NIH GUIDE, Volume 21, Number 20, May 29, 1992

PA NUMBER:  PA-92-86

P.T. 34



  Medical/Diagnostic Imaging 

National Cancer Institute


The National Cancer Institute (NCI), through the Diagnostic Imaging

Research Branch (DIRB) of the Radiation Research Program, seeks grant

applications through Interactive Research Project Grants (IRPGs) in

order to establish multidisciplinary research in the area of early

detection and prediction of tumor response to treatment using magnetic

resonance imaging (MRI)-guided magnetic resonance spectroscopy (MRS).


The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This program

announcement, Magnetic Resonance Spectroscopy and Cancer Treatment, is

related to the priority area of cancer.  Potential applicants may

obtain a copy of "Healthy People 2000" (Full Report:  Stock No. 017-

001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by foreign and domestic, for-profit and

non-profit, public and private organizations, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal Government.

Applications from minority individuals and women are encouraged.


It is intended that this program will be supported through the

interactive R01 mechanism.  Elements of the program may be supported as

individual R01 grants.  The NCI seeks to encourage the coordinated

submission of related research project grant applications from

investigators who want to collaborate on a common cancer research

theme, but do not require extensive shared physical resources or core

functions.  A minimum of three independent investigators with related

research objectives are encouraged to submit concurrent, collaborative,

cross-referenced individual research project grant applications (R01)

that share a common research focus.  Applications may be from either a

single institution or a consortium of institutions.  Applications will

be reviewed independently for scientific merit.  Meritorious

applications will be considered for funding both as independent awards

and in the context of the overall proposed collaboration.

Applicants will be responsible for the planning, direction, and

execution of the proposed projects.  One Principal Investigator out of

the group MUST be identified as the "Program Coordinator," and must be

cited in all applications on page 2 of form PHS 398.  Individual

investigators may request funds for the time and effort contributed

toward the coordination of the overall research and for collaborative

resource activities.

Additional information about the interactive R01 mechanism may be found

in the NIH Guide for Grants and Contracts, January 10, 1992, in

PA-92-29, "Interactive Research Project Grants for Cancer."

Awards will be administered in accordance with Public Health Service

Policy as described in the PHS Grant Policy Statement, DHHS.

Publication No. (OASH) 90-50,000 revised October 1, 1990.


Background Information

Conventional, or proton, MRI provides predominantly anatomic

information, whereas MRS is essentially an in vivo assay of tissue

biochemistry.  Recently, it has become possible to integrate MRS  with

routine MRI, so that local abnormalities detected by MRI can be

examined biochemically by MRS before and after therapeutic

interventