [162]. Individuals with
a positive family history are recommended to begin
screening at age 40 with any of the above tests. In the
setting of a strong family history, defined as colon cancer in a first-degree relative at < 50 years, or two affected first-degree relatives, screening should be done
by colonoscopy, and begin at age 40 years or 10 years
younger than the earliest diagnosis in the family. An
extensive family history should be obtained if a strong
family history is present in immediate relatives, and if
indicated, genetic testing and special surveillance may
be necessary.
Patient-acceptable, non-invasive screening for colon
cancer is needed. Colonoscopy, though a great tool,
requires more resources and trained gastroenterologists
than will likely be available in the foreseeable future.
Current advances in screening include immunohistochemical FOBT [228] and stool DNA testing [8]. Virtual colonoscopy is an exciting new technique which
may become part of regular colon cancer screening in
the future [138]. In this new procedure, CT images of
the patient’s abdomen are used with a computer visualization system to virtually navigate within a constructed 3D model of the colon. This technology has the
potential to be accurate, cost-effective, non-invasive,
and comfortable for screening large segments of the
population.
The standard of care for treatment for stages I–
III colon cancer is surgery with adjuvant or neoadjuvant chemo-radiation therapy for stages II and
III rectal cancers, and adjuvant chemotherapy for
stage III and selected cases of stage II colon cancer. The standard of care for stage IV colon cancer is chemotherapy with surgery in selected cases
and adjuvant or neo-adjuvant chemo-radiation therapy if rectal. Fluorouracil/leucovorin with oxaliplatin or irinotecan (FOLFOX and FOLFIRI) is the
most effective chemotherapy regimen for stage III
and IV colon cancers [143,197]. The anti-EGFR
and anti-vascular endothelial growth factor (VEGF)
monoclonal antibodies cetuximab (Erbitux ) and bevacizumab (Avastin ), respectively, and oral fluoropyrimidines (e.g., capecitabine) are new treatment
agents that appear to further improve colon cancer outcomes. In addition, agents under development include other anti-VEGF monoclonal antibodies, other anti-angiogenesis compounds, tyrosine kinase inhibitors (TKI), and anti-EGFR or anti-carcino embryonic antigen vaccines [116].
One goal in studies of precancer and early cancer is
to precisely isolate susceptibility, using currently available predictive biomarkers and imaging tools. At-risk
patients would be identified through serum testing or
imaging using a broad spectrum of genetic markers.
However, specific markers not have been identified yet,
and it is too early to tell which will be most important.
Efforts in the field aim to develop beacon markers and
biomarker panels. Patients with specific markers would
then need aggressive screening using improved wholebody surveillance. Also needed are probes that would
be useful for spatially locating lesions together with
different types of validation methodologies. Recently, attention has been paid to biomarkers for prognosis
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
(methylation markers, CIMP, BRAF, MSI, BAX, TGFβ1, SMAD, p53, and WAF1), diagnosis (Galectin-3
and NF1), and drug study (aberrant crypt foci) [19,
219].
Dr. Ruth Pfeiffer, NCI, described development of
a colorectal cancer risk assessment tool [25,30,183–
186]. A statistical model was developed to estimate
the probability of first incidence of proximal, distal,
and rectal cancer in white men and women ages 50 and
older. Using logistic regression, relative risk was estimated separately for proximal, distal, and rectal cancer for a number of previously identified risk and protective factors (e.g., history of polyps, family history
of colorectal cancer, smoking, body mass index, hormone replacement therapy, vegetable intake, vigorous
exercise, regular aspirin/NSAID use, sigmoidoscopy in
last 10 years). Data on white men and women ages
50 was taken from two large population-based casecontrol colon cancer studies. Age-specific incidence
rates from the Surveillance Epidemiology and End Results (SEER) study were used to compute baseline agespecific hazard rates. National mortality rates were
used to estimate the hazard for competing causes of
death. Relative risk estimates and risk factors differed
among proximal, distal, and rectal cancer sites. Future
plans include validation of the risk model in several
large cohort studies, extension of the model to blacks
and Hispanics using SEER baseline hazard rates, and
distribution of a colorectal cancer risk assessment questionnaire for further testing and development [50].
Recently, researchers have been linking carcinogenesis and the Warburg effect, indicating that bioenergetics may lie at the heart of malignant transformation [54,
127]. It is now known that FDG uptake in colon, previously thought to be an incidental physiological finding, is associated with pathologic processes including
malignancy in a majority of instances. Dr. John Hoffman, University of Utah, described several studies that
confirmed that the presence of focal colonic FDG uptake on PET or PET/CT scan justifies a colonoscopy
to detect premalignant or malignant lesions. The more
metabolically active the polyp, the greater malignant
potential exists.
A study of incidental colonic FDG uptake in 15
patients and its correlation with colonoscopic and
histopathologic findings [201] concluded that nodular
high FDG uptake (on a four-point scale) implies at least
a 79% chance of abnormal histopathology. Another
evaluation of (pre-)malignant colonic abnormalities in
39 patients for endoscopic validation of FDG-PET [37]
found that, compared with colonoscopy, FDG-PET had
17
sensitivity of 74%, specificity of 84%, and positive predictive value of 78%, though it failed to detect small
polyps in four patients. Further, in a study of wholebody PET/CT tumor staging with integrated PET/CT
colonography [213], PET/CT colonography proved accurate in local lymph node staging and staged nine out
of 11 patients correctly. In addition, six additional extracolonic tumor sites were detected based on wholebody staging.
In certain populations at risk, such as patients with
FAP and attenuated FAP, the use of FDG-PET/CT
and FDG-PET/CT virtual colonoscopy may allow for
less invasive surveillance and assessment of overall
polyp burden as well as detection of advanced lesions in the stomach and small bowel in addition to
colon [227]. A study of FDG-PET’s ability to detect cancers in FAP patients and its impact on clinical management [211] found that it detected all cancers present; no patients with negative FDG-PET developed cancer. This suggests that positive FDG-PET
in FAP patients should lead to further examinations to
rule out cancer, and seems to justify a more conservative approach in patients with negative FDG-PET.
Careful study and validation of this technique is still
needed. Virtual colonoscopy is a less onerous potential screening tool than colonoscopy for surveillance
of both routine and high-risk populations. Combining
anatomic detail from virtual colonoscopy with metabolic information obtained through FDG may improve accuracy over either test alone. It is doubtful that FDGPET/CT virtual colonoscopy would replace standard
colonoscopy. However, it may prove useful as adjunct to assist surveillance in these complicated patient
groups.
Dr. Hemant Roy, Evanston-Northwestern Healthcare, maintained that screening the entire average-risk
population (more than 70 million Americans over the
age of 50) for colon cancer is impractical given the expense, lack of sufficient endoscopic capacity, and complication rates [103]. Therefore, limiting colonoscopy
to those patients who harbor polyps/carcinoma is essential for efficacious and cost-effective colorectal cancer
screening.
Many risk-stratification techniques currently exploit the field effect, which proposes that the genetic/environmental milieu leading to tumorigenesis in one
area of the colon should be detectable in some form
throughout the colon. The presence of a carcinogenic
field effect or malignancy-associated changes can be
inferred from finding distal focal neoplastic lesions
(predictive of proximal lesions) and diffuse alterations
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
in histologically normal mucosa [14,29,67,155,199].
However, these current field effect markers lack sensitivity and, therefore, require expansion and additional
development to improve diagnostic precision.
Light scattering, using the scattering angle and intensity of light at a particular wavelength to determine the size and structure of particles [96,169], is
sensitive to particles 10–20 times smaller than regular microscopy. The new generation of light-scattering
technology provides quantitative assessment of microarchitecture by four dimensional analyses including
wavelength of light, scattering angle, azimuthal angle
of scattering, and polarization of scattered light.
Two novel light-scattering technologies,four-dimensional elastic light-scattering fingerprinting (4D-ELF),
and low-coherence enhanced backscattering spectroscopy (LEBS), allow quantitative assessment of the
nanoscale architecture of cells, providing a practical
marker for genetic/epigenetic changes of the field. Initial studies in two experimental animal models indicated that altered light-scattering signatures from histologically normal mucosa preceded the earliest conventional markers of colon carcinogenesis [168].
Initial clinical studies have been conducted with support from NCI and the National Science Foundation.
Current data collected from > 200 patients indicate
that 4D-ELF analysis has > 90% accuracy in identifying risk of colon polyps/cancers [168]. Spectral markers are also being used to evaluate familial syndromes
such as FAP and HNPCC. In sporadic lesion risk stratification, free-standing probes would be developed to
use in conjunction with current screening techniques
by physicians during annual physical exams; the probe
would be inserted into the rectum similarly to taking a
rectal temperature.
Dr. Thomas Wang, Stanford University, described
the uses of in vivo molecular colon imaging, including
understanding the dynamic behavior of mucosa, observing spatial relationships in situ, and guiding and
monitoring response to therapy.
Candidate dysplasia-binding peptides have been
identified as imaging probes using phage display [28,
192]. Phage display provides a highly complex library
of peptides that can be screened to identify ligands
that preferentially bind to molecular markers of disease. Advantages of using small peptides as probes include low immunogenicity, short plasma half-life, high
diversity, good mucosal penetration, and easy synthesis. These peptides can be conjugated to fluorescent
molecules, permitting optical visualization of dysplasia
in vivo by confocal microendoscopy.
Potential targets in the colon include cell junction,
anti-apoptosis, cell growth, and cell proliferation markers. Clinical endpoints include detecting dysplasia,
identifying tumor margins, assessing stage of transformation, and performing risk stratification. This will require validation of results with immunohistochemistry
to confirm the identity of peptide binding biomarkers.
2.8. Head and neck cancers
Drs. Vali Papadimitrakopoulou and Walter Hittelman, University of Texas MD Anderson Cancer Center, discussed the detection of head and neck carcinogenesis. Dr. Papadimitrakopoulou described several
limitations to current oral cancer screening methods
that could be addressed by imaging, including overreliance on clinical experience for visual recognition,
mimicking of early neoplastic lesions by more common benign lesions, and reluctance of many patients
to undergo biopsy. Vital dye staining has been used
to increase sensitivity, but has low specificity and also requires expertise. Using brush biopsy for cytology delays diagnosis and has an unknown false negative rate. Optical technologies like fluorescence spectroscopy are promising ways to detect the changes in
autofluorescence associated with carcinogenesis.
Identification of biomarkers that could serve as risk
predictors has benefited from producing several candidates. Among the most significant are genetic instability in the form of chromosomal polysomy and aneuploidy, overexpression of cyclin D1 and EGFR, and
allelic losses at 3p and 9p, and p53 alterations [76,81,
110,147,166,167].
Current chemoprevention studies involve interventions targeted toward p53 abnormalities and inflammation using selective COX-2 inhibitors, natural products
such as green tea components (epigallocatechin gallate
(EGCG) and green tea catechins), and EGFR kinase
inhibitors [132,222,223]. EGCG inhibits activation of
HER-2/neu and downstream pathways in human head
and neck and breast carcinoma cells and inhibits activation of EGFR and downstream Stat3 and cyclin D1
promoter activity and level. Green tea catechins inhibit angiogenesis of human umbilical vein endothelial cells by inhibiting VEGFR, inhibit chemotaxis and
invasion, and induce apoptosis at high concentrations.
EGCG inhibits DNA methyltransferase and reactivates
methylation-silenced genes in cancer cell lines (e.g.,
p16, RARβ, MGMT, hMLH1).
Retinoid chemoprevention trials have found that
RARβ is up-regulated in oral premalignant lesions
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
(OPL) by retinoids, and up-regulation is correlated with
response. High-dose retinoids reverse oral leukoplakia
and prevent second primary head and neck tumors;
however, high doses of retinoids are too toxic for patients to take for long periods of time [51,115]. There
is a slow return to malignant phenotype when treatment
ceases. Low-dose retinoids are superior to β-carotene
for maintenance of leukoplakia remission.
Dr. Hittelman described the multistep process of field
cancerization and tumorigenesis in the upper aerodigestic tract and opportunities for imaging this process at
the molecular level by chromosomal in situ hybridization (CISH). Exposure of epithelium to carcinogenic
insults and cofactors results in chronic tissue damage
and wound repair. Early in the process, damaged tissue contains DNA adducts, mutations, and polysomy.
Further damage results in clonal formation and aneuploidy. Subsequently, the damaged tissue becomes
premalignant, characterized by clonal outgrowth and
clonal evolution. CISH techniques quantify levels of
genetic changes in head and neck tumors and adjacent
epithelium. Cells with abnormal chromosome copy
numbers are detected in normal-appearing epithelium
within the head and neck cancer field; the level of chromosome polysomy increases with histological progression to cancer [76,110].
Genomic instability increases during tumorigenesis.
Spatial genetic mapping studies indicate a process of
random chromosome instability and multifocal clonal outgrowth throughout the epithelium at cancer risk.
Chromosome instability is also detected in oral and laryngeal biopsies from leukoplakias [10,36,62,89,117,
141,142,145,158,202]. Individuals exhibiting high levels of chromosome instability have a high rate of subsequent cancer development. A study in the bronchial
epithelium of current and former smokers found that
genetic instability decreases as a function of time after smoking cessation, but chromosome indices remain
elevated [76]. These studies suggest that genetic instability is a driving force for head and neck tumorigenesis. Targeting processes that promote genetic instability may slow progression in head and neck cancer. Down-modulation of genetic instability may delay
time to cancer onset. Assessing ongoing genetic instability and clonal outgrowth may therefore be useful to
identify individuals at high cancer risk and monitor the
impact of chemopreventive intervention.
New approaches are needed to detect and treat OPL,
the precursor of oral cancer and indicator of increased
risk. However, no reliable clinical or histologic features identify OPL, and its natural history is variable.
19
Optical interrogation in vivo may provide improved understanding of the ways in which light interacts with
the structural and molecular changes of oral cavity neoplasia. Dr. Calum MacAulay, British Columbia Cancer
Research Center, described a simple hand-held optical
diagnostic tool designed to serve this purpose.
The visually enhanced lesion scope (VELScope TM)
illuminates the mouth with blue light, which excites
certain molecules in mucosal cells, causing them to absorb the light energy and re-emit it as visible fluorescence. Dysplastic cells emit dark green to black fluorescence, whereas normal tissue emits a pale green
fluorescence. The device has been tested in 44 people; in all but one instance, normal and abnormal tissue
could be distinguished correctly. The findings were
confirmed by biopsy and standard pathology [105].
2.9. Cervical cancer
Drs. Diane Solomon and Jose Jeronimo, NCI, explained that cervical cancer is the second most common
cause of cancer deaths in women worldwide. Most
cervical cancers are squamous and arise in the transformation zone. Cervical squamous abnormalities are described in cytologic terms as low-grade and high-grade
squamous intraepithelial lesions, and histologically as
cervical intraepithelial neoplasia (CIN) grades 1, 2, and
3. Approximately 25% of cervical cancers in the US
are adenocarcinomas arising in the endocervical canal,
less accessible by screening modalities than squamous
cancers.
Virtually all cervical cancer is caused by human papillomavirus (HPV). In particular, HPV 16, 18, 31, and
45 together account for approximately 80% of cervical cancers worldwide, with HPV 16 being the most
likely to cause cancer. Evolution from HPV infection
to precancer usually takes several years to a decade.
Most recently, an understanding of the role of HPV in
cervical carcinogenesis has been translated into clinical
utility. Cervical cancer screening for the past 50 years
has relied on cytologic evaluation of cells scraped from
the surface of the cervix – the Papanicolaou test. Cell
abnormalities can be identified and treated before cancer develops. Unfortunately, cytology is not perfectly
sensitive or predictive. Cervical HPV testing has been
utilized as a primary screening test in conjunction with
cytology in women > 30 years old. The higher prevalence of HPV in younger women precludes the use of
HPV testing in that age group.
The goals of imaging in the early detection of cervical cancer are to survey and document areas at risk and
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
to provide tools to accurately assess morphological and
molecular biomarkers using inexpensive, portable, automated systems with high sensitivity, specificity, and
significant positive and negative predictive values. Colposcopy and biopsy (previously the gold standard of diagnosis) detects only about two-thirds of prevalent CIN
2 and above, although taking more biopsies improves
sensitivity.
Dr. Rebecca Richards-Kortum, University of Texas,
related development of dual field of view (FOV) systems which image the morphologic and molecular signatures of various neoplasias non-invasively in real
time. These systems image reflected and fluorescent
light at two spatial scales. Small FOV imaging systems
have high resolution and maximize specificity. Confocal microscopy with fiberoptics and miniature components allows visualization of morphology in vivo in real time [113]. Large FOV imaging systems use multispectral digital imaging with low (millimeter) resolution to image tissue morphology and maximize sensitivity (e.g., multispectral digital colposcope).
Imaging the molecular features of cancer requires
molecular-specific contrast agents which can safely be
used in vivo. To address this problem, optically active contrast agents have been developed to image the
expression of three well-known molecular signatures
of cervical neoplasia: overexpression of EGFR, matrix
metalloproteinases (MMPs), and oncoproteins associated with HPV infection [188]. Contrast agents include
dyes and nanoparticles. Overexpression of glucose
transporters in tumor cells allows use of fluorescently
labeled 2-NBD-deoxyglucose (2-NBDG) as a marker
of cancer cells.
RNA is also being used as a target marker for HPV
detection, as its expression can signal active HPV infection. RNA can also help differentiate between highrisk and low-risk HPV isotypes. It is imaged in living samples without washing using molecular beaconbased approaches, and can also be detected in fixed
cells using in situ hybridization [39]. Both approaches
can be easily adapted to the clinical setting. Detection
using RNA has a high specificity.
Visualization of gold nanoparticle scattering can
be used to screen for cervical cancer. This technique has the benefit of strong scattering, it causes no photobleaching, and is inert and biocompatible. The nanoparticle complex formed is simple, stable, and well-understood. In addition, use of metal
nanoparticles provides up to five-fold more contrast.
Procedure-induced toxicity is limited to localized heating with gold nanoparticles to temperatures well below
the threshold of thermal damage.
Research involving integration of optical imaging
systems and contrast agents with advances in functional genomics is on-going. Molecule-specific, optically active contrast agents and inexpensive, rugged, and
portable imaging systems are being developed to monitor the 3D profile of targeted biomarkers for cervical,
oral, and lung cancer. Four molecular signatures of
neoplasia will be targeted: EGFR, MMP, telomerase,
and integrins. The safety and efficacy of these agents
and systems will be tested in animal models to provide
support data for phase 1 and 2 clinical trials.
2.10. Skin cancer
Dr. Steve Stratton, University of Arizona, provided
an overview of skin cancer prevention and its implications for imaging research. More than one million new
skin cancer cases are diagnosed in the US annually. The
estimated number of skin cancer deaths is 10,710 in
2006, 7,010 from melanoma and 2,800 from other skin
cancers. One in five Americans will develop skin cancer. Incidence of melanoma has increased 690% from
1950 to 2001, with a 165% increase in mortality [5].
Skin cancer is usually preventable with early detection, and most skin cancer is curable when recognized
and treated early. Basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC) have > 95% five-year
survival rates. Behavioral risk factors for skin cancer,
all related to excess ultraviolet radiation exposure, are
modifiable. Biological risk factors include fair skin, individuals who tan poorly, burn easily, have a tendency
to freckle, and have many moles (especially dysplastic
moles).
BCC is by far the most common skin cancer, accounting for about 80% of nonmelanoma skin cancers
(NMSC). It is locally destructive and rarely metastasizes. SCC accounts for about 20% of common NMSC.
More than 10% of SCC will metastasize. About 60%
arise from pre-existing actinic keratosis (AK). Most
AK spontaneously regresses; however, 0.1–10% may
convert to SCC [193]. Treatment of AK includes surgical therapy such as cryotherapy or curettage; topical
drugs such as 5-FU, diclofenac, imiquimod, and ALA;
and photodynamic therapy with ALA.
Melanoma is the deadliest form of skin cancer. One
in five diagnosed will die from the disease. The role
of ultraviolet radiation is less well-defined than in NMSC; however, more than five severe sunburns in adolescence doubles risk. Clinical melanoma visual criteria are asymmetry, uneven borders, multiple colors or
shades, and a diameter greater than 6 mm (ABCD cri-
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
teria). Dysplastic nevi (DN) may convert to melanoma,
though there is controversy over whether they are considered precancerous lesions [65]. In case-control studies of risk markers for melanoma, 34% of patients with
melanoma had DN. Relative risk estimates range from
1.0–16.7 for melanoma in the presence of DN.
Currently, drugs in Phase 2 clinical development for
skin cancer chemoprevention include DFMO, perillyl
alcohol (target: farnesyl transferase), and resiquimod
(target: toll-like receptor). Phase 2 clinical trial endpoints include lesion regression, epidermal/nevus normalization by histopathology, protein biomarkers by
immunohistochemistry, detection of DN by epiluminescence microscopy (dermoscopy), detection of AK
and DN by nuclear karyometry, and detection of AK
by OCT.
Skin cancer imaging can be used for early detection to avoid unnecessary resection, to assist diagnosis, and for therapy monitoring. Early detection of
melanoma while it is thin is crucial. When < 1 mm
thick, melanoma’s five-year survival rate is 95%; however, thickness > 4 mm decreases the five-year survival
rate to 24%. A naked-eye exam is only 65–80% accurate in determining lesion thickness. In addition, the
standard ABCD criteria may fail.
Dermoscopy (epiluminescence microscopy) uses a
hand-held device for enhanced visualization of pigmented lesions, revealing atypical pigment networks
and diffuse pigmentation. The diagnosis of atypical
nevi is based on algorithms with specific pattern analysis and WHO clinical criteria. Dermoscopy improves
diagnostic accuracy [125], and decreases the number
of benign lesions misidentified and excised [27].
Nuclear karyometry is an optical imaging technique
used for quantitative histopathology and cancer risk
prediction [11]. Digitized images of abnormal nuclei in
formalin-fixed, paraffin-embedded, H&E-stained tissue yield information about nuclear chromatin patterns
of epithelial tumor cells [11]. Karyometric features
and measurements of nuclear abnormality are computed, and discriminant function analyses are employed to
define deviations from normal and to identify the subpopulations of nuclei exhibiting changes. When karyometry becomes more automated, it will be useful as
a screening tool; currently, karyometric analysis can
perform risk quantitation and be used as a surrogate
biological endpoint in chemoprevention trials.
OCT, based on reflection delays of light directed into tissue, is similar to ultrasound imaging in that tissue structures are mapped based on delay times corresponding to the depths of measured structures; how-
21
ever, ultrasound imaging is based on echo delays of
sound [52]. Using light instead of sound, OCT results in much higher resolution imaging. Since light
travels so quickly, conventional techniques cannot be
used to measure the reflection delay times needed to
resolve such small (1 µm) structures. Short reflection
delays are measured using interferometery. Light from
a broadband source is split into reference and sample
arms. Interference occurs when the optical path length
to the reference arm mirror and a reflector in the sample are nearly matched. The interference signals contain information on the distance to the reflecting surfaces within the tissue, as well as velocity of any moving components within the tissue [38,208,217]. Single
wavelength imaging is currently being used because it
allows better imaging on the surface. However, a move
towards multispectral imaging is being made.
ThorLabs, Inc. has created a compact OCT system that may be more comfortable for patients than
investigator-built systems; however, the depth of imaging is reduced. The goals of OCT analysis in skin are to
develop noninvasive imaging systems for characterization of sun damage and neoplasia, and to develop quantitative image metrics based on grayscale images that
discriminate image cellular changes [12]. Improved instruments will permit therapeutic monitoring of topical
skin cancer chemoprevention drugs during trials, and
aid in developing a more objective index of therapeutic
efficacy.
Currently, 80% of the 5.5 million skin biopsies performed per year in the US, at a cost of 2.15 billion dollars, are benign. There are 63,150 new cases of potentially fatal invasive melanomas and 40,780 new cases of
melanoma in situ (lentigo maligna) each year [4,5,84,
130,198]. Dr. Milind Rajadhyaksha, Memorial SloanKettering Cancer Center, presented data showing that
optical imaging can potentially eliminate excess costs
and improve the accuracy of procedures associated with
screening for melanoma.
As noted by Dr. Stratton, pigmented lesions as they
progress from normal to malignant follow ABCD criteria, including disorder in the epidermis and dermis, disrupted cell borders, irregular and atypical shapes, pagetoid distribution of cells, elongated and thickened dendrites, and eccentric melanin patterns [22,23,56,106,
148–152,161,200]. Confocal reflectance microscopy
allows image-guided mapping of the developing lesions and has the potential to guide surgical excision
of melanomas by detecting sub-clinical margins of
melanoma in vivo.
Presurgical mapping of melanomas is important due
to high rates of postsurgical local recurrence and unde-
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G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
tected subclinical margins. The current clinical standard uses presurgical biopsies to detect subsurface
cancer-to-normal tissue margins, which can take 10–
30 biopsies for large melanomas. Presurgical confocal
mapping to determine subclinical, subsurface margins
of melanomas in vivo, and in particular lentigo malignas, may guide precise surgical excision, topical drug
treatment, and monitoring.
Two confocal reflectance microscopes (VivaScope
1000 and VivaScope 3000 ) are being studied to enable improved screening, diagnosis, presurgical planning, and intra-operative intervention in melanoma,
with the goal of minimizing biopsy numbers and decreasing associated pain and expense. Results to date
of one phase 1 study still in progress confirm that the
confocal reflectance map correlates well to pathology
in seven lentigo maligna and amelanotic melanoma patients. Clear margins were seen for surgical excisions
from the scalp, cheek, and legs.
A phase 2 study is also being performed to determine the feasibility of using dermoscopy-guided confocal imaging to find differences between melanomas
and sun-damaged skin, and to detect margins to guide
surgery. Thirty-six patients with four types of poorly defined melanomas were studied to determine the
correlation of conventional dermoscopy versus confocal imaging versus histology. Image analysis was performed by independent dermatologists/pathologists. In
another application, confocal mosaicing of BCC is also
being studied to potentially guide Mohs surgery.
Due to the complexity of light scattering, a gap exists between development and application in medical
optical imaging. Much work in spectral measurement
is lacking. Large modeling equations are possible, but
the question of normalization, which has to be referenced to localized sites, remains to be addressed. Simulations are only a starting point to look for solutions.
A database is also required for spectral measurements
for inter- and intra-person variations.
Dr. Atam Dhawan, New Jersey Institute of Technology, indicated that the current general clinical diagnosis rate of melanoma is < 70%. Imaging methods such
as dermoscopy for imaging skin lesions to detect skin
cancer use predominantly surface illumination and rely
heavily on the pattern, texture, and color of the skin lesion. Although clinicians have found that dermoscopy
methods like optical epiluminescence (ELM) can improve diagnostic accuracy by approximately 10–20%,
room for significant improvement remains for in vivo
diagnosis of skin cancer [1,61,122]. The Nevoscope
was developed as a novel, noninvasive optical instru-
ment for in situ imaging of skin lesions that combines
ELM with optical transillumination (TLM), which is
more sensitive in visualizing the superficial vascular
network and increased blood volume associated with
malignant melanoma and BCC.
Better imaging and mapping sensitivity with multiring, multi-directional, multi-spectral TLM imaging is
needed. In addition, validation of these techniques is
needed.
2.11. Discussion session on development of imaging
devices for esophagus and bladder precancer
and cancer
The discussion session after the presentations on
esophagus and bladder touched on several issues common to imaging cancer and precancer in hollow organs and how current endoscopy/cytoscopy strategies
might benefit from cross-disciplinary technology applications. Miniaturization approaches developed in
endoscopy/bronchoscopy might be used to better visualize the ureter and upper tract cancers in urology.
The standard four-quadrant cytoscopic exam might be
improved by spectral or scattering imaging modalities
developed for Barrett’s that would permit increased detection of the bladder surface, allowing inspection of
suspicious regions for nuclear or structural abnormalities by magnification endoscopy. Most discussants
believed that additional multicenter, controlled trials
are needed to investigate whether the various ablation
strategies employed for managing Barrett’s esophagus
improve long-term outcomes compared to esophagectomy. Since thermal ablation itself induces an injury/repair process that might foster additional pathologies, adjunctive therapies with chemopreventive drugs
such as NSAIDs should be evaluated in concert.
Continued investigation of heritable or molecular
risk factors in bladder and esophageal cancer was of
considerable interest. The well-known association between N -acetyltransferase (NAT) genotypes, smoking,
and bladder cancer risk [165] may have analogues in
aerodigestive cancers such as the recently described
risk variation seen with certain single nucleotide polymorphisms (SNPs) in the interleukin (IL)-1B and tumor
necrosis factor (TNF) genes in gastric cancer [153].
New genotypic predictors of responsiveness to intravesical agents such as BCG have also been reported for
bladder cancer [66,111], but none of these methods
have been fully used for clinical trial design cohort
selection or stratification.
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
Preclinical approaches to understanding the mechanism of novel anticancer agents such as histone
deacetylase (HDAC) inhibitors could benefit from these
new imaging techniques. Nuclear chromatin size and
shape factor changes and their correlation with various
spectral or optical scattering signals could be examined
in animal models that employ DNA adduct-forming
carcinogens, as could the impact of chromatin remodeling agents such as HDAC inhibitors. Molecular imaging of nuclear (e.g., apoptosis) and tissue architecture
alterations in response to thermal coagulation and repair/regeneration might also provide critical information about the long-term safety of these interventions.
2.12. Discussion on development of devices for breast
and prostate imaging
Several opinions on advantages and limitations of
the described imaging technologies were voiced. Reduced radiation exposure compared to conventional
mammography was seen as a distinct advantage for optical spectroscopic or MRI monitoring of the breast,
particularly for high-risk younger women more likely
to have dense breasts and requiring follow-up for longer
periods of time. Although optical/spectral mammography is lower cost and less invasive than DCE-MRI,
validation in a clinical setting will enable better understanding of its accuracy vis a vis tumor confounders
(e.g., cysts, hematomas, water/lipid/oxygen signature
variations during the menstrual cycle, etc.). Use of
FUS for ablation or enhanced drug delivery in breast or
prostate presented some unique challenges for gaining
regulatory approval and clinical adoption. Concerns
were voiced that high mechanical index FUS could produce the kinds of residual seromas or telengectasias
seen with other thermal therapy modalities. A scenario
was raised in which heat shock protein induction might
induce resistance to subsequent chemotherapy. All
agreed that well-designed clinical studies could help assuage some of these concerns. FUS might have an advantage over lumpectomy in multifocal breast disease,
where cosmesis is still desirable. This would not avoid
the need to monitor local node status, but validation of
axilary incision or percutaneous sentinel node biopsy
used in concert with FUS could be compared to mastectomy for multifocal disease. In prostate cancer, the
biggest challenge now is not diagnosis, but how to differentiate men with indolent versus aggressive disease
in order to avoid overtreating one population and undertreating the other. At present, the resolution available
for imaging modalities described (e.g., ∼5 mm voxel
23
size for MRS) is less than the size of typical tumor foci,
but instruments and agents available to control rather
than kill prostate cancer cells are improving rapidly.
2.13. Roundtable discussion on lung and colon
cancer
The discussion of lung and colon cancer focused on
the goals for both colon and lung cancer screening – to
precisely isolate susceptibility, and to find a broad spectrum of serum or imaging based markers. Efforts in
the field are already underway to develop beacon markers and cocktails. Patients with the specific markers
would then be screened aggressively. Specific markers may not yet have been identified or stratified for
their importance. Biospecimen repositories and image
databases from large clinical trials will aid in this identification [70,134]. Once at-risk patients are identified,
lesions will need to be spatially located. Also needed
is improved whole body surveillance. Different types
of validation methodologies need to be explored.
Lung lesions can be detected at an early stage, but it
is still impossible to know whether the lesions will go
on to be malignant. Since 25% of cured lung cancer patients will get a second cancer within five years, it is important to follow some early lesions in order to acquire
information on lesion progression that may be lost with
ablation. The process of monitoring some lesions in atrisk patients using some type of optical technique and
ablating other lesions would have to be repeated every
couple of years, much as AKs are followed and ablated
for skin cancer control. Coupling microendoscopy with
CT for visualizing peripheral lesions is an emerging
technique. More precise, population-friendly treatment
methods are needed. Image-guided intervention [59]
and inhalational chemotherapy are potential treatment
options for lung cancer.
For colon cancer screening, there is a need for
patient-acceptable, noninvasive colon screening. While
colonoscopy is a great tool, it is not the answer. Stool
testing is an option; however, the fecal milieu and
colonic preparative methods may negatively affect the
ability to find markers. FOBT can be useful if done
regularly. Fecal DNA testing is also an option [8]. PET
scanning can be useful, since the more metabolically
active the polyp, the greater the malignant potential [7].
A pill-cam device may permit evaluation of mucosal
health during transit of the GI tract [60].
24
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
2.14. Discussion on head and neck, cervix, and skin
cancer
The roundtable discussion on head and neck, cervix,
and skin cancer focused on what needs to be done to
close the gap between development and application of
the imaging techniques discussed in the presentations.
Several investigators received FDA 510k approval for
devices presented after demonstrating safety in the development process. However, the gap between what is
academically proven and what can be used clinically
must be bridged. Optical devices require more work on
spectral measurement, creation of large modeling equations, and databases for spectral measurements outlining inter- and intra-person variations. Simulations are
important tools but can only be used as a starting point
to help ask the right clinical questions.
Several aspects of cervical cancer screening were
specifically discussed by the panel. Visualization using gold nanoparticle scattering raised concerns about
light-induced toxicity. However, the localized heating stays well below the threshold of thermal damage.
A poor correlation between HPV seroconversion as a
biomarker and infection in the cervix was also noted.
Discussion about the HPV status of male partners centered on the lack of an equivalent to cervical epithelium in the male reproductive tract, making it difficult
to know when men are infected with HPV. As risk of
penile cancer is lower for men than is risk of cervical
cancer for women, studies of HPV infection in men associated with bladder cancer results are controversial.
Interestingly, there is some association between HPV
and head and neck cancer, mainly HPV 16 [77].
2.15. Translational opportunities for molecular
imaging
Dr. Martin Pomper, Johns Hopkins University, provided a keynote overview on translational opportunities
for molecular imaging across the field of oncology, illustrating additional advances in the areas of radiotracer development and more innovative cancer imaging
applications in several organ systems presented at the
Workshop. Modern pharmaceutical chemistry has applied molecular design and targeting approaches to drug
development. Now the challenge is clinical testing of
novel molecules which may have cytostatic rather than
cytotoxic effects and which do not produce the frank
tumor shrinkage assessable by conventional anatomic
imaging approaches. Molecular imaging approaches
address and solve these problems by producing tumor
metabolic response maps, as well as providing new solutions to continuing problems of dose selection and
pharmacokinetic/dynamic characterization that always
confront early phase investigational drug optimization
programs [91]. For instance, FDG-PET imaging has
helped direct the development of EGFR tyrosine kinase
inhibitors (TKI) such as erlotinib, which inhibit tumor
glucose metabolism, a good reflection of clinical benefit. Development of a labeled probe of gefitinib, another EGFR TKI, may better define optimal pharmacokinetics and patient responders, much as labeled cytotoxics such as C11 -paclitaxel did in the past. A prostatespecific membrane antigen (PSMA) monoclonal antibody labeled with 111 indium is the basis for developing
a successful radiotracer (ProstaScint TM) widely used in
nuclear medicine to diagnose the presence of metastatic androgen-independent prostate disease and monitor
its treatment [224]. Targeting this cell surface enzyme
has also been the focus of therapeutic drug design efforts. Development of PSMA-specific inhibitors [230]
has been accelerated by radiosynthesis of several analogues as PET tracers [154] to evaluate biodistribution of the molecule in animal models of prostate cancer [49]. Though PPARγ may be a more amenable target for development of cancer preventive agents, its labeled agonists may not have predictable kinetics when
examined in vivo. For example, uptake of radiolabeled
PPARγ ligand 11 C-GW7845 (rosiglitazone) was unaffected by cold chase with the unlabeled agent [126].
Similar preclinical testing of candidate imaging probes
directed to early IEN biomarkers (e.g., prostate stem
cell antigen, claudin) are also underway [49]. The pivotal role played by steroid hormone signaling in reproductive tract cancers suggested the value of developing
probes to image their distribution and regulation in laboratory and clinical studies [95,129]. 18 F-estradiol and
18
F-progestins have been used to visualize breast and
ovarian cancers; 18 F-dihydrotestosterone has similar
application in prostate cancer androgen-receptor studies [107]. A variety of novel reporter probe constructs
have served as tools to dissect cancer-specific signal
transduction cascades [88,229] and gene transcription
(E2F, HGF monoclonal antibody), and to evaluate gene
therapy and biological therapy strategies [16].
2.16. Overview of NCI and FDA programs relevant to
imaging science development
Drs. Daniel Sullivan (Cancer Imaging Program),
Jorge Gomez (Specialized Programs of Research Excellence), Sudhir Srivastava (Early Detection Research
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
25
Table 1
Internet resources for imaging science development
http://dtp.nci.nih.gov/docs/raid/raid index.html
http://www.cancer.gov/prevention/rapid/index.html
http://imaging.cancer.gov/programsandresources/specializedinitiatives/dcide
http://spores.nci.nih.gov/
http://edrn.nci.nih.gov/
http://deainfo.nci.nih.gov/concepts/CA-02-016.htm
http://www.cancer.gov/trwg/
http://imaging.cancer.gov/programsandresources/specializedinitiatives/SAIRP
http://imaging.cancer.gov/programsandresources/specializedinitiatives/icmics
http://imaging.cancer.gov/
http://www.cancer.gov/prevention/index.html
http://www.fda.gov/cdrh/index.html http://www.fda.gov/oc/combination/
http://admetech.org/
Network), Eva Szabo of Division of Cancer Prevention (DCP), and Ernest Hawk (Translational Research
Working Group) of NCI; Dr. Miriam Provost of FDA;
and Dr. Faina Schtern of the advocacy community
(Cancer Imaging Foundation) all emphasized collaboration and consultation opportunities available to researchers and industry in developing and validating innovative cancer imaging technologies (Table 1). Investigators, businesses, and other stakeholders can access a number of resources to assist in moving their
imaging platform, molecular probe, or contrast agent
past the various barriers to clinical translation in a more
timely fashion. Resources include grants and program
projects funded through the Molecular Screening Libraries Network, the Network for Translational Research in Optical Imaging (NTROI), the In Vivo Cellular and Molecular Imaging Centers, the Small Animal
Imaging Research Program, and the Development of
Clinical Imaging Drug Enhancers (DCIDE) and Rapid
Access to Intervention Development/Rapid Access to
Prevention Intervention Development (RAID/RAPID)
programs. FDA’s CDER/CDRH combination product
review process should expedite the review assignment
of drug/device/diagnostic packages or cross-labeled
product candidates for evaluation by the appropriate
group of experts within the agency.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
References
[13]
[1]
[2]
W. Abramovits and L.C. Stevenson, Changing paradigms in
dermatology: new ways to examine the skin using noninvasive imaging methods, Clin Dermatol 21 (2003), 353–358.
A.J. Aguirre, N. Bardeesy, M. Sinha, L. Lopez, D.A. Tuveson, J. Horner, M.S. Redston and R.A. DePinho, Activated Kras and Ink4a/Arf deficiency cooperate to produce
metastatic pancreatic ductal adenocarcinoma, Genes Dev 17
(2003), 3112–3126.
[14]
N.A. Ahmad, M.L. Kochman, W.B. Long, E.E. Furth and
G.G. Ginsberg, Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases, Gastrointest Endosc 55 (2002), 390–396.
J.F. Aitken, M. Janda, M. Elwood, P.H. Youl, I.T. Ring and
J.B. Lowe, Clinical outcomes from skin screening clinics
within a community-based melanoma screening program, J
Am Acad Dermatol 54 (2006), 105–114.
S.C. American, Cancer Facts and Figures 2006, American
Cancer Society, Atlanta, 2006.
N. Arber, C.J. Eagle, J. Spicak, I. Racz, P. Dite, J. Hajer, M.
Zavoral, M.J. Lechuga, P. Gerletti, J. Tang, R.B. Rosenstein,
K. Macdonald, P. Bhadra, R. Fowler, J. Wittes, A.G. Zauber,
S.D. Solomon and B. Levin, Celecoxib for the prevention of
colorectal adenomatous polyps, N Engl J Med 355 (2006),
885–895.
N. Arslan, F. Dehdashti and B.A. Siegel, FDG uptake in
colonic villous adenomas, Ann Nucl Med 19 (2005), 331–
334.
W. Atkin and J.P. Martin, Stool DNA-based colorectal cancer
detection: finding the needle in the haystack, J Natl Cancer
Inst 93 (2001), 798–799.
M. Babjuk, V. Soukup, R. Petrik, M. Jirsa and J. Dvoracek, 5aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in
stage Ta/T1 bladder cancer, BJU Int 96 (2005), 798–802.
J. Bartek and J. Lukas, Chk1 and Chk2 kinases in checkpoint
control and cancer, Cancer Cell 3 (2003), 421–429.
P.H. Bartels, J. Ranger-Moore, M.S. Stratton, P. Bozzo, J.
Einspahr, Y. Liu, D. Thompson and D.S. Alberts, Statistical
analysis of chemopreventive efficacy of vitamin A in sunexposed, normal skin, Anal Quant Cytol Histol 24 (2002),
185–197.
J.K. Barton, K.W. Gossage, W. Xu, J.R. Ranger-Moore,
K. Saboda, C.A. Brooks, L.D. Duckett, S.J. Salasche, J.A.
Warneke and D.S. Alberts, Investigating sun-damaged skin
and actinic keratosis with optical coherence tomography: a
pilot study, Technol Cancer Res Treat 2 (2003), 525–535.
I. Bedrosian, J. Schlencker, F.R. Spitz, S.G. Orel, D.L. Fraker, L.S. Callans, M. Schnall, C. Reynolds and B.J. Czerniecki, Magnetic resonance imaging-guided biopsy of mammographically and clinically occult breast lesions, Ann Surg
Oncol 9 (2002), 457–461.
C. Bernstein, H. Bernstein, H. Garewal, P. Dinning, R. Jabi,
R.E. Sampliner, M.K. McCuskey, M. Panda, D.J. Roe, L.
L’Heureux and C. Payne, A bile acid-induced apoptosis assay
26
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
for colon cancer risk and associated quality control studies,
Cancer Res 59 (1999), 2353–2357.
M.M. Bertagnolli, C.J. Eagle, A.G. Zauber, M. Redston, S.D.
Solomon, K. Kim, J. Tang, R.B. Rosenstein, J. Wittes, D.
Corle, T.M. Hess, G.M. Woloj, F. Boisserie, W.F. Anderson, J.L. Viner, D. Bagheri, J. Burn, D.C. Chung, T. Dewar,
T.R. Foley, N. Hoffman, F. Macrae, R.E. Pruitt, J.R. Saltzman, B. Salzberg, T. Sylwestrowicz, G.B. Gordon and E.T.
Hawk, Celecoxib for the prevention of sporadic colorectal
adenomas, N Engl J Med 355 (2006), 873–884.
C. Bettegowda, C.A. Foss, I. Cheong, Y. Wang, L. Diaz,
N. Agrawal, J. Fox, J. Dick, L.H. Dang, S. Zhou, K.W.
Kinzler, B. Vogelstein and M.G. Pomper, Imaging bacterial
infections with radiolabeled 1-(2’-deoxy-2’-fluoro-beta-Darabinofuranosyl)-5-iodouracil, Proc Natl Acad Sci USA 102
(2005), 1145–1150.
A.C. Borczuk, L. Shah, G.D. Pearson, K.L. Walter, L. Wang,
J.H. Austin, R.A. Friedman and C.A. Powell, Molecular signatures in biopsy specimens of lung cancer, Am J Respir Crit
Care Med 170 (2004), 167–174.
S. Bota, J.B. Auliac, C. Paris, J. Metayer, R. Sesboue, G.
Nouvet and L. Thiberville, Follow-up of bronchial precancerous lesions and carcinoma in situ using fluorescence endoscopy, Am J Respir Crit Care Med 164 (2001), 1688–1693.
R.S. Bresalier, J.C. Byrd, D. Tessler, J. Lebel, J. Koomen,
D. Hawke, E. Half, K.F. Liu and N. Mazurek, A circulating
ligand for galectin-3 is a haptoglobin-related glycoprotein
elevated in individuals with colon cancer, Gastroenterology
127 (2004), 741–748.
R.H. Breuer, A. Pasic, E.F. Smit, E. van Vliet, A. Vonk Noordegraaf, E.J. Risse, P.E. Postmus and T.G. Sutedja, The natural course of preneoplastic lesions in bronchial epithelium,
Clin Cancer Res 11 (2005), 537–543.
L.M. Brown and S.S. Devesa, Epidemiologic trends in
esophageal and gastric cancer in the United States, Surg Oncol Clin N Am 11 (2002), 235–256.
K.J. Busam, C. Charles, G. Lee and A.C. Halpern, Morphologic features of melanocytes, pigmented keratinocytes, and
melanophages by in vivo confocal scanning laser microscopy,
Mod Pathol 14 (2001), 862–868.
K.J. Busam, C. Charles, C.M. Lohmann, A. Marghoob, M.
Goldgeier and A.C. Halpern, Detection of intraepidermal
malignant melanoma in vivo by confocal scanning laser microscopy, Melanoma Res 12 (2002), 349–355.
N.S. Buttar, K.K. Wang, T.J. Sebo, D.M. Riehle, K.K. Krishnadath, L.S. Lutzke, M.A. Anderson, T.M. Petterson and L.J.
Burgart, Extent of high-grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma, Gastroenterology 120 (2001), 1630–1639.
N.J. Camp and M.L. Slattery, Classification tree analysis: a
statistical tool to investigate risk factor interactions with an
example for colon cancer (United States), Cancer Causes
Control 13 (2002), 813–823.
L.A. Cannon-Albright, M.H. Skolnick, D.T. Bishop, R.G.
Lee and R.W. Burt, Common inheritance of susceptibility to
colonic adenomatous polyps and associated colorectal cancers, N Engl J Med 319 (1988), 533–537.
P. Carli, V. de Giorgi, A. Chiarugi, P. Nardini, M.A. Weinstock, E. Crocetti, M. Stante and B. Giannotti, Addition
of dermoscopy to conventional naked-eye examination in
melanoma screening: a randomized study, J Am Acad Dermatol 50 (2004), 683–689.
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
J.A. Chappel, M. He and A.S. Kang, Modulation of antibody
display on M13 filamentous phage, J Immunol Methods 221
(1998), 25–34.
L.C. Chen, C.Y. Hao, Y.S. Chiu, P. Wong, J.S. Melnick, M.
Brotman, J. Moretto, F. Mendes, A.P. Smith, J.L. Bennington, D. Moore and N.M. Lee, Alteration of gene expression
in normal-appearing colon mucosa of APC(min) mice and
human cancer patients, Cancer Res 64 (2004), 3694–3700.
A.O. Coates, J.D. Potter, B.J. Caan, S.L. Edwards and M.L.
Slattery, Eating frequency and the risk of colon cancer, Nutr
Cancer 43 (2002), 121–126.
L.C. Costello, R.B. Franklin and P. Narayan, Citrate in the
diagnosis of prostate cancer, Prostate 38 (1999), 237–245.
M. Cruz, K. Tsuda, Y. Narumi, Y. Kuroiwa, T. Nose, Y.
Kojima, A. Okuyama, S. Takahashi, K. Aozasa, J.O. Barentsz
and H. Nakamura, Characterization of low-intensity lesions
in the peripheral zone of prostate on pre-biopsy endorectal
coil MR imaging, Eur Radiol 12 (2002), 357–365.
A.V. D’Amico, R. Cormack, C.M. Tempany, S. Kumar, G.
Topulos, H.M. Kooy and C.N. Coleman, Real-time magnetic resonance image-guided interstitial brachytherapy in the
treatment of select patients with clinically localized prostate
cancer, Int J Radiat Oncol Biol Phys 42 (1998), 507–515.
A.M. DeMarzo, W.G. Nelson, W.B. Isaacs and J.I. Epstein,
Pathological and molecular aspects of prostate cancer, Lancet
361 (2003), 955–964.
W.M. Deserno, M.G. Harisinghani, M. Taupitz, G.J. Jager,
J.A. Witjes, P.F. Mulders, C.A. Hulsbergen van de Kaa, D.
Kaufmann and J.O. Barentsz, Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR
imaging, Radiology 233 (2004), 449–456.
R.A. DiTullio, Jr., T.A. Mochan, M. Venere, J. Bartkova, M.
Sehested, J. Bartek and T.D. Halazonetis, 53BP1 functions in
an ATM-dependent checkpoint pathway that is constitutively
activated in human cancer, Nat Cell Biol 4 (2002), 998–1002.
J.P. Drenth, F.M. Nagengast and W.J. Oyen, Evaluation of
(pre-)malignant colonic abnormalities: endoscopic validation of FDG-PET findings, Eur J Nucl Med 28 (2001), 1766–
1769.
W. Drexler, Ultrahigh-resolution optical coherence tomography, J Biomed Opt 9 (2004), 47–74.
M. Durst, D. Glitz, A. Schneider and H. zur Hausen, Human papillomavirus type 16 (HPV 16) gene expression and
DNA replication in cervical neoplasia: analysis by in situ
hybridization, Virology 189 (1992), 132–140.
W.S. El-Deiry, C.C. Sigman and G.J. Kelloff, Imaging and
oncologic drug development, J Clin Oncol 24 (2006), 3261–
3273.
T. Endo, T. Awakawa, H. Takahashi, Y. Arimura, F. Itoh,
K. Yamashita, S. Sasaki, H. Yamamoto, X. Tang and K.
Imai, Classification of Barrett’s epithelium by magnifying
endoscopy, Gastrointest Endosc 55 (2002), 641–647.
C.J. Fabian, B.F. Kimler, J.R. Anderson, C. Chamberlain,
M.S. Mayo, C.M. Zalles, J.A. O’Shaughnessy, H.T. Lynch,
K.A. Johnson and D. Browne, Phase II breast cancer chemoprevention trial of the third generation selective estrogen receptor modulator arzoxifene, J Clin Oncol 24 (Suppl) (2006),
abst. No. 1001.
C.J. Fabian, B.F. Kimler, C.M. Zalles, J.R. Klemp, S. Kamel,
S. Zeiger and M.S. Mayo, Short-term breast cancer prediction
by random periareolar fine-needle aspiration cytology and the
Gail risk model, J Natl Cancer Inst 92 (2000), 1217–1227.
E.J. Feleppa, R.D. Ennis, P.B. Schiff, C.S. Wuu, A. Kalisz, J.
Ketterling, S. Urban, T. Liu, W.R. Fair, C.R. Porter and J.R.
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
Gillespie, Ultrasonic spectrum-analysis and neural-network
classification as a basis for ultrasonic imaging to target
brachytherapy of prostate cancer, Brachytherapy 1 (2002),
48–53.
W. Feng, W. Liu, C. Li, Z. Li, R. Li, F. Liu, B. Zhai, J. Shi and
G. Shi, Percutaneous microwave coagulation therapy for lung
cancer, Zhonghua Zhong Liu Za Zhi 24 (2002), 388–390.
J.S. Ferguson and G. McLennan, Virtual bronchoscopy, Proc
Am Thorac Soc 2 (2005), 488–491, 504–485.
K.W. Ferrara, C.R. Merritt, P.N. Burns, F.S. Foster, R.F.
Mattrey and S.A. Wickline, Evaluation of tumor angiogenesis
with US: imaging, Doppler, and contrast agents, Acad Radiol
7 (2000), 824–839.
T. Filbeck, U. Pichlmeier, R. Knuechel, W.F. Wieland and W.
Roessler, Clinically relevant improvement of recurrence-free
survival with 5-aminolevulinic acid induced fluorescence diagnosis in patients with superficial bladder tumors, J Urol
168 (2002), 67–71.
C.A. Foss, R.C. Mease, H. Fan, Y. Wang, H.T. Ravert, R.F.
Dannals, R.T. Olszewski, W.D. Heston, A.P. Kozikowski
and M.G. Pomper, Radiolabeled small-molecule ligands for
prostate-specific membrane antigen: in vivo imaging in experimental models of prostate cancer, Clin Cancer Res 11
(2005), 4022–4028.
A.N. Freedman, D. Seminara, M.H. Gail, P. Hartge, G.A.
Colditz, R. Ballard-Barbash and R.M. Pfeiffer, Cancer risk
prediction models: a workshop on development, evaluation,
and application, J Natl Cancer Inst 97 (2005), 715–723.
S.J. Freemantle, K.H. Dragnev and E. Dmitrovsky, The
retinoic acid paradox in cancer chemoprevention, J Natl Cancer Inst 98 (2006), 426–427.
J.G. Fujimoto, Optical coherence tomography for ultrahigh
resolution in vivo imaging, Nat Biotechnol 21 (2003), 1361–
1367.
M.H. Gail, L.A. Brinton, D.P. Byar, D.K. Corle, S.B. Green,
C. Schairer and J.J. Mulvihill, Projecting individualized
probabilities of developing breast cancer for white females
who are being examined annually, J Natl Cancer Inst 81
(1989), 1879–1886.
K. Garber, Energy deregulation: licensing tumors to grow,
Science 312 (2006), 1158–1159.
A. Gelet, J.Y. Chapelon, R. Bouvier, C. Pangaud and Y.
Lasne, Local control of prostate cancer by transrectal high
intensity focused ultrasound therapy: preliminary results, J
Urol 161 (1999), 156–162.
A. Gerger, S. Koller, T. Kern, C. Massone, K. Steiger, E.
Richtig, H. Kerl and J. Smolle, Diagnostic applicability of in
vivo confocal laser scanning microscopy in melanocytic skin
tumors, J Invest Dermatol 124 (2005), 493–498.
L.B. Gerson, K. Shetler and G. Triadafilopoulos, Prevalence
of Barrett’s esophagus in asymptomatic individuals, Gastroenterology 123 (2002), 461–467.
D. Gianfelice, A. Khiat, Y. Boulanger, M. Amara and A. Belblidia, Feasibility of magnetic resonance imaging-guided focused ultrasound surgery as an adjunct to tamoxifen therapy
in high-risk surgical patients with breast carcinoma, J Vasc
Interv Radiol 14 (2003), 1275–1282.
S.N. Goldberg, J. Bonn, G. Dodd, D. Dupuy, J.H. Geschwind,
M. Hicks, K.M. Hume, F.T. Lee, C.A. Lewis, R.A. Lencioni,
R.A. Omary, J.H. Rundback, S. Silverman and G.S. Dorfman,
Society of Interventional Radiology Interventional Oncology
Task Force: interventional oncology research vision statement and critical assessment of the state of research affairs,
J Vasc Interv Radiol 16 (2005), 1287–1294.
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
27
M.I. Golding, D.B. Doman and H.J. Goldberg, Take your
Pill(Cam): it might save your life, Gastrointest Endosc 62
(2005), 196–198.
S. Gonzalez, K. Swindells, M. Rajadhyaksha and A. Torres, Changing paradigms in dermatology: confocal microscopy in clinical and surgical dermatology, Clin Dermatol
21 (2003), 359–369.
V.G. Gorgoulis, L.V. Vassiliou, P. Karakaidos, P. Zacharatos,
A. Kotsinas, T. Liloglou, M. Venere, R.A. Ditullio, Jr., N.G.
Kastrinakis, B. Levy, D. Kletsas, A. Yoneta, M. Herlyn, C.
Kittas and T.D. Halazonetis, Activation of the DNA damage
checkpoint and genomic instability in human precancerous
lesions, Nature 434 (2005), 907–913.
L. Gotz, S.H. Heywang-Kobrunner, O. Schutz and H.
Siebold, Optical mammography in preoperative patients, Aktuelle Radiol 8 (1998), 31–33.
C.A. Granville and P.A. Dennis, An overview of lung cancer
genomics and proteomics, Am J Respir Cell Mol Biol 32
(2005), 169–176.
M.H. Greene, Genetics of cutaneous melanoma and nevi,
Mayo Clin Proc 72 (1997), 467–474.
J. Gu, H.B. Grossman, C.P. Dinney and X. Wu, The pharmacogenetic impact of inflammatory genes on bladder cancer
recurrence, Pharmacogenomics 6 (2005), 575–584.
C.H. Halbert, H. Lynch, J. Lynch, D. Main, S. Kucharski,
A.K. Rustgi and C. Lerman, Colon cancer screening practices
following genetic testing for hereditary nonpolyposis colon
cancer (HNPCC) mutations, Arch Intern Med 164 (2004),
1881–1887.
W. Harms, R. Krempien, C. Grehn, F. Hensley, J. Debus and
H.D. Becker, Electromagnetically navigated brachytherapy
as a new treatment option for peripheral pulmonary tumors,
Strahlenther Onkol 182 (2006), 108–111.
L.J. Havrilesky, S.L. Kulasingam, D.B. Matchar and E.R.
Myers, FDG-PET for management of cervical and ovarian
cancer, Gynecol Oncol 97 (2005), 183–191.
R.B. Hayes, A. Sigurdson, L. Moore, U. Peters, W.Y. Huang,
P. Pinsky, D. Reding, E.P. Gelmann, N. Rothman, R.M. Pfeiffer, R.N. Hoover and C.D. Berg, Methods for etiologic and
early marker investigations in the PLCO trial, Mutat Res 592
(2005), 147–154.
P.M. Heavey, D. McKenna and I.R. Rowland, Colorectal cancer and the relationship between genes and the environment,
Nutr Cancer 48 (2004), 124–141.
E. Heffer, V. Pera, O. Schutz, H. Siebold and S. Fantini,
Near-infrared imaging of the human breast: complementing
hemoglobin concentration maps with oxygenation images, J
Biomed Opt 9 (2004), 1152–1160.
H.W. Herr, B.H. Bochner, G. Dalbagni, S.M. Donat, V.E.
Reuter and D.F. Bajorin, Impact of the number of lymph
nodes retrieved on outcome in patients with muscle invasive
bladder cancer, J Urol 167 (2002), 1295–1298.
S.R. Hingorani, E.F. Petricoin, A. Maitra, V. Rajapakse, C.
King, M.A. Jacobetz, S. Ross, T.P. Conrads, T.D. Veenstra,
B.A. Hitt, Y. Kawaguchi, D. Johann, L.A. Liotta, H.C. Crawford, M.E. Putt, T. Jacks, C.V. Wright, R.H. Hruban, A.M.
Lowy and D.A. Tuveson, Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse, Cancer
Cell 4 (2003), 437–450.
W.K. Hirota, T.M. Loughney, D.J. Lazas, C.L. Maydonovitch, V. Rholl and R.K. Wong, Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and
esophagogastric junction: prevalence and clinical data, Gastroenterology 116 (1999), 277–285.
28
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
W.N. Hittelman, Genetic instability in epithelial tissues at
risk for cancer, Ann N Y Acad Sci 952 (2001), 1–12.
C.G. Hobbs, J.A. Sterne, M. Bailey, R.S. Heyderman, M.A.
Birchall and S.J. Thomas, Human papillomavirus and head
and neck cancer: a systematic review and meta-analysis, Clin
Otolaryngol 31 (2006), 259–266.
R. Holland, S.H. Veling, M. Mravunac and J.H. Hendriks,
Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery,
Cancer 56 (1985), 979–990.
H. Hoshino, K. Shibuya, M. Chiyo, A. Iyoda, S. Yoshida,
Y. Sekine, T. Iizasa, Y. Saitoh, M. Baba, K. Hiroshima, H.
Ohwada and T. Fujisawa, Biological features of bronchial
squamous dysplasia followed up by autofluorescence bronchoscopy, Lung Cancer 46 (2004), 187–196.
R.H. Hruban, N.V. Adsay, J. Albores-Saavedra, C. Compton,
E.S. Garrett, S.N. Goodman, S.E. Kern, D.S. Klimstra, G.
Kloppel, D.S. Longnecker, J. Luttges and G.J. Offerhaus,
Pancreatic intraepithelial neoplasia: a new nomenclature and
classification system for pancreatic duct lesions, Am J Surg
Pathol 25 (2001), 579–586.
J.G. Izzo, V.A. Papadimitrakopoulou, D.D. Liu, P.L. den
Hollander, I.M. Babenko, J. Keck, A.K. El-Naggar, D.M.
Shin, J.J. Lee, W.K. Hong and W.N. Hittelman, Cyclin D1
genotype, response to biochemoprevention, and progression
rate to upper aerodigestive tract cancer, J Natl Cancer Inst
95 (2003), 198–205.
I.J. Jacobs, S.J. Skates, N. MacDonald, U. Menon, A.N.
Rosenthal, A.P. Davies, R. Woolas, A.R. Jeyarajah, K. Sibley,
D.G. Lowe and D.H. Oram, Screening for ovarian cancer: a
pilot randomised controlled trial, Lancet 353 (1999), 1207–
1210.
M. Jeanmart, S. Lantuejoul, F. Fievet, D. Moro, N. Sturm, C.
Brambilla and E. Brambilla, Value of immunohistochemical
markers in preinvasive bronchial lesions in risk assessment
of lung cancer, Clin Cancer Res 9 (2003), 2195–2203.
A. Jemal, S.S. Devesa, P. Hartge and M.A. Tucker, Recent
trends in cutaneous melanoma incidence among whites in the
United States, J Natl Cancer Inst 93 (2001), 678–683.
D. Jocham, F. Witjes, S. Wagner, B. Zeylemaker, J. van
Moorselaar, M.O. Grimm, R. Muschter, G. Popken, F. Konig,
R. Knuchel and K.H. Kurth, Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a
prospective, phase III multicenter study, J Urol 174 (2005),
862–866; discussion 866.
Y. Kaji, J. Kurhanewicz, H. Hricak, D.L. Sokolov, L.R.
Huang, S.J. Nelson and D.B. Vigneron, Localizing prostate
cancer in the presence of postbiopsy changes on MR images:
role of proton MR spectroscopic imaging, Radiology 206
(1998), 785–790.
M. Kara, R.S. DaCosta, B.C. Wilson, N.E. Marcon and J.
Bergman, Autofluorescence-based detection of early neoplasia in patients with Barrett’s esophagus, Dig Dis 22 (2004),
134–141.
S.S. Karhadkar, G.S. Bova, N. Abdallah, S. Dhara, D. Gardner, A. Maitra, J.T. Isaacs, D.M. Berman and P.A. Beachy,
Hedgehog signalling in prostate regeneration, neoplasia and
metastasis, Nature 431 (2004), 707–712.
M.B. Kastan and J. Bartek, Cell-cycle checkpoints and cancer, Nature 432 (2004), 316–323.
M. Kawamura, Y. Izumi, N. Tsukada, K. Asakura, H.
Sugiura, H. Yashiro, K. Nakano, S. Nakatsuka, S. Kuribayashi and K. Kobayashi, Percutaneous cryoablation of small
pulmonary malignant tumors under computed tomographic
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
guidance with local anesthesia for nonsurgical candidates, J
Thorac Cardiovasc Surg 131 (2006), 1007–1013.
G.J. Kelloff, K.A. Krohn, S.M. Larson, R. Weissleder, D.A.
Mankoff, J.M. Hoffman, J.M. Link, K.Z. Guyton, W.C. Eckelman, H.I. Scher, J. O’Shaughnessy, B.D. Cheson, C.C. Sigman, J.L. Tatum, G.Q. Mills, D.C. Sullivan and J. Woodcock,
The progress and promise of molecular imaging probes in
oncologic drug development, Clin Cancer Res 11 (2005),
7967–7985.
G.J. Kelloff, S.M. Lippman, A.J. Dannenberg, C.C. Sigman, H.L. Pearce, B.J. Reid, E. Szabo, V.C. Jordan, M.R.
Spitz, G.B. Mills, V.A. Papadimitrakopoulou, R. Lotan, B.B.
Aggarwal, R.S. Bresalier, J. Kim, B. Arun, K.H. Lu, M.E.
Thomas, H.E. Rhodes, M.A. Brewer, M. Follen, D.M. Shin,
H.L. Parnes, J.M. Siegfried, A.A. Evans, W.J. Blot, W.H.
Chow, P.L. Blount, C.C. Maley, K.K. Wang, S. Lam, J.J.
Lee, S.M. Dubinett, P.F. Engstrom, F.L. Meyskens, Jr., J.
O’Shaughnessy, E.T. Hawk, B. Levin, W.G. Nelson and W.K.
Hong, Progress in chemoprevention drug development: the
promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer – a plan to move forward, Clin
Cancer Res 12 (2006), 3661–3697.
G.J. Kelloff, C.C. Sigman, K.M. Johnson, C.W. Boone, P.
Greenwald, J.A. Crowell, E.T. Hawk and L.A. Doody, Perspectives on surrogate end points in the development of drugs
that reduce the risk of cancer, Cancer Epidemiol Biomarkers
Prev 9 (2000), 127–137.
A. Khiat, D. Gianfelice, M. Amara and Y. Boulanger, Influence of post-treatment delay on the evaluation of the response
to focused ultrasound surgery of breast cancer by dynamic
contrast enhanced MRI, Br J Radiol 79 (2006), 308–314.
D.O. Kiesewetter, M.R. Kilbourn, S.W. Landvatter, D.F.
Heiman, J.A. Katzenellenbogen and M.J. Welch, Preparation of four fluorine- 18-labeled estrogens and their selective
uptakes in target tissues of immature rats, J Nucl Med 25
(1984), 1212–1221.
Y.L. Kim, Y. Liu, R.K. Wali, H.K. Roy, M.J. Goldberg, A.K.
Kromin, K. Chen and V. Backman, Simultaneous measurement of angular and spectral properties of light scattering for
characterization of tissue microarchitecture and its alteration
in early precancer, IEEE J Selected Topics Quantum Electron
9 (2003), 243–256.
B.F. Kimler, G. Ursin, C.J. Fabian, J.R. Anderson, C. Chamberlain, M.S. Mayo, J.A. O’Shaughnessy, H.T. Lynch, K.A.
Johnson and D. Browne, Effect of the third generation selective estrogen receptor modulator arzoxifene on mammographic breast density, J Clin Oncol 24 (Suppl) (2006), abst.
No. 562.
K. Kinkel, H. Hricak, Y. Lu, K. Tsuda and R.A. Filly, US
characterization of ovarian masses: a meta-analysis, Radiology 217 (2000), 803–811.
E.A. Klein and C.D. Zippe, Transrectal ultrasound guided
prostate biopsy – defining a new standard, J Urol 163 (2000),
179–180.
J.S. Klein and M.A. Zarka, Transthoracic needle biopsy, Radiol Clin North Am 38 (2000), 235–266, vii.
M. Kriege, C.T. Brekelmans, C. Boetes, P.E. Besnard, H.M.
Zonderland, I.M. Obdeijn, R.A. Manoliu, T. Kok, H. Peterse,
M.M. Tilanus-Linthorst, S.H. Muller, S. Meijer, J.C. Oosterwijk, L.V. Beex, R.A. Tollenaar, H.J. de Koning, E.J. Rutgers and J.G. Klijn, Efficacy of MRI and mammography for
breast-cancer screening in women with a familial or genetic
predisposition, N Engl J Med 351 (2004), 427–437.
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
A.B. Kurtz, J.V. Tsimikas, C.M. Tempany, U.M. Hamper,
P.H. Arger, R.L. Bree, R.J. Wechsler, I.R. Francis, J.E.
Kuhlman, E.S. Siegelman, D.G. Mitchell, S.G. Silverman,
D.L. Brown, S. Sheth, B.G. Coleman, J.H. Ellis, R.J. Kurman, D.J. Caudry and B.J. McNeil, Diagnosis and staging of
ovarian cancer: comparative values of Doppler and conventional US, CT, and MR imaging correlated with surgery and
histopathologic analysis – report of the Radiology Diagnostic
Oncology Group, Radiology 212 (1999), 19–27.
U. Ladabaum and K. Song, Projected national impact of colorectal cancer screening on clinical and economic outcomes
and health services demand, Gastroenterology 129 (2005),
1151–1162.
S. Lam, C. MacAulay, J.C. Le Riche, Y. Dyachkova, A. Coldman, M. Guillaud, E. Hawk, M.O. Christen and A.F. Gazdar, A randomized phase IIb trial of anethole dithiolethione
in smokers with bronchial dysplasia, J Natl Cancer Inst 94
(2002), 1001–1009.
P.M. Lane, T. Gilhuly, P. Whitehead, H. Zeng, C.F. Poh,
S. Ng, P.M. Williams, L. Zhang, M.P. Rosin and C.E.
MacAulay, Simple device for the direct visualization of oralcavity tissue fluorescence, J Biomed Opt 11 (2006), 024006.
R.G. Langley, M. Rajadhyaksha, P.J. Dwyer, A.J. Sober,
T.J. Flotte and R.R. Anderson, Confocal scanning laser microscopy of benign and malignant melanocytic skin lesions
in vivo, J Am Acad Dermatol 45 (2001), 365–376.
S.M. Larson, M. Morris, I. Gunther, B. Beattie, J.L. Humm,
T.A. Akhurst, R.D. Finn, Y. Erdi, K. Pentlow, J. Dyke,
O. Squire, W. Bornmann, T. McCarthy, M. Welch and
H. Scher, Tumor localization of 16beta-18F-fluoro-5alphadihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer, J Nucl Med 45 (2004),
366–373.
M.O. Leach, C.R. Boggis, A.K. Dixon, D.F. Easton, R.A.
Eeles, D.G. Evans, F.J. Gilbert, I. Griebsch, R.J. Hoff, P.
Kessar, S.R. Lakhani, S.M. Moss, A. Nerurkar, A.R. Padhani, L.J. Pointon, D. Thompson and R.M. Warren, Screening with magnetic resonance imaging and mammography of
a UK population at high familial risk of breast cancer: a
prospective multicentre cohort study (MARIBS), Lancet 365
(2005), 1769–1778.
J.M. Lee, G.Y. Jin, S.N. Goldberg, Y.C. Lee, G.H. Chung,
Y.M. Han, S.Y. Lee and C.S. Kim, Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer
and metastases: preliminary report, Radiology 230 (2004),
125–134.
J.S. Lee, S.Y. Kim, W.K. Hong, S.M. Lippman, J.Y. Ro,
M.L. Gay and W.N. Hittelman, Detection of chromosomal
polysomy in oral leukoplakia, a premalignant lesion, J Natl
Cancer Inst 85 (1993), 1951–1954.
D. Leibovici, H.B. Grossman, C.P. Dinney, R.E. Millikan, S.
Lerner, Y. Wang, J. Gu, Q. Dong and X. Wu, Polymorphisms
in inflammation genes and bladder cancer: from initiation
to recurrence, progression, and survival, J Clin Oncol 23
(2005), 5746–5756.
J. Leyton, M. Lockley, J.L. Aerts, S.K. Baird, E.O.
Aboagye, N.R. Lemoine and I.A. McNeish, Quantifying
the activity of adenoviral E1A CR2 deletion mutants using renilla luciferase bioluminescence and 3’-deoxy-3’[18F]fluorothymidine positron emission tomography imaging, Cancer Res 66 (2006), 9178–9185.
C. Liang, K.B. Sung, R.R. Richards-Kortum and M.R. Descour, Design of a high-numerical-aperture miniature micro-
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
29
scope objective for an endoscopic fiber confocal reflectance
microscope, Appl Opt 41 (2002), 4603–4610.
P. Lichtenstein, N.V. Holm, P.K. Verkasalo, A. Iliadou, J.
Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe and K. Hemminki, Environmental and heritable factors in the causation
of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland, N Engl J Med 343 (2000), 78–85.
S.M. Lippman, J.G. Batsakis, B.B. Toth, R.S. Weber, J.J.
Lee, J.W. Martin, G.L. Hays, H. Goepfert and W.K. Hong,
Comparison of low-dose isotretinoin with beta carotene to
prevent oral carcinogenesis, N Engl J Med 328 (1993), 15–
20.
A.C. Lockhart and J.D. Berlin, The epidermal growth factor
receptor as a target for colorectal cancer therapy, Semin Oncol
32 (2005), 52–60.
M.L. Loupart, S.A. Krause and M.S. Heck, Aberrant replication timing induces defective chromosome condensation in
Drosophila ORC2 mutants, Curr Biol 10 (2000), 1547–1556.
C. MacAulay, P. Lane and R. Richards-Kortum, In vivo
pathology: microendoscopy as a new endoscopic imaging
modality, Gastrointest Endosc Clin N Am 14 (2004), 595–
620, xi.
S. Madersbacher, M. Pedevilla, L. Vingers, M. Susani and
M. Marberger, Effect of high-intensity focused ultrasound
on human prostate cancer in vivo, Cancer Res 55 (1995),
3346–3351.
C.C. Maley, P.C. Galipeau, X. Li, C.A. Sanchez, T.G. Paulson, P.L. Blount and B.J. Reid, The combination of genetic instability and clonal expansion predicts progression to
esophageal adenocarcinoma, Cancer Res 64 (2004), 7629–
7633.
C.C. Maley and B.J. Reid, Natural selection in neoplastic
progression of Barrett’s esophagus, Semin Cancer Biol 15
(2005), 474–483.
A.A. Marghoob, L.D. Swindle, C.Z. Moricz, F.A. Sanchez
Negron, B. Slue, A.C. Halpern and A.W. Kopf, Instruments
and new technologies for the in vivo diagnosis of melanoma,
J Am Acad Dermatol 49 (2003), 777–797; quiz 798–779.
M.E. Martinez, Primary prevention of colorectal cancer:
lifestyle, nutrition, exercise, Recent Results Cancer Res 166
(2005), 177–211.
P. Maruvada, W. Wang, P.D. Wagner and S. Srivastava,
Biomarkers in molecular medicine: cancer detection and diagnosis, Biotechniques Suppl (2005), 9–15.
C. Massone, A. Di Stefani and H.P. Soyer, Dermoscopy for
skin cancer detection, Curr Opin Oncol 17 (2005), 147–153.
W.B. Mathews, C.A. Foss, D. Stoermer, H.T. Ravert, R.F.
Dannals, B.R. Henke and M.G. Pomper, Synthesis and
biodistribution of (11)C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-gamma, J
Nucl Med 46 (2005), 1719–1726.
S. Matoba, J.G. Kang, W.D. Patino, A. Wragg, M. Boehm,
O. Gavrilova, P.J. Hurley, F. Bunz and P.M. Hwang, p53 regulates mitochondrial respiration, Science 312 (2006), 1650–
1653.
D.M. McDonald and P.L. Choyke, Imaging of angiogenesis:
from microscope to clinic, Nat Med 9 (2003), 713–725.
A.H. McGuire, F. Dehdashti, B.A. Siegel, A.P. Lyss, J.W.
Brodack, C.J. Mathias, M.A. Mintun, J.A. Katzenellenbogen and M.J. Welch, Positron tomographic assessment of
16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic
breast carcinoma, J Nucl Med 32 (1991), 1526–1531.
30
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
C.C. McLaughlin, X.C. Wu, A. Jemal, H.J. Martin,
L.M. Roche and V.W. Chen, Incidence of noncutaneous
melanomas in the US, Cancer 103 (2005), 1000–1007.
T. Melo, J. Duncan, J.R. Ballinger and A.M. Rauth, BRU5921, a second-generation 99mTc-labeled 2-nitroimidazole for
imaging hypoxia in tumors, J Nucl Med 41 (2000), 169–176.
D.B. Mendel, A.D. Laird, X. Xin, S.G. Louie, J.G. Christensen, G. Li, R.E. Schreck, T.J. Abrams, T.J. Ngai, L.B. Lee,
L.J. Murray, J. Carver, E. Chan, K.G. Moss, J.O. Haznedar, J.
Sukbuntherng, R.A. Blake, L. Sun, C. Tang, T. Miller, S. Shirazian, G. McMahon and J.M. Cherrington, In vivo antitumor
activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived
growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship, Clin Cancer Res 9 (2003),
327–337.
E.M. Messing, T.B. Young, V.B. Hunt, K.W. Gilchrist, M.A.
Newton, L.L. Bram, W.J. Hisgen, E.B. Greenberg, M.E.
Kuglitsch and J.D. Wegenke, Comparison of bladder cancer
outcome in men undergoing hematuria home screening versus those with standard clinical presentations, Urology 45
(1995), 387–396; discussion 396–387.
C.R. Meyer, T.D. Johnson, G. McLennan, D.R. Aberle, E.A.
Kazerooni, H. Macmahon, B.F. Mullan, D.F. Yankelevitz,
E.J. van Beek, S.G. Armato, 3rd, M.F. McNitt-Gray, A.P.
Reeves, D. Gur, C.I. Henschke, E.A. Hoffman, P.H. Bland,
G. Laderach, R. Pais, D. Qing, C. Piker, J. Guo, A. Starkey,
D. Max, B.Y. Croft and L.P. Clarke, Evaluation of lung MDCT nodule annotation across radiologists and methods, Acad
Radiol 13 (2006), 1254–1265.
D. Moro-Sibilot, F. Fievet, M. Jeanmart, S. Lantuejoul, F. Arbib, M.H. Laverribre, E. Brambilla and C. Brambilla, Clinical prognostic indicators of high-grade pre-invasive bronchial
lesions, Eur Respir J 24 (2004), 24–29.
C.D. Morris, J.P. Byrne, G.R. Armstrong and S.E. Attwood,
Prevention of the neoplastic progression of Barrett’s oesophagus by endoscopic argon beam plasma ablation, Br J Surg
88 (2001), 1357–1362.
J.R. Mourant, I.J. Bigio, J. Boyer, R.L. Conn, T. Johnson and
T. Shimada, Spectroscopic diagnosis of bladder cancer with
elastic light scattering, Lasers Surg Med 17 (1995), 350–357.
B.P. Mulhall, G.R. Veerappan and J.L. Jackson, Metaanalysis: computed tomographic colonography, Ann Intern
Med 142 (2005), 635–650.
G. Nabi, D.R. Greene and M. O’Donnell, How important
is urinary cytology in the diagnosis of urological malignancies?, Eur Urol 43 (2003), 632–636.
W.G. Nelson, T.L. DeWeese and A.M. DeMarzo, The diet, prostate inflammation, and the development of prostate
cancer, Cancer Metastasis Rev 21 (2002), 3–16.
K.A. Nyberg, R.J. Michelson, C.W. Putnam and T.A. Weinert, Toward maintaining the genome: DNA damage and replication checkpoints, Annu Rev Genet 36 (2002), 617–656.
M.J. O’Connell and K.A. Cimprich, G2 damage checkpoints:
what is the turn-on? J Cell Sci 118 (2005), 1–6.
B.H. O’Neil and R.M. Goldberg, Chemotherapy for advanced
colorectal cancer: let’s not forget how we got here (until we
really can), Semin Oncol 32 (2005), 35–42.
J.A. O’Shaughnessy, G.J. Kelloff, G.B. Gordon, A.J. Dannenberg, W.K. Hong, C.J. Fabian, C.C. Sigman, M.M.
Bertagnolli, S.P. Stratton, S. Lam, W.G. Nelson, F.L.
Meyskens, D.S. Alberts, M. Follen, A.K. Rustgi, V. Papadimitrakopoulou, P.T. Scardino, A.F. Gazdar, L.W. Wattenberg,
M.B. Sporn, W.A. Sakr, S.M. Lippman and D.D. Von Hoff,
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development, Clin
Cancer Res 8 (2002), 314–346.
A.J. Osborn, S.J. Elledge and L. Zou, Checking on the fork:
the DNA-replication stress-response pathway, Trends Cell
Biol 12 (2002), 509–516.
B.F. Overholt, C.J. Lightdale, K.K. Wang, M.I. Canto, S. Burdick, R.C. Haggitt, M.P. Bronner, S.L. Taylor, M.G. Grace
and M. Depot, Photodynamic therapy with porfimer sodium
for ablation of high-grade dysplasia in Barrett’s esophagus:
international, partially blinded, randomized phase III trial,
Gastrointest Endosc 62 (2005), 488–498.
V.A. Papadimitrakopoulou, D.D. Liu, L. Mao, D.M. Shin,
A. El-Naggar, H. Ibarguen, J.J. Lee, W.K. Hong and W.N.
Hittelman, Biologic correlates of a biochemoprevention trial
in advanced upper aerodigestive tract premalignant lesions,
Cancer Epidemiol Biomarkers Prev 11 (2002), 1605–1610.
G. Pellacani, A.M. Cesinaro, C. Grana and S. Seidenari,
In vivo confocal scanning laser microscopy of pigmented
Spitz nevi: comparison of in vivo confocal images with dermoscopy and routine histopathology, J Am Acad Dermatol
51 (2004), 371–376.
G. Pellacani, A.M. Cesinaro, C. Longo, C. Grana and S. Seidenari, Microscopic in vivo description of cellular architecture of dermoscopic pigment network in nevi and melanomas,
Arch Dermatol 141 (2005), 147–154.
G. Pellacani, A.M. Cesinaro and S. Seidenari, In vivo assessment of melanocytic nests in nevi and melanomas by reflectance confocal microscopy, Mod Pathol 18 (2005), 469–
474.
G. Pellacani, A.M. Cesinaro and S. Seidenari, In vivo
confocal reflectance microscopy for the characterization of
melanocytic nests and correlation with dermoscopy and histology, Br J Dermatol 152 (2005), 384–386.
G. Pellacani, A.M. Cesinaro and S. Seidenari, Reflectancemode confocal microscopy for the in vivo characterization
of pagetoid melanocytosis in melanomas and nevi, J Invest
Dermatol 125 (2005), 532–537.
F. Perri, A. Piepoli, C. Bonvicini, A. Gentile, M. Quitadamo,
M. Di Candia, R. Cotugno, F. Cattaneo, M.R. Zagari, L.
Ricciardiello, M. Gennarelli, F. Bazzoli, G.N. Ranzani and
A. Andriulli, Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer
prevalence, Cytokine 30 (2005), 293–302.
M.G. Pomper, J.L. Musachio, J. Zhang, U. Scheffel, Y.
Zhou, J. Hilton, A. Maini, R.F. Dannals, D.F. Wong and A.P.
Kozikowski, 11C-MCG: synthesis, uptake selectivity, and
primate PET of a probe for glutamate carboxypeptidase II
(NAALADase), Mol Imaging 1 (2002), 96–101.
M. Ponz de Leon, L. Roncucci, P. Di Donato, L. Tassi, O.
Smerieri, M.G. Amorico, G. Malagoli, D. De Maria, A. Antonioli, N.J. Chahin et al., Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel,
Cancer Res 48 (1988), 4121–4126.
J.D. Potter, Colorectal cancer: molecules and populations, J
Natl Cancer Inst 91 (1999), 916–932.
D. Price, B. Stein, P. Sieber, R. Tutrone, J. Bailen, E. Goluboff, D. Burzon, D. Bostwick and M. Steiner, Toremifene
for the prevention of prostate cancer in men with high grade
prostatic intraepithelial neoplasia: results of a double-blind,
placebo controlled, phase IIB clinical trial, J Urol 176 (2006),
965–970; discussion 970–961.
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
[158]
[159]
[160]
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
J. Puc, M. Keniry, H.S. Li, T.K. Pandita, A.D. Choudhury,
L. Memeo, M. Mansukhani, V.V. Murty, Z. Gaciong, S.E.
Meek, H. Piwnica-Worms, H. Hibshoosh and R. Parsons,
Lack of PTEN sequesters CHK1 and initiates genetic instability, Cancer Cell 7 (2005), 193–204.
J.W. Pyhtila, J.D. Boyer, K.J. Chalut and A. Wax, Fourierdomain angle-resolved low coherence interferometry through
an endoscopic fiber bundle for light-scattering spectroscopy,
Opt Lett 31 (2006), 772–774.
S.M. Rahman, Y. Shyr, P.B. Yildiz, A.L. Gonzalez, H. Li, X.
Zhang, P. Chaurand, K. Yanagisawa, B.S. Slovis, R.F. Miller,
M. Ninan, Y.E. Miller, W.A. Franklin, R.M. Caprioli, D.P.
Carbone and P.P. Massion, Proteomic patterns of preinvasive
bronchial lesions, Am J Respir Crit Care Med 172 (2005),
1556–1562.
M. Rajadhyaksha, S. Gonzalez and J.M. Zavislan, Detectability of contrast agents for confocal reflectance imaging of skin
and microcirculation, J Biomed Opt 9 (2004), 323–331.
D.F. Ransohoff, Colon cancer screening in 2005: status and
challenges, Gastroenterology 128 (2005), 1685–1695.
B.J. Reid, P.L. Blount, Z. Feng and D.S. Levine, Optimizing endoscopic biopsy detection of early cancers in Barrett’s
high-grade dysplasia, Am J Gastroenterol 95 (2000), 3089–
3096.
B.J. Reid, D.S. Levine, G. Longton, P.L. Blount and P.S.
Rabinovitch, Predictors of progression to cancer in Barrett’s
esophagus: baseline histology and flow cytometry identify
low- and high-risk patient subsets, Am J Gastroenterol 95
(2000), 1669–1676.
E. Reszka and W. Wasowicz, Genetic polymorphism of
N-acetyltransferase and glutathione S-transferase related to
neoplasm of genitourinary system. Minireview, Neoplasma
49 (2002), 209–216.
M.P. Rosin, X. Cheng, C. Poh, W.L. Lam, Y. Huang, J. Lovas,
K. Berean, J.B. Epstein, R. Priddy, N.D. Le and L. Zhang,
Use of allelic loss to predict malignant risk for low-grade oral
epithelial dysplasia, Clin Cancer Res 6 (2000), 357–362.
M.P. Rosin, W.L. Lam, C. Poh, N.D. Le, R.J. Li, T. Zeng, R.
Priddy and L. Zhang, 3p14 and 9p21 loss is a simple tool for
predicting second oral malignancy at previously treated oral
cancer sites, Cancer Res 62 (2002), 6447–6450.
H.K. Roy, Y.L. Kim, Y. Liu, R.K. Wali, M.J. Goldberg, V.
Turzhitsky, J. Horwitz and V. Backman, Risk stratification of
colon carcinogenesis through enhanced backscattering spectroscopy analysis of the uninvolved colonic mucosa, Clin
Cancer Res 12 (2006), 961–968.
H.K. Roy, Y. Liu, R.K. Wali, Y.L. Kim, A.K. Kromine, M.J.
Goldberg and V. Backman, Four-dimensional elastic lightscattering fingerprints as preneoplastic markers in the rat
model of colon carcinogenesis, Gastroenterology 126 (2004),
1071–1081; discussion 1948.
Y. Satoh, Y. Ishikawa, K. Nakagawa, T. Hirano and E.
Tsuchiya, A follow-up study of progression from dysplasia
to squamous cell carcinoma with immunohistochemical examination of p53 protein overexpression in the bronchi of
ex-chromate workers, Br J Cancer 75 (1997), 678–683.
J. Schmidbauer, F. Witjes, N. Schmeller, R. Donat, M. Susani
and M. Marberger, Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy,
J Urol 171 (2004), 135–138.
M.D. Schnall, J. Blume, D.A. Bluemke, G.A. Deangelis, N.
Debruhl, S. Harms, S.H. Heywang-Kobrunner, N. Hylton,
C.K. Kuhl, E.D. Pisano, P. Causer, S.J. Schnitt, S.F. Smazal,
C.B. Stelling, C. Lehman, P.T. Weatherall and C.A. Gatsonis,
[173]
[174]
[175]
[176]
[177]
[178]
[179]
[180]
[181]
[182]
[183]
[184]
[185]
[186]
[187]
31
MRI detection of distinct incidental cancer in women with
primary breast cancer studied in IBMC 6883, J Surg Oncol
92 (2005), 32–38.
T.G. Schnell, S.J. Sontag, G. Chejfec, G. Aranha, A. Metz,
S. O’Connell, U.J. Seidel and A. Sonnenberg, Long-term
nonsurgical management of Barrett’s esophagus with highgrade dysplasia, Gastroenterology 120 (2001), 1607–1619.
Y. Schwarz, J. Greif, H.D. Becker, A. Ernst and A. Mehta,
Real-time electromagnetic navigation bronchoscopy to peripheral lung lesions using overlaid CT images: the first human study, Chest 129 (2006), 988–994.
I.A. Scotiniotis, M.L. Kochman, J.D. Lewis, E.E. Furth, E.F.
Rosato and G.G. Ginsberg, Accuracy of EUS in the evaluation of Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma, Gastrointest Endosc 54 (2001), 689–
696.
K. Shah and R. Weissleder, Molecular optical imaging: applications leading to the development of present day therapeutics, NeuroRx 2 (2005), 215–225.
P. Sharma, A. Bansal, S. Mathur, S. Wani, R. Cherian, D.
McGregor, A. Higbee, S. Hall and A. Weston, The utility of
a novel narrow band imaging endoscopy system in patients
with Barrett’s esophagus, Gastrointest Endosc 64 (2006),
167–175.
P. Sharma, B.F. Kimler, J.L. Clark, T.L. Metheny, C.M. Zalles, M. Hall and C.J. Fabian, ER-alpha expression in benign breast ductal cells obtained from random periareolar
fine needle aspiration correlates with menopausal status and
abnormal cytomorphology, Proc Amer Assoc Cancer Res 46
(2005).
P. Sharma, A.P. Weston, M. Topalovski, R. Cherian, A.
Bhattacharyya and R.E. Sampliner, Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett’s oesophagus, Gut 52 (2003), 24–27.
L.M. Siegel, P.D. Stevens, C.J. Lightdale, P.H. Green, S.
Goodman, R.J. Garcia-Carrasquillo and H. Rotterdam, Combined magnification endoscopy with chromoendoscopy in the
evaluation of patients with suspected malabsorption, Gastrointest Endosc 46 (1997), 226–230.
M.K. Simick and L. Lilge, Optical transillumination spectroscopy to quantify parenchymal tissue density: an indicator
for breast cancer risk, Br J Radiol 78 (2005), 1009–1017.
S.J. Skates, F.J. Xu, Y.H. Yu, K. Sjovall, N. Einhorn, Y.
Chang, R.C. Bast, Jr. and R.C. Knapp, Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor
markers, Cancer 76 (1995), 2004–2010.
M.L. Slattery and R.A. Kerber, Family history of cancer and
colon cancer risk: the Utah Population Database, J Natl
Cancer Inst 86 (1994), 1618–1626.
M.L. Slattery, T.R. Levin, K. Ma, D. Goldgar, R. Holubkov
and S. Edwards, Family history and colorectal cancer: predictors of risk, Cancer Causes Control 14 (2003), 879–887.
M.L. Slattery, J.D. Potter, D.M. Duncan and T.D. Berry,
Dietary fats and colon cancer: assessment of risk associated
with specific fatty acids, Int J Cancer 73 (1997), 670–677.
M.L. Slattery, J.D. Potter and A.W. Sorenson, Age and
risk factors for colon cancer (United States and Australia):
are there implications for understanding differences in casecontrol and cohort studies? Cancer Causes Control 5 (1994),
557–563.
D.B. Sodee, R. Conant, M. Chalfant, S. Miron, E. Klein, R.
Bahnson, J.P. Spirnak, B. Carlin, E.M. Bellon and B. Rogers,
Preliminary imaging results using In-111 labeled CYT-356
32
[188]
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
[201]
[202]
[203]
[204]
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
(Prostascint) in the detection of recurrent prostate cancer,
Clin Nucl Med 21 (1996), 759–767.
K. Sokolov, J. Aaron, B. Hsu, D. Nida, A. Gillenwater, M.
Follen, C. MacAulay, K. Adler-Storthz, B. Korgel, M. Descour, R. Pasqualini, W. Arap, W. Lam and R. RichardsKortum, Optical systems for in vivo molecular imaging of
cancer, Technol Cancer Res Treat 2 (2003), 491–504.
M.B. Sporn and K.T. Liby, Cancer chemoprevention: scientific promise, clinical uncertainty, Nat Clin Pract Oncol 2
(2005), 518–525.
M.S. Steiner and C.R. Pound, Phase IIA clinical trial to test
the efficacy and safety of Toremifene in men with high-grade
prostatic intraepithelial neoplasia, Clin Prostate Cancer 2
(2003), 24–31.
M. Stoeckli, P. Chaurand, D.E. Hallahan and R.M. Caprioli,
Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues, Nat Med 7
(2001), 493–496.
T. Stratmann and A.S. Kang, Cognate peptide-receptor ligand
mapping by directed phage display, Proteome Sci 3 (2005),
7.
S.P. Stratton, Prevention of non-melanoma skin cancer, Curr
Oncol Rep 3 (2001), 295–300.
N. Subhas, P.V. Patel, H.K. Pannu, H.A. Jacene, E.K. Fishman and R.L. Wahl, Imaging of pelvic malignancies with
in-line FDG PET-CT: case examples and common pitfalls of
FDG PET, Radiographics 25 (2005), 1031–1043.
R.D. Suh, A.B. Wallace, R.E. Sheehan, S.B. Heinze and J.G.
Goldin, Unresectable pulmonary malignancies: CT-guided
percutaneous radiofrequency ablation–preliminary results,
Radiology 229 (2003), 821–829.
D.C. Sullivan and G. Kelloff, Seeing into cells. The promise
of in vivo molecular imaging in oncology, EMBO Rep 6
(2005), 292–296.
W. Sun and D.G. Haller, Adjuvant therapy of colon cancer,
Semin Oncol 32 (2005), 95–102.
S.M. Swetter, B.L. Waddell, M.D. Vazquez and V.S. Khosravi, Increased effectiveness of targeted skin cancer screening in the Veterans Affairs population of Northern California,
Prev Med 36 (2003), 164–171.
T. Takayama, S. Katsuki, Y. Takahashi, M. Ohi, S. Nojiri,
S. Sakamaki, J. Kato, K. Kogawa, H. Miyake and Y. Niitsu,
Aberrant crypt foci of the colon as precursors of adenoma
and cancer, N Engl J Med 339 (1998), 1277–1284.
Z.S. Tannous, M.C. Mihm, T.J. Flotte and S. Gonzalez, In vivo examination of lentigo maligna and malignant melanoma
in situ, lentigo maligna type by near-infrared reflectance confocal microscopy: comparison of in vivo confocal images
with histologic sections, J Am Acad Dermatol 46 (2002),
260–263.
R. Tatlidil, H. Jadvar, J.R. Bading and P.S. Conti, Incidental
colonic fluorodeoxyglucose uptake: correlation with colonoscopic and histopathologic findings, Radiology 224 (2002),
783–787.
L. Teixeira da Costa and C. Lengauer, Exploring and exploiting instability, Cancer Biol Ther 1 (2002), 212–225.
C.M. Tempany, E.A. Stewart, N. McDannold, B.J. Quade,
F.A. Jolesz and K. Hynynen, MR imaging-guided focused
ultrasound surgery of uterine leiomyomas: a feasibility study,
Radiology 226 (2003), 897–905.
I.M. Thompson, P.J. Goodman, C.M. Tangen, M.S. Lucia, G.J. Miller, L.G. Ford, M.M. Lieber, R.D. Cespedes,
J.N. Atkins, S.M. Lippman, S.M. Carlin, A. Ryan, C.M.
Szczepanek, J.J. Crowley and C.A. Coltman, Jr., The influ-
[205]
[206]
[207]
[208]
[209]
[210]
[211]
[212]
[213]
[214]
[215]
[216]
ence of finasteride on the development of prostate cancer, N
Engl J Med 349 (2003), 215–224.
J.A. Tice, S.R. Cummings, E. Ziv and K. Kerlikowske, Mammographic breast density and the gail model for breast cancer
risk prediction in a screening population, Breast Cancer Res
Treat 94 (2005), 115–122.
M. Tsuboi, A. Hayashi, N. Ikeda, H. Honda, Y. Kato, S.
Ichinose and H. Kato, Optical coherence tomography in the
diagnosis of bronchial lesions, Lung Cancer 49 (2005), 387–
394.
T. Uchida, N.T. Sanghvi, T.A. Gardner, M.O. Koch, D. Ishii,
S. Minei, T. Satoh, T. Hyodo, A. Irie and S. Baba, Transrectal high-intensity focused ultrasound for treatment of patients with stage T1b-2n0m0 localized prostate cancer: a
preliminary report, Urology 59 (2002), 394–398; discussion
398–399.
A. Unterhuber, B. Povazay, K. Bizheva, B. Hermann, H.
Sattmann, A. Stingl, T. Le, M. Seefeld, R. Menzel, M. Preusser, H. Budka, C. Schubert, H. Reitsamer, P.K. Ahnelt, J.E.
Morgan, A. Cowey and W. Drexler, Advances in broad bandwidth light sources for ultrahigh resolution optical coherence
tomography, Phys Med Biol 49 (2004), 1235–1246.
A. Urisman, R.J. Molinaro, N. Fischer, S.J. Plummer, G.
Casey, E.A. Klein, K. Malathi, C. Magi-Galluzzi, R.R.
Tubbs, D. Ganem, R.H. Silverman and J.L. Derisi, Identification of a Novel Gammaretrovirus in Prostate Tumors of
Patients Homozygous for R462Q RNASEL Variant, PLoS
Pathog 2 (2006), e25.
J.S. van den Brink, Y. Watanabe, C.K. Kuhl, T. Chung, R.
Muthupillai, M. Van Cauteren, K. Yamada, S. Dymarkowski,
J. Bogaert, J.H. Maki, C. Matos, J.W. Casselman and R.M.
Hoogeveen, Implications of SENSE MR in routine clinical
practice, Eur J Radiol 46 (2003), 3–27.
M.C. van Kouwen, J.P. Drenth, J.H. van Krieken, H. van
Goor, P. Friederich, W.J. Oyen and F.M. Nagengast, Ability
of FDG-PET to detect all cancers in patients with familial
adenomatous polyposis, and impact on clinical management,
Eur J Nucl Med Mol Imaging 33 (2006), 270–274.
J.R. van Nagell, Jr., P.D. DePriest, M.B. Reedy, H.H. Gallion,
F.R. Ueland, E.J. Pavlik and R.J. Kryscio, The efficacy of
transvaginal sonographic screening in asymptomatic women
at risk for ovarian cancer, Gynecol Oncol 77 (2000), 350–
356.
P. Veit, C. Kuhle, T. Beyer, H. Kuehl, C.U. Herborn, G.
Borsch, H. Stergar, J. Barkhausen, A. Bockisch and G. Antoch, Whole body positron emission tomography/computed
tomography (PET/CT) tumour staging with integrated
PET/CT colonography: technical feasibility and first experiences in patients with colorectal cancer, Gut 55 (2006),
68–73.
R.W. Veltri, A.W. Partin and M.C. Miller, Quantitative Nuclear Grade (QNG): The clinical applications of the quantitative measurement of nuclear structure using image analysis, (Vol. 2), G.J. Kelloff, E.T. Hawk and C.C. Sigman, eds,
Totowa, NJ, Humana Press, 2005, pp. 97–108.
B.J. Venmans, T.J. van Boxem, E.F. Smit, P.E. Postmus and
T.G. Sutedja, Outcome of bronchial carcinoma in situ, Chest
117 (2000), 1572–1576.
T.J. Vogl, R. Straub, T. Lehnert, K. Eichler, T. Luder-Luhr,
J. Peters, S. Zangos, O. Sollner and M. Mack, Percutaneous
thermoablation of pulmonary metastases. Experience with
the application of laser-induced thermotherapy (LITT) and
radiofrequency ablation (RFA), and a literature review, Rofo
176 (2004), 1658–1666.
G.J. Kelloff et al. / Workshop on imaging science development for cancer prevention and preemption
[217]
[218]
[219]
[220]
[221]
[222]
[223]
Y. Wang, Y. Zhao, J.S. Nelson, Z. Chen and R.S. Windeler, Ultrahigh-resolution optical coherence tomography by
broadband continuum generation from a photonic crystal
fiber, Opt Lett 28 (2003), 182–184.
E. Warner, D.B. Plewes, R.S. Shumak, G.C. Catzavelos, L.S.
Di Prospero, M.J. Yaffe, V. Goel, E. Ramsay, P.L. Chart,
D.E. Cole, G.A. Taylor, M. Cutrara, T.H. Samuels, J.P. Murphy, J.M. Murphy and S.A. Narod, Comparison of breast
magnetic resonance imaging, mammography, and ultrasound
for surveillance of women at high risk for hereditary breast
cancer, J Clin Oncol 19 (2001), 3524–3531.
T. Watanabe, T.T. Wu, P.J. Catalano, T. Ueki, R. Satriano,
D.G. Haller, A.B. Benson, 3rd and S.R. Hamilton, Molecular
predictors of survival after adjuvant chemotherapy for colon
cancer, N Engl J Med 344 (2001), 1196–1206.
A. Wax, C. Yang, V. Backman, K. Badizadegan, C.W. Boone,
R.R. Dasari and M.S. Feld, Cellular organization and substructure measured using angle-resolved low-coherence interferometry, Biophys J 82 (2002), 2256–2264.
A. Wax, C. Yang, M.G. Muller, R. Nines, C.W. Boone, V.E.
Steele, G.D. Stoner, R.R. Dasari and M.S. Feld, In situ detection of neoplastic transformation and chemopreventive effects in rat esophagus epithelium using angle-resolved lowcoherence interferometry, Cancer Res 63 (2003), 3556–3559.
S.R. Wedge, D.J. Ogilvie, M. Dukes, J. Kendrew, R. Chester,
J.A. Jackson, S.J. Boffey, P.J. Valentine, J.O. Curwen, H.L.
Musgrove, G.A. Graham, G.D. Hughes, A.P. Thomas, E.S.
Stokes, B. Curry, G.H. Richmond, P.F. Wadsworth, A.L.
Bigley and L.F. Hennequin, ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor
growth following oral administration, Cancer Res 62 (2002),
4645–4655.
S.M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh,
[224]
[225]
[226]
[227]
[228]
[229]
[230]
33
Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L.
Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich,
A. Voznesensky, B. Riedl, L.E. Post, G. Bollag and P.A. Trail,
BAY 43-9006 exhibits broad spectrum oral antitumor activity
and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis,
Cancer Res 64 (2004), 7099–7109.
S. Wilkinson and G. Chodak, The role of 111indiumcapromab pendetide imaging for assessing biochemical failure after radical prostatectomy, J Urol 172 (2004), 133–136.
M.R. Wrensch, N.L. Petrakis, R. Miike, E.B. King, K. Chew,
J. Neuhaus, M.M. Lee and M. Rhys, Breast cancer risk in
women with abnormal cytology in nipple aspirates of breast
fluid, J Natl Cancer Inst 93 (2001), 1791–1798.
K. Yanagisawa, Y. Shyr, B.J. Xu, P.P. Massion, P.H. Larsen,
B.C. White, J.R. Roberts, M. Edgerton, A. Gonzalez, S.
Nadaf, J.H. Moore, R.M. Caprioli and D.P. Carbone, Proteomic patterns of tumour subsets in non-small-cell lung cancer, Lancet 362 (2003), 433–439.
S. Yasuda, H. Fujii, T. Nakahara, N. Nishiumi, W. Takahashi,
M. Ide and A. Shohtsu, 18F-FDG PET detection of colonic
adenomas, J Nucl Med 42 (2001), 989–992.
G.P. Young, D.J. St John, S.J. Winawer and P. Rozen, Choice
of fecal occult blood tests for colorectal cancer screening:
recommendations based on performance characteristics in
population studies: a WHO (World Health Organization)
and OMED (World Organization for Digestive Endoscopy)
report, Am J Gastroenterol 97 (2002), 2499–2507.
Y. Zhang, J. Laterra and M.G. Pomper, Imaging modulation
of hedgehog signaling in vivo, Society of Molecular Imaging
Annual Meeting (2005), Abst. No. 295.
J. Zhou, J.H. Neale, M.G. Pomper and A.P. Kozikowski,
NAAG peptidase inhibitors and their potential for diagnosis
and therapy, Nat Rev Drug Discov 4 (2005), 1015–1026.