April 22 - 23, 1999: Rockville, MD
Introduction
On April 22 - 23, 1999 experts in clinical magnetic resonance
spectroscopy met for two days at the DoubleTree Hotel in Rockville, Maryland to
discuss the current state-of-the-art, potential future progress in, and benefit
of, magnetic resonance spectroscopy (MRS) in clinical oncology. The specific
goal of the focus group was to formulate recommendations that would assist the
NCI in its programmatic decision making. Specifically, the focus group
identified five areas that deserve renewed and increased attention by the NCI.
Below, these five areas are concisely described. Following that,
an appendix is included that provides brief summaries of many of the
presentations made by focus group participants, a roster of participants, and
the meeting agenda.
Focus Group Recommendations
1. NMR Spectroscopy: Clinical Research and Multi-Center Studies
The goal of funding clinical MR spectroscopy studies is to
facilitate introduction of NMR spectroscopy/imaging to well-designed clinical
studies to determine their clinical utility. The introduction of this expensive
and technically demanding but non-invasive method of monitoring tissue
biochemistry and physiology will require academic, industrial and governmental
cooperation and interaction. The necessity of industrial support [hardware
specific for spectroscopic applications (decoupler, transmit/receive coils,
etc.)], improved reliability of equipment and improvement in the speed of
repairs, and stable system platforms is paramount and is discussed separately.
The need for robust analytical techniques and standardization cannot be
overemphasized and is also discussed in a different section. These are
important for obtaining maximum data from a given study, and obtaining reliable
multi-voxel data reproducibly and reliably. This section focuses on potential
projects recommended to the National Cancer Institute for funding to facilitate
the introduction of quantitative NMR measurements to oncology.
A potential mechanism for some of these funding requirements may
fall under ACRIN or cooperative groups such as the Pediatric Brain Tumor
Consortium (PBTC). This is a new mechanism and needs to be explored and
possibly expanded further.
Specific Recommendations:
A. The NCI should support single institution studies designed to
obtain pilot data. This research will test novel ideas and obtain preliminary
data. This research falls into a "high risk" category, but with important
potential gain. It thus requires a fast "turnaround time", and should provide
ca. $100,000 to an investigator with a clinically related project that is "high
risk, high yield". The R21 mechanism might be suitable but needs to be
streamlined (both in length of application and response time).
B. The NCI should support rapid funding of "add-on"
spectroscopic or imaging studies to ongoing clinical trials. This would allow
accumulation of important preliminary data on technological feasibility, or on
clinical questions in select populations. It would allow NMR investigators to
take advantage of the infrastructure from the clinical trial (statistics,
uniform patient population, data base etc.) and provide new data to the ongoing
clinical trial. This could be coordinated through CTEP.
C. The NCI should support multi-center studies falling into two
categories, those involving a small number of institutions (2 - 4) and those
involving larger groups of institutions.
(i) Multi-center studies involving a small number of (2-4)
institutions would have the dual goals of technology transfer and validating
how "robust" the technique is. These studies would obtain preliminary data
focused on a significant clinical question for subsequent larger studies.
Examples of these include (but are not restricted to): directed biopsy,
diagnosis (image guided), and treatment planning. Possible disease sites
should include: (i) prostate - 1H NMR, (ii) brain tumors (pediatric
and adult) - 1H NMR, (iii) breast - 1H NMR (e.g.,
choline), and (iv) lymphoma - 31P NMR [note, pharmacokinetics (such
as with fluorinated pyrimidines), while not a "disease site", would fall into
this category].
(ii) Multi-center studies involving a larger number of
institutions (>4) would focus on collaborations that investigate significant
clinical questions and obtain definitive data. These studies will include a
short preparation period (~6 months) to ensure successful technology and
uniformity of techniques, prior to obtaining "definitive data". Three areas
have sufficient preliminary data to warrant consideration. The use of 31P
MRS in continued investigation of the predictive value of the phosphomonoester
region as an early marker of tumor response, the use of 1H MRS for
study of prostate cancer, and the use of 1H MRS for evaluation of
brain tumors
D. The NCI should support the further training of physicians in
MRS. This will be required if the potential of these techniques is to be
realized. This should focus on training individuals in the correct
interpretation of NMR spectra, obtained with relatively complex techniques.
Possible NCI programs/mechanisms for this activity are: the T32 program for
fellows and house staff and The K23 program, with a Ph.D. spectroscopist as
mentor.
2. Instrument Specifications and Relations with Commercial
Manufactures
Clinical applications of MRS in cancer have been sorely
compromised by inadequate availability and maintenance of MRS capabilities on
clinical MRI/MRS scanners. The maintenance of robust MRS capabilities on
scanners located in clinical environments is essential for ongoing clinical MRS
research.
Specific Recommendations:
A The NCI should invite representatives from relevant MRI
scanner and ancillary equipment manufacturers, and key MRS investigators to
participate in a discussion to address the problem of establishing and
maintaining MRS functionality on whole-body MRI/MRS scanners for the purpose of
cancer research and clinical studies. Specifically, to discuss the maintenance
of basic proton (1H) MRS functionality, broadband MRS functionality,
the ability to image nuclei other-than-1H, state-of-the-art detector
coils and associated hardware, and MRS data processing. Invitees should include
major clinical scanner manufacturers (GE, Siemens, Philips, Picker, etc),
small-bore MR instrument and third party MR equipment manufacturers (Varian,
Bruker, SMIS, MEDRAD etc). The discussions should address the timely
maintenance of the above capabilities in system upgrades as it affects ongoing
NCI sponsored research and, especially, multi-center trials. The discussions
should include possible mechanisms for NCI support of industry or partnerships
for multi-center trials, as well as safety, legal, and proprietary issues
associated with third party suppliers.
B. The NCI should provide programmatic means whereby
manufacturers, and moreover, appropriately qualified scientists and engineers
from the manufacturers' research and development effort, can be invited to
participate directly in multi-institutional trials as partners. The focus group
feels that a binding commitment from equipment manufacturers for maintaining
MRS functionality over the course of a multi-year multi-institutional research
study is essential to the success of such studies.
C. The NCI should develop funding mechanisms to directly support
industrial development of technologies key to human MRS studies including
state-of-the-art hardware (optimized coils, phased-arrays, non-1H
quadrature detectors etc), software (pulse sequences etc), and data processing.
The focus group recognizes that the development and inclusion of MRS is ideally
addressed in a MRS product fully integrated into standard clinical commercial
clinical scanners. The NCI MRS Focus group strongly recommends that the major
commercial MRI scanner manufacturers embrace MRS in such a fully integrated
product. This is the preferable solution for the long term but its realization
faces an uphill battle given the reluctance to date of the major commercial MRI
scanner manufactures to embrace MRS. However, the significance and potential
impact of MRS in cancer that is evident from the data available so far urge
that a short term solution be supported that will ensure the timely
availability of clinical MRS in ongoing studies. NCI support of niche
manufacturers and third party vendors may provide a viable means of addressing
the need for state-of-the-art MRS technology in the short term.
3. High Field MR Systems for Cancer Research
In vivo MR spectroscopy is limited by sensitivity and spectral
resolution. These limitations can be overcome by making available MR magnets
that are at higher field strength than current clinical MR magnets possessing
field strengths £ 1.5 tesla. With higher magnetic
fields (³ 3 tesla), significant gains in sensitivity
and spectral resolution are possible, and these improvements will have a major
impact on clinical cancer research. Currently, access to high field human
systems for cancer research is very limited.
Specific Recommendations:
A. The NCI should provide programmatic means to make available
high field MR systems at NCI funded Cancer Centers as well as other
institutions demonstrating an equivalent level of clinical cancer research. It
is recommended that the magnetic fields of such high field systems be
³ 3 tesla.
B. The NCI should provide programmatic support for technical
development (e.g., transmit/receive coils, pulse sequences, etc.) specific to
the high magnetic field clinical research MRS applications.
4. Technical Development
Clinical MRS is a technically demanding modality, which in
general has been only partially developed, supported and exploited by the
manufacturers. It has also been difficult to obtain investigator initiated
funding for the development of the software and hardware necessary to support
the evolution and optimization of clinical MR studies.
Specific Recommendations:
A. Specific NCI programmatic funding should be allocated for the
development of pulse sequences, data analysis, spectroscopic standardization,
informatics technology, display strategies and methods for the integration of
MRS data with the large range of other clinical information.
B. Likewise, NCI support should be directed toward the
development of robust, high-speed shimming algorithms and multinuclear
transmit/receive coils.
C. In addition we recommend the funding of specific training
programs for clinical MRS at all levels. (See also, 1D above.)
5. Pre-clinical research
Applications of MRS to cancer have a history of strong and
fruitful interactions between clinical and pre-clinical (basic) research. This
has involved a two-way transfer of information: i.e. discoveries made in animal
models have been used to formulate hypotheses underlying clinical research, and
clinical observations have spawned important research into underlying
biochemical mechanisms. For example, dramatic changes in phosphomonoester
levels in response to therapy, first observed by 31P-MRS in humans,
have been characterized in tumor xenograft models. Similarly, the consistent 1H-MRS
visible difference in choline levels between malignant and normal brain,
prostate and breast tissues has stimulated basic research into the metabolism
of these compounds in cultured cells and tumors.
Current technical developments in MRS also place this technology
at the cutting edge of non-invasively investigating the distribution and
metabolism of conventional and novel therapeutic agents, such as transgene
expression. Significant differences between humans and animal/cellular models
must, however, be taken into account. The overall goals for MRS involving model
systems are to help cancer prognosis and to improve cancer therapy. Toward this
end we recommend NCI programmatic funding directed at the four fundamental,
basic research areas described below.
Specific Recommendations:
A. The NCI should provide support for research directed toward
the delineation of the mechanisms underlying metabolic processes observed by
MRS in the clinic. Knowledge of the biochemistry underlying spectral changes is
essential to the rational utilization of MRS in clinical practice. More
profound basic knowledge could be used to improve the sensitivity or
specificity of the clinical MRS exams.
B. The NCI should provide support for basic MRS research
directed toward pharmacokinetics and pharmacodynamics and other biochemical
methods of enhancing tumor response. Development of novel therapeutic agents
requires accurate knowledge of their biodistribution and metabolism. This can
involve the use of MRS markers as early surrogate endpoints, or actual
monitoring of drugs, gene therapy or immunotherapy. MRS-visible metabolites can
change early in response to successful therapy. Hence, monitoring tumor
response with MRS can be used to predict the eventual effectiveness of the
putative therapy. Additionally, the regional delivery of therapies can be
directly monitored with MRS and MRI.
C The NCI should provide support for basic research directed
toward development of novel MRS-visible markers of tumor-specific physiology or
metabolism. There is a long history of developing exogenous markers of in vivo
physiology and metabolism and this effort should continue. For example,
indicators of phospholipid metabolism, pH, Ca2+, pO2 and
compartment specific volume have all been successfully applied to tumor model
systems.
D The NIH should provide support for the emerging application of
exogenous markers or agents that recognize specific enzymes or gene expression
products to generate MRS-visible signals. It is conceivable that methods could
be developed to not only identify tumors at different stages, but also to
interact with signaling pathways to abort carcinogenesis.
Appendix
A.1. Summaries of Presentations by Focus Group Participants.
Jeffry R. Alger
University of California, Los Angeles
Magnetic Resonance Spectroscopy of Brain Cancer
The presentation summarized background and recent findings
related to MRS characteristics of primary glioma and the clinical
implementation of routine MRS scanning for glioma. The presentation did not
consider metastatic infiltration of the brain; this condition has not been
significantly evaluated with MRS. Rarer forms of primary glioma were also not
discussed. The discussion of pediatric glioma was deferred to Dr. June Taylor.
Primary glioma represents a significant health problem. Each
year, there are approximately 35,000 new cases of primary glioma diagnosed in
the United States and 17,000 deaths are annually attributed to this condition.
Over half the newly diagnosed cases are gliobastoma multiforme; these patients
have a statistical life expectancy of about 9 months. There is epidemiological
evidence supporting an increased incidence of primary glioma beginning in the
1960's. The histopathological assessment of readily identifiable microscopic
features (pleomorphism, endothelial proliferation, mitoses and necrosis) within
a standardized simplified classification system developed at the Mayo Clinic is
used to grade primary glioma. The presently-used histopathological
classification system is justified by its prognostic value; it predicts
survival well. This emphasizes that diagnosis and prognosis are not independent
of each other. Hence when new imaging technologies such as MRS are assessed,
one can not arbitrarily separate their diagnostic and prognostic capabilities.
The first proton MRS study of human glioma appeared in 1989. The
majority of subsequent papers and the clinical use emphasis has been on proton
(1H) MRS. Nevertheless, there are some examples of successful 31P
MRS studies of human glioma. Technological factors have biased the progress in
the direction of proton MRS. The 1989 paper addressed the possibility of
obtaining a preoperative (noninvasive) diagnosis of tumor type and grade using
proton MRS. Since this time there have been more that 60 publications reporting
the results of single and multiple center studies of the MRS characteristics of
glioma. The majority of the existing work points toward the ability of MRS to
make preoperative diagnoses. Given that surgical resection is palliative for
glioma and that a growing armamentarium of neurosurgical navigation tools now
permits safe neurosurgery, patients having suspected glioma are rarely treated
without surgical debulking or biopsy. The need for a noninvasive diagnostic
procedure, such as MRS is thereby lessened. On the other hand, the glioma
management represents an area of opportunity for MRS. MRS can provide valuable
clues regarding when to initiate further palliative treatment and whether
treatments are being effective in reducing tumor burden.
Paul A. Bottomley
Johns Hopkins University
Metabolic Imaging of Nuclei other than Hydrogen.
While our research has focused primarily on developing
metabolite quantification and imaging technologies for the human heart, these
technologies are also directly applicable to human cancer studies.
Specifically, we have developed methods for quantifying absolute concentrations
of the creatine kinase metabolites, phosphocreatine and adenosine triphosphate
using phosphorus (31P) MRS and total creatine using 1H
MRS, and of total sodium with sodium (23Na) MRI (1-3). An important
focus is the development of techniques to directly image metabolites on a
clinical 1.5 T research scanner (3). Technologies that have long been
established and proven advantageous for clinical 1H MRI such as
phased-arrays and quadrature detection are simply unavailable for MRS on many
clinical scanners. Nor is MRI commercially available for non-1H
nuclei. We have developed our own broadband phased-array system for use with a
conventional narrowband 1H phased-array system, incorporating
multi-channel RF mixers. This system was implemented in human cardiac studies
with both 23Na and chemically-selective 31P phased-arrays
(3). I show here some preliminary 3D 23Na MRI data (collaboration
with C. Constantinides and M. Pomper) obtained indicating elevated sodium in a
brain tumor, consistent with early work showing elevated sodium levels in
cancerous tissue. The future of broadband MRS and standard detector coil and
decoupling technologies on clinical research scanners is a significant concern
for our work.
1. Bottomley PA, Atalar E, Weiss RG. Human cardiac high-energy
phosphate metabolite concentrations by 1D-resolved NMR spectroscopy. Magn Reson
Med 1996; 35: 664-670.
A. Bottomley PA, Weiss RG. Noninvasive MRS detection of localized creatine
depletion in non-viable, infarcted myocardium. The Lancet 1998; 351: 714-718.
B. Lee RF, Giaquinto R, Constantinides, Souza, S, Weiss RG, Bottomley PA. A
broadband phased-array system for direct phosphorus and sodium metabolic MRI on
a clinical scanner. Magn Reson Med 1999 (submitted)
Zaver M. Bhujwalla
Johns Hopkins University
Magnetic Resonance Spectroscopy in Exerimental Models of Breast
and Prostate Cancer
The role of MRS in Clinical Oncology was discussed in the
context of data obtained by us (Oncology Section - MR Research, JHU Radiology)
in experimental studies using human breast and prostate cancer models. These
data further support the role of MRS in (i) Detection / Diagnosis / Prognosis
and (ii) Therapy.
Detection/Diagnosis/Prognosis
- Malignant Transformation: Using a panel of human mammary
epithelial cells we observed that total choline and phosphocholine increased
with progression from normal mammary epithelial cells to fully transformed
malignant invasive human breast cancer cells (Ref: Aboagye and Bhujwalla,
Cancer Research, 1999). Similar increases were also observed for lactate
concentrations.
- Metastatic behavior: Transfection of highly metastatic human
breast cancer cells (MDA-MB-435) with the metastasis suppressor gene nm23-H1
resulted in a significant increase in PDE/PME levels in solid tumors derived
from the nm23 transfected line compared to the non transfected tumors.
Significant differences in pHi and pHe were also observed.
(Ref: Bhujwalla et al., MRM, 1999 (in press)).
Therapy
- Treatment of malignant human breast cancer cells with the
cyclooxygenase inhibitor indomethacin (50 _m) altered the 'invasive
phospholipid phenotype' towards the 'non-malignant phospholipid phenotype'.
(Data to be presented at ISMRM, 1999)
- It is possible to detect the conversion of the prodrug
5-Fluorocytosine to 5-Fluorouracil in vivo using 19F MRS. In vivo
tumor data were presented for receptor targetted antibodies carrying the
cytosine deaminase gene directed to antigens on the surface of cancer cells.
(Ref: Aboagye et al., Cancer Research, 1998).
- Pharmacoangiography data were presented to demonstrate the
role of 1H/13C MRI/MRSI in predicting and detecting
delivery and distribution of drugs within solid tumors. (Data to be presented
by Artemov et al., ISMRM, 1999).
Patrick M. Colletti
University of Southern California
Spectroscopy with 5FU and Pharmacokinetic Imaging in Cancer
With regard to tumor, there are usually three general questions:
(1)What is it? (Single Voxel MRS), (2) Where is it? (2D/3D MRS), (3) What is
happening to it? (Sequential/Dynamic MRS).
For cancer treatment to be successful, targeting of
chemotherapeutic drugs must be individually optimized. A dose that may be
effective in one patient may be ineffective in another and toxic in a third,
due in large part to tumor heterogeneity, both spatial and temporal.
Noninvasive studies (functional imaging and pharmacokinetic imaging) are
critical in measuring, in a given patient at a given stage of disease, both the
pathophysiology of tumors as well as whether the chemotherapeutic agent will be
delivered to that tumor mass at the right rate and at the right dose.
Fluorinated drugs, including but not limited to 5-FU, gemzar,
FdUR, capecitabine, UFT, and many others, offer a unique opportunity for
noninvasive studies using the high NMR sensitivity of 19F in the
absence of naturally occurring fluorinated compounds. Integration of such
noninvasive 19F measurements with pharmacokinetic methods allows,
for the first time, direct measurements of tumoral pharmacokinetics of
anticancer agents, and thereby, the prediction of response, dose optimization,
quantitation of the effect of modulators, as well as mechanistic studies. Not
only are such 19F measurements of great significance to the very
large number of patients treated with fluorinated drugs, but they also serve as
models for the expansion of such pharmacokinetic imaging studies to drugs where
the nuclei to be measured would be 1H, 13C or others.
Jeffrey L. Evelhoch
Wayne State University
MultiCenter 31P Magnetic Resonance Spectroscopy Trial
A group of 6 institutions from the US (Duke University, Fox
Chase Cancer Center, Memorial Sloan-Kettering Cancer Center, University of
California at San Francisco, University of Pennsylvania, Wayne State
University), 2 institutions from the UK (The Royal Marsden Hospital, St.
George's Hospital Medical School) and 1 institution from The Netherlands
(University Hospital Nijmegen) have been participating in a multi-center
project to develop and implement 31P MRS in clinical oncology since
1995. The major goals of this project are to test the hypothesis that the in
vivo 31P MR spectrum can predict sensitivity or resistance
to treatment in patients with non-Hodgkin's lymphoma, soft tissue sarcomas, or
head and neck cancer by correlating the initial response to metabolic features
in the baseline spectrum and to changes that occur in the spectrum early after
the initiation of treatment.
During the first three years we received NCI support enabling us
to implement uniform spectroscopic and imaging procedures, develop and
distribute tumor-specific 1H/31P coils, establish
protocols for transfer of imaging and spectroscopic data in a common format,
establish procedures for quality control and quality assurance, and test
spectral analysis and quantification. With these capabilities in place at all
institutions and increased NCI support during the fourth and fifth years of
this project, patient accrual has begun at an increased rate. Initial results
for non-Hodgkin's lymphoma are very encouraging showing both a decrease in the
ratio of phosphomonoesters to NTP (PME:NTP) in patients responding to treatment
and, more exciting, a lower PME:NTP in naïve tumors prior to treatment.
Michael Garwood
University of Minnesota
Future Technical Prospects for Clinical MRS
The biochemical information and spatial resolution achievable
with localized MRS are limited by the inherent low sensitivity of MRS and the
low concentrations of metabolites in vivo. Significant gains in sensitivity and
spectral resolution are possible with higher magnetic fields (³
3 tesla), and such improvements will have a major impact on the usefulness of
in vivo MRS in clinical cancer research. Recent results obtained from human
studies at 4 tesla and animal studies at 9.4 tesla provide solid evidence of
the benefits of high fields. Increases in sensitivity, chemical-shift
dispersion, and spectral simplifications of coupled spin systems allow
previously unresolved resonances to be readily observed and accurately
quantified. For most applications, high field MRS will not be limited by FDA
guidelines regarding the allowable specific absorption rates (SAR), since
spectroscopy scans are usually performed using a low duty cycle (i.e., long
repetition time, TR).
Further methodological developments are also needed to optimize
sensitivity and to fully extract the wealth of physiologic information that
high field MRS can offer. (1) RF transmit/receive coil developments. (2)
Spectral editing methods to separate lactate from overlapping mobile lipid
peaks in tumors. (3) Indirect (1H) detection methods which will
maximize sensitivity in dynamic studies of the metabolism of
isotopically-enriched substrates (e.g., 13C-labeled glucose). (4)
Fast automated shimming of first and second order shims is essential to
maximize spectral resolution and information content. (5) Broadband selective
RF pulses that minimize chemical-shift-induced displacement of the volume of
interest (VOI) in single-voxel spectroscopy.
Robert J. Gillies
University of Arizona
MRS of Cancer: Metabolic Basis
The major points of my presentation were that (1) MRS reveals
information not obtainable by other techniques, (2) pre-clinical studies are
important and (3) exogenous indicators of physiology are useful.
MRS reveals information not obtainable by other techniques
because only compounds with short correlation times are visible. This is
exemplified by the fact that alanine or lactate are often not completely
visible in vivo, yet extracts of the same tissues reveal much higher levels.
This suggests that these metabolites may be compartmentalized in a non-visible
pool (e.g. bound to macromolecules). Another example is the observation of
mobile lipids in cancer cells with high metabolic potential. These lipids
correspond to small intracellular lipid droplets, which would not be
distinguished by other techniques. MRS can be used to investigate the
biophysical behavior of these droplets. Additionally, MRS is uniquely
appropriate for in vivo longitudinal studies of metabolism since it is
non-destructive. In many experiments the steady-state levels of metabolites can
be monitored in at the same time as pathway flux, providing an unprecedented
window on metabolic control.
Model systems include animals, cultured cells in bioreactors,
and extracts of cells and tissues. These can be used to develop hypotheses for
later application in the clinic, or can be used to follow up clinical
observations with high resolution. For example, phosphomonoesters have long
been shown to be altered in tumors relative to normal tissues, and to change in
response to successful therapy. These observations have been followed up in
animal models and in vitro to characterize the control of phosphomonoester
metabolism.
A final, important application of MRS is the use of exogenous
indicators of physiology and metaoblism. These have included phosphonoium
choline, 2-deoxyglucose, 3-Amino propylphosphonate, Dimethyl methylphosphonate,
Fluoro BAPTA, and Imidazoles (e.g. IEPA). These allow the observation of
metabolic and physiologic parameters that are not accessible via non-invasive
spectroscopy and increase the applicability of the technique in vitro and in
vivo.
Jerry D. Glickson
University of Pennsylvania
Molecular Targets for MRS & "Smart MRI" in Oncology
Endogenous Probes
Phosphorus-31 was the first nucleus studied by in vivo NMR
spectroscopy of tumors. Detectable molecules include energy metabolites
(nucleoside di- and triphosphates (NTP, NDP), phosphocreatine (PCr), inorganic
phosphate (Pi)), pH indicators (Pi) and phospholipid
metabolites (phospomonoesters (PME) and phosphodiesters (PDE)). This phase of
MRS cancer research has now progressed to clinical evaluation. Proton
spectroscopy has been used to detect lactate, choline metabolites (Cho),
creatine and PCr, citrate (in the prostate), N-acetylaspartate (NAA; in the
brain) and various amino acids (e.g., alanine, glutamate and taurine). This
research has reached a mature state with brain tumors, but is still in the
developmental stage for detection of tumors outside the brain. Other nuclei
need to be explored at natural abundance.
The third most sensitive naturally occurring NMR is 23Na.
Of particular interest to cancer are reports originating from Ephraim Racker
that tumors contain an aberrant Na+,K+ ATPase, leading to
an increase in intracellular levels of 23Na. This could provide a
basis for tumor diagnosis if appropriate methods can be developed for
distinguishing between intracellular and extracellular sodium. In addition, 23Na
NMR could provide a sensitive method for detecting edema and for monitoring
response to therapy. Dr. Navin Bansal has been developing methods to
distinguish between intracellular and extracellular sodium in tumors, using a
sodium shift reagent TmDOTP and multiple quantum coherence transfer. The shift
reagent displaces the resonance of extracellular sodium from the intracellular
sodium peak in the single quantum spectrum; however, this agent cannot be used
in the clinic because it modifies blood pressure. For clinical studies multiple
quantum measurements permit approximate distinction between intracellular and
extracellular compartments, the intracellular component remaining approximately
constant in intensity, while the intracellular component changes in intensity
with various interventions. Robert Lenkinski has obtained 23Na
images of the human brain at 4T, which are comparable in quality to 1H
brain images obtained in the early stages of development of 1H MRI.
Exogenous Probes
Physiological indicators. Gillies' laboratory has
pioneered the development of probes for monitoring extracellular pH. Their
first agent was 3-aminopropylphosphonate (3APP); Pi served as an
indicator of the approximate intracellular pH (since this metabolite occurs in
both compartments at comparable concentrations, but the intracellular
compartment usually comprises ~70% of the tumor volume). The key limitation of
3APP was the limited spatial resolution of 31P MRS. Much higher
resolution has recently been obtained by Gillies' laboratory using imidazole
derivatives, which are detectable by 1H MRS. Sha He and Ralph Mason
have recently developed 6-fluoropyridoxamine (6FPAM), a fluorinated derivative
of vitamin B6 detectable by 19F MRS. This agent
simultaneously measures both intracellular and extracellular pH with
sensitivity comparable to the imidazole analogs of Gillies. In highly necrotic
tumors the extracellular volume may be comparable to or greater than the
intracellular volume; consequently, Pi is no longer a good indicator
of pH under these conditions. 6FPAM does not suffer from this limitation.
There is a need to develop indicators for monitoring various
other physiological properties of tumors. These include the calcium
concentration, since F-BAPTA has proven to be of limited utility, and the pO2,
which is a critical determinant of tumor radiosensitivity. Meade's laboratory
has developed an ingenious scheme for sensitive detection of calcium. They have
synthesized caged chelates of Gd in which all seven ligation sites of the
lanthanide are coordinated to the chelate. In the presence of calcium one arm
of the chelate swings over to bind to the calcium ion, thereby exposing the Gd
to water and producing efficient water relaxation that is readily detected by
MRI. The method is capable of detecting free calcium concentrations in the
micromolar range, i.e. the physiologically relevant range. Pefluorocarbons have
been used as oxygen indicators, but have limited utility because they are not
sensitive in the radiobiologically relevant range of hypoxia (< 5 Torr), and
because they have to be administered in very large concentrations as lipid
emulsions, which bind oxygen and, hence, may modify the physiological parameter
they measure. More effective oxygen probes need to be developed for MRS.
The Warburg Hypothesis, i.e. that tumors exhibit anomalously
high levels of aerobic glycolysis, has been the foundation of tumor detection
by PET using 2'-fluorodeoxyglucose (FDG). While this hypothesis has been
questioned as a universal indicator of malignancy, it still has proven useful
in detection of many tumors and metastases. Shulman's laboratory has
demonstrated the power of 13C MRS measurements not only of
glycolysis but of virtually all aspects of glucose metabolism, e.g. the pentose
shunt, the glycogen pathway and the TCA cycle. While 13C-labeled
glucose is expensive, the overall cost of such measurements is less than that
of PET examinations, and the method can be implemented virtually on all
clinical MRI instruments operating at 1.5 T or higher. This methodology needs
to be implemented in the clinic and in animal models.
Gene Therapy Markers. Gene therapy is currently being
explored as a novel and promising method for treatment of cancer. There is a
need to develop markers of transfection consisting of proteins which produce
products detectable by MRS or MRI that are expressed together with the target
gene. One such agent, arginine kinase an enzyme that normally does not occur in
mammals, has recently been developed by Walter and Sweeney for gene therapy of
muscular dystrophy. This enzyme produces phosphoarginine whose resonance can be
distinguished from PCr in the 31P spectrum. Phosphoarginine may
serve as a marker gene for gene therapy of other diseases, including neoplasms
such as rhabydomyosarcomas. Of particular current interest in oncology is the
use of suicide gene therapy - transfection of tumors with genes that
selectively sensitize them to cytotoxic agents. Drs. Ross and Bhujwalla will
present data at this meeting on the use of cytosine deaminase to convert the
prodrug fluorocytosine to the cytotoxic agent 5-fluorouracil (5FU). In this
instance the cytoxic agent is acting as both a marker of gene expression and a
drug for treatment of the neoplasm. Similar schemes are being implemented with
herpes simplex virus thymidine kinase transduction of tumors to sensitize them
to gancyclovir therapy, which can be monitored by PET with 18F-labeled
gancyclovir.
Receptor Targeting. A number of tumors over express low
density lipoprotein (LDL) receptors, presumably because of requirements for
cholesterol and fatty acids in membrane synthesis. Since the classic studies of
Goldstein and Brown elucidating how these receptors function, it has been
recognized that the LDL receptor system could be used for the selective
delivery of antineoplastic agents to tumors over expressing these receptors.
This is accomplished by replacing the lipid core of LDL with lipids containing
lipophilic antineoplastic agents. The same strategy could be used for the
detection of these neoplasms by delivery of MRS detectable or MRI detectable
molecules. Of particular interest is the possibility of replacing LDL by lipid
vesicles to which the much smaller lipoprotein, apoE (which is available in a
recombinant form), is attached. Incorporation of MRI/S detectable agents is
much more easily accomplished in vesicles than in the lipid core of LDL. The
LDL molecules or the apoE labeled vesicles bind to receptors on the cell
surface, are internalized and incorporated into lysosomes, in which the LDL or
apoE are hydrolyzed to amino acids, and the cholesterol esters and
phospholipids are hydrolyzed to their constituent components. Any agents that
are incorporated in the LDL or apoE/vesical are released. The receptors are
recycled to the cell surface, where they bind to and transport more LDL and
apoE/vesicle complexes into the cell. Our laboratory is developing this system
for delivery of various agents detectable by MRI/S or optical imaging to tumor
cells. This approach can be extended to other receptors. For example,
Weissleder's laboratory is developing a method for delivery of MRI contrast
agents to transferrin receptors, which are also over expressed by some tumors.
Some agents can be delivered by a nonspecific delivery system. For example,
molecular beacons, which utilize antisense technology to selectively identify
cells with specific mRNA molecules may be delivered by virosomes--influenzae
virus envelopes encapsulating the constructs. Gewirtz's laboratory has
developed these agents. The development of specific and nonspecific methods for
delivery of drugs, transfection agents and MRI/S contrast agents will go hand
in hand with the development of these novel therapeutic agents.
Specific Enzyme Probes. Meade's laboratory has
developed an extremely clever and potentially very useful method for detecting
specific enzymes by MRI. Again they have used the caged Gd strategy, but in
this instance the lanthanide is encapsulated not only by the chelator but also
by a cap consisting of a substrate for a specific enzyme. For example, they
have used a galactose cap to detect _-galactosidase (b-Gal). b-Gal hydroyzes
the bonds holding the galactose cap in place, thereby exposing the Gd ion for
coordination by water, whose relaxivity is thereby increased in proportion to
the concentration of the enzyme. They have demonstrated the methods in Xenopus
embryos, in which they have coexpressed b-Gal with the green fluorescent
protein. Regions that expressed the b-Gal were detectable both by MRI and by
fluorescence microscopy. They have also developed these probes for other
enzymes, such as glucuronidase; proteinases could also be targeted. Delivery of
such constructs could be accomplished by the vehicles we have described in the
previous section. This research demonstrates the feasibility of developing
novel contrast agents targeted at specific enzymes that occur in cancer cells.
Development of such "smart contrast agents" needs to be encouraged.
Cell Tagging. Weissleder and also Koretzky and Ho have
recently demonstrated that cells can be tagged with ferromagnetic iron
particles, which serve as MRI tracers for monitoring the transport of these
cells in the body. Such methods could be used to track the course of tumor
metastasis or other critical pathways.
Molecular Switches. I wish to illustrate an important
principle that is currently being developed for optical imaging, but which may
eventually be implemented in MRI/S. Molecular beacons are molecules consisting
of a loop of DNA or antisense DNA that is complementary to a specific target
mRNA. At the ends of the loop are 'stems" consisting of short sequences of
complementary DNA, which hold the ends of the loop together. Attached to the
stems are linkers, one of which is attached to a fluorophore, the other to a
quencher. The hydrogen bonds in the stem keep the fluorophore and quencher in
close enough contact to quench all the fluorescence. Consequently, in the
absence of the target mRNA no fluorescence is detected. When the target mRNA is
present, the loop hybridizes with it, and because there are many more base
pairs in the loop DNA-target mRNA hybrid than in the stem, the hydrogen bonds
holding the stem together are broken, thereby separating the fluorophore from
the quencher and producing detectable fluorescence. It is generally recognized
that these molecular probes can be used to detect specific RNA sequences. NMR
can, of course, never match the sensitivity of fluorescence spectroscopy;
consequently, NMR could not be used for nucleic acid detection, but it might be
used to detect more abundant enzymes, as Meade has recently demonstrated (see
above). Now consider more carefully what the molecular beacon is doing. When it
finds its target mRNA, the fluorophore emits a quantum of light energy that is
detected by the observer. Suppose, however, that on the other side of
fluorophore there was a molecule that could capture that quantum of light
energy and convert it into chemical energy to produce superoxide or hydroxy
radicals that were toxic to the cells, i.e. the fluorophore could activate an
agent suitable for photodynamic therapy. We would then never see the
fluorescence, but we might selectively kill the cells containing the target
sequence of mRNA. Agents such as this might be targeted to mRNA for mutant
tumor respressor or oncogenes, and might be used to selectively destroy not
only tumors but preneoplastic cells. Now, this is only a dream, and it will
require a great deal of resaearch to develop, but it provides a very attractive
strategy for development of very specific antineoplastic agents. The analog for
fluorescence quenching in MRS might be anti-ferromagnetic coupling, such as
exists in plant ferrodoxins, and instead of targeting mRNA, one might target
specific proteins in critical cell signalling pathways. The key principle we
are proposing is to design agents that detect specific molecules that are
modified in tumor progression, i..e. the "signatures of cancer," and generate
signals that either lead to cell death or turn off cell replication. I would
like to suggest to the NCI that it should encourage this type of research.
Pharmacokinetics
Fluorine Labeled Drugs: 5FU. The paradigm for MRS
pharmacokinetics of antineoplastic agents is 5FU. Griffiths' laboratory first
demonstrated in rats that 19F MRS could detect catabolism of this
agent in the liver and its anabolism in tumors. They have further shown in
animal models that response to this agent varies directly with the production
of 5FU nucleotides in the tumor; however, these key molecular predictors of
therapeutic response have only rarely been detected in the clinic (by Leach and
colleagues, personal communication). In most clinical studies only the parent
drug has been detected in the tumor. Wolf and coworkers have been conducting a
pilot clinical study of patients with colorectal cancer having metastases in
the liver. By measuring the half lives of 5FU in the liver (presumably in the
tumor) they have divided the patients into two categories - trappers (half life
> 20 minutes) and non-trappers (half life < 20 minutes). The trappers
consisted of patients that exhibited a response (16) and those that didn't
(11), but none of the non-trappers (30) exhibited response. Moreover, the
non-trappers comprised more than half the overall population of patients in the
study. If these results can be confirmed in a larger multi-institutional trial,
one would have a very simple method for identifying patients that are reliably
expected not to respond to this agent. These patients could be spared the
unnecessary toxicity and expense of treatment with this drug, or they could be
switched to other therapeutic regimens involving other agents or agents that
modulate 5FU activity.
Therefore, to quote a colleague of mine at this meeting (T.R.
Brown), "the time is ripe" for a clinical trial of MRS monitoring 5FU therapy
of colorectal cancer metastases to the liver. In addition, a great deal can be
done to improve the already impressive accomplishments of this method. No
localization was employed in monitoring these colorectal tumor metastases.
Localization methods need to be perfected for such studies. Sensitivity also
has been enhanced by using appropriate proton decoupling schemes and/or using
higher magnetic fields. These improvements would facilitate detection of 5FU
nucleotides that might prove much more reliable in predicting tumor responders.
Carbon-13 Labeled Drugs: Temozolomide. It is essential to
implement the principles demonstrated with 5FU with other, more potent agents.
Recognizing that labeling of non-fluorinated drugs with fluorine often modified
their pharmacological activity, Artemov et al. demonstrated that it was
possible to label and detect antineoplastic agents with 13C with
little or no modification of pharmacological activity. We chose to demonstrate
this principle on temozolomide, a new alkylating agent active against brain
tumors and melanomas. Studies were performed on RIF-1 tumors subcutaneously
implanted in mice. The drug was detected by 13C MRS with
polarization-transfer from protons. Even higher sensitivity might be achieved
by 1H detection of heteronuclear multiple quantum coherence, but at
the time this study was performed, the indirect detection method produced
excessive heating of the tumor. The mouse studies employed a substantially
higher concentration of the drug than is used in the clinic. Studies in dogs
have been proposed to determine if the drug can be detected at clinically
relevant levels by using larger voxels.
Proton MRS Detection of Antineoplastic Agents. Cisplatin
and its analogs are widely employed in cancer chemotherapy. The parent drug is
used at too low a concentration for detection by MRS, but the organoplatin
analogs are used in more appropriate concentrations. Iproplatin, one of these
analogs, contains 12 equivalent methyl protons, which unfortunately coresonate
with the methyl protons of lactic acid. However, He et al. demonstrated that it
is possible to selectively detect this agent by using multiple quantum
coherence transfer from the methine hydrogen on the isopropyl groups. While
this agent is not widely used in the clinic, the same principle could be used
to detect other cisplatin analogs such as carboplatin. This approach is more
practical than labeling with 13C (see above) because it avoids the
very difficult problem of custom synthesis of these agents under Good
Manufacturing Practice conditions for clinical use. Therefore, we recommend
that the NCI encourage the development of MRS methods for monitoring the
pharmacokinetics of effective antineoplastic agents (such as cisplatin analogs)
which can be detected in their native state without isotopic or fluorine
labeling.
MRI Detection of Paramagnetic Antineoplastic Agents.
It has long been recognized that porphyrins tend to selectively localize in
tumors. In fact, this forms the basis of photodynamic therapy. The Texophryns
are porphyrin-like agents that contain Gd coordinated to the "porphyrin" ring.
They also have been proposed as photosensitizers in photodynamic therapy. At
the meeting showed an image (provided by Dr. David Rosenthal, U. Penn) of a
patient with brain metastases of a non-small cell lung carcinoma. No tumor was
visible in the brain, but after administration of texophryn the tumor was
clearly delineated; no other enhancement was detected in the brain. The
photosensitizer was simultaneously serving as a tumor selective MRI contrast
agent. Development of such tumor selective MRI contrast agents/therapeutic
agents should be encouraged by the NCI
Jason A. Koutcher
Memorial Sloan Kettering Cancer Center
Magnetic Resonance Spectroscopy in Oncology at Memorial Sloan
Kettering
Dr. Koutcher presented some of the ongoing magnetic resonance
spectroscopy at Memorial Sloan Kettering Cancer Center (MSKCC). As part of the
Multi-Institutional 31P NMR Tumor Consortium, the NMR group at MSKCC
has been studying sarcomas, breast and head and neck tumors. Dr. Koutcher
showed several spectra showing differences in responding and non-responding
patients with sarcomas. These included early studies without decoupling, and
more recent studies with decoupling. High quality spectra with resolution of PE
and PC were shown. Non-responding patients often showed little change in the
spectra over time. Spectra from normal breast tissue and advanced breast
carcinomas were also presented.
Preoperative studies of osteogenic sarcoma of the lower
extremity using Gd-DTPA uptake were also presented. After measuring the initial
slope of the increase in signal intensity vs. time, the fraction of voxels with
a slope less than a predetermined threshold was used to estimate the tumor
necrotic fraction. Using this technique, data on 8 patients showed a good
correlation between the "Huvos grade" and predicted necrotic fraction, with 7
out of 8 patients classified correctly.
1H NMR prostate and brain studies are also ongoing at
MSKCC. The brain studies focus on primary lymphoma of the brain. The prostate
studies are done using software obtained from the University of California at
San Francisco (Dr. Kurhanewicz, Nelson and Vigneron) and are focusing on
assessing response and residual tumor in "poor risk" patients undergoing
pre-operative neoadjuvant chemotherapy (estramustine, carbo-platinum and
paclitaxel) and hormones. Serial spectra were shown which displaying the
effects of these drugs on 1H NMR spectra and pathologic correlation
is ongoing. In conjunction with this research effort, studies of 1H
NMR spectra of human xenografts to determine whether the spectra can monitor
the effects of different therapies and predict response were also presented.
Since the interaction between animal/cell and clinical studies
is considered essential for the further development of MRS in oncology, 2
potential applications were presented in animal tumor models. With the
development of cytostatic anti-neoplastic agents for clinical trials ongoing, a
method of assessing response is essential. 31P NMR spectra from
murine mammary carcinomas were presented which were sued to assess the effect
of Combretastatin A-4 phosphate on tumor metabolism, as a surrogate of blood
flow. Within 30-60 minutes there was almost complete loss of nucleoside
triphosphates and phosphocreatine. In contrast to previous studies evaluating
the effect of this drug on tumor perfusion, significant recovery was present in
4 hours, suggesting that multiple doses or continuous infusion of the drug may
be necessary. NMR spectroscopy is an ideal tool for studying the effects of
metabolic inhibitors. The effect of a 3 drug combination
(N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR),
and 6-aminonicotinamide (6AN)) on tumor metabolism was presented. The NMR data
was used to determine the timing between the drugs and radiation based on when
tumor metabolism was maximally inhibited. While the drugs alone induced no
complete responses (CRs), and radiation only induced a single (1/20) CR which
only lasted a few weeks, the combination of the drugs and radiation
(administered when the NMR data demonstrated maximal metabolic inhibition),
yielded a 65% CR rate and a 25 % durable (< 1 year) CR rate, without further
treatmennt.
A.2. Roster of Focus Group Participants.
Invitees and Meeting Organizers
- Joseph J.H. Ackerman, Washington University, St.
Louis (Focus Group Chair)
Addr: Washington University
Department of Chemistry
Campus Box 1134
One Brookings Drive
St. Louis
St/Zip: MO 63130-4899
Office: (314) 935-6593/6582
Fax: (314) 935-4481
Email: ackerman@wuchem.wustl.edu
- Jeffry R. Alger, University of California, Los
Angeles
Addr: UCLA - Dept of Radiological Sciences
10833 Le Conte Avenue
Los Angeles
St/Zip: CA 90024-1721
Office: (310) 206-3344
Fax: (310) 794-7406
Email: jralger@ucla.edu
- Zaver M. Bhujwalla, Johns Hopkins University,
Baltimore
Addr: The Johns Hopkins University School of Medicine.
Department of Radiology
NMR Research Lab.
Rm 208C Traylor Bldg.
720 Rutland Avenue
Baltimore
St/Zip: MD 21205
Office: (410) 955-9698/4221
Fax: (410) 614-1948
Email: zaver@mri.jhu.edu
- Paul A. Bottomley, Johns Hopkins University,
Baltimore
Addr: The Johns Hopkins University School of Medicine
Department of Radiology
601 North Caroline Street
Baltimore
St/Zip: MD 21287-0843
Office: (410) 955-0366
Fax: (410) 614-1977
Email: bottoml@mri.jhu.edu
- Truman R. Brown, Fox Chase Cancer Center,
Philadelphia
Addr: Fox Chase Cancer Center
NMR Laboratory
7701 Burholme Avenue
Philadelphia
St/Zip: PA 19111
Office: (215) 728-3049
Fax: (215) 728-2822
Email: tbrown@abel.fccc.edu
- H. Cecil Charles, Duke University, Durham
Addr: Department of Radiology
MRI Center
Room 1800
Mail Drop Box 3808
Duke University Medical Center
Durham
St/Zip: NC 27710
Office: (919) 684-7350
Fax: (919) 684-7126
Email: cecil@ethel.mc.duke.edu
- Patrick M. Colletti, University of Southern
California, Los Angeles
Addr: LAC-USC Imaging Science Center
1744 Zonal Avenue
Los Angeles
St/Zip: CA 90033
Office: (323) 221-2744
Fax: (323) 221-2982
Email: colletti@hsc.usc.edu
- Jeffrey L. Evelhoch, Wayne State University, Detroit
Addr: Harper Hospital
Magnetic Resonance Center
3990 John R. Street
Detroit
St/Zip: MI 48201
Office: (313) 745-1395
Fax: (313) 745-1374
Email: evelhoch@med.wayne.edu
- Michael Garwood, University of Minnesota,
Minneapolis
Addr: Center for Magnetic Resonance Research
385 East River Road
University of Minnesota
Minneapolis
St/Zip: MN 55455
Office: (612) 626-2436
Fax: (612) 626-7005
Email: gar@cmrr.umn.edu
- Robert J. Gillies, University of Arizona, Tucson
Addr: University of Arizona Arizona Health Science Center
Department of Biochemistry
Tucson
St/Zip: AZ 85724
Office: (602) 626-5050
Fax: (520) 626-2110
Email: gillies@biosci.arizona.edu
OR gillies@u.arizona.edu
- Jerry D. Glickson, University of Pennsylvania,
Philadelphia
Addr: University of Pennsylvania
Dept. of Radiology
422 Curie Blvd. b1 Stellar-Chance Laboratories
Philadelphia
St/Zip: PA 19104
Office: (215) 898-1805
Fax: (215) 573-2113
Home: (215) 654-9772
Email: glickson@mail.med.upenn.edu
- Jason A. Koutcher, Memorial Sloan Kettering Cancer
Center, New York
Addr: Memorial-Kettering Cancer Ctr.
Dept. of Medical Physics
1275 York Avenue
New York
St/Zip: NY 10021
Office: (212) 639-8834
Fax: (212) 717-3010
Email: koutcher@mpcs.mskcc.org OR
koutcher_jason/mskcc_medicine@mskmail.mskcc.org
- John Kurhanewicz, University of California, San
Francisco
Addr: University of California at San Francisco
Department of Radiology
Magnetic Resonance Center, Box 1290
1 Irving Street
San Francisco
St/Zip: CA 94143
Office: (415) 476-0312
Fax: (415) 476-8809
Email: john.kurhanewicz@mrsc.ucsf.edu
OR johnk@mrsc.ucsf.edu
- Robert E. Lenkinski, University of Pennsylvania,
Philadelphia
Addr: University of Pennsylvania Hospitals
Department of Radiology
David W. Devon Imaging Center
3400 Spruce Street
Philadelphia
St/Zip: PA 19104
Office: (215) 662-6054
Fax: (215) 662-3013
Email: bob@mrssparc.mri.upenn.edu
OR bob@oasis.rad.upenn.edu
- Sarah J. Nelson, University of California, San
Francisco
Addr: University of California
Department of Radiology
Magnetic Resonance Science Center
San Francisco
St/Zip: CA 94143-0628
Office: (415) 476-6383
Fax: (415) 476-8809
Email: nelson@mrsc.ucsf.edu
- Brian D. Ross, University of Michigan, Ann Arbor,
Addr: University of Michigan
Department of Radiology
1150 West Medical Center Drive
MSRB III, Room 9303, Box 0648
Ann Arbor
St/Zip: MI 48109-0648
Office: (734) 763-2099
Fax: (734) 747-2563
Email: bdross@umich.edu
- Dan M. Spielman, Stanford University, Stanford
Addr: Stanford University
Radiology Department
Lucas MRS Building
1201 Welch Road
Stanford
St/Zip: CA 94305
Office: (650) 723-8697
Fax: (650) 723-5795
Email: dan@s-word.stanford.edu OR
dan@lucas.stanford.edu
- Daniel C. Sullivan, National Cancer Institute,
Bethesda
Associate Director
Diagnostic Imaging Program, NCI
EPN, Room 800
6130 Executive Blvd.
Rockville, MD 20892-7440
Tel: 301 496 9531
Fax: 301 480 5785
sullivand@dtpepn.nci.nih.gov
ds274k@nih.gov
- James Tatum, National Cancer Institute, Bethesda
tatum@hsc.vcu.edu, tatumj@mail.nih.gov
- June S. Taylor, St. Jude Children's Research
Hospital,Memphis
Addr: St. Jude Childrens' Resarch Hospital
Department of Diagnostic Imaging
332 North Lauderdals
Memphis
St/Zip: TN 38105-2794
Office: (901) 495-2501
Fax: (901) 527-0054
Email: june.taylor@stjude.org
A.3 National Cancer Institute MRS Focus Group Agenda
1H and 31P Magnetic Resonance Spectroscopy in Clinical
Oncology
Day 01: Thursday, April 22, 1999
2:00 Opening Remarks
Dan Sullivan and Joe Ackerman
2:15 Biological Basis for MRS in Oncology
Robert Gillies (15 min)
Jerry Glickson (15 min)
- Background; accessible molecules; what might
distinguish tumors fromnormal tissue and/or define classes of tumors and/or
appropriate therapy; use of labeled drugs or metabolic markers; probing
specific aspects of metabolism at pharmacologic doses.
3:00 Technical Overview of Clinical MRS
Sarah Nelson (15 min)
Cecil Charles (15 min)
3:45 Future Technical Prospects for Clinical MRS
Mike Garwood (15 min)
- High field, novel coils, new pulse designs.
Truman Brown (15 min)
4:30 Break
5:00 Biology and Technology: Brief Contributed Presentations and Discussion
Attendees (5 - 10 min, overheads preferred)
- Contributions related to afternoon topics.
6:30 Break
7:00 Working Dinner (Entire Focus Group)
Clinical MRS Results
Jeff Evelhoch (15 min)
- Cooperative NCI/U01 Group.
John Kurhanewicz (15 min)
Robert Lenkinski (15 min)
Dan Spielman (15 min)
Jeffrey Alger (15 min)
June Taylor (15)
9:00 Day 01 Concluding Remarks
Joseph Ackerman and Dan Sullivan
Day 02: Friday, April 23, 1999
8:30 Clinical MRS: Brief Contributed Presentations and Discussion
Attendees (5 - 10 min, overheads preferred)
- Contributions related to working dinner topics.
10:00 Group Discussion
Attendees
- Is there justification for further substantive
funding of clinical MRS in cancer for (i) detection, (ii) diagnosis, (iii)
monitoring of therapy, and/or (iv) monitoring of recurrence? Nuclides of
interest (1H/31P)?
- What are the acceptable minimum technical
requirements?
- What barriers must still be overcome?
- What is the relationship between MRS and MRI in the
cancer clinic?
(Is MRS of value as a stand-alone technique?)
12:00 Working Lunch (Small Breakout Groups)
- Formulation of Summary and Recommendations.
2:00 Conclusion of MRS Focus Group Mtg.: Summary and Recommendations
Joseph Ackerman, Dan Sullivan, and attendees
- Presentation and discussion regarding workshop
conclusions.
3:30 Depart |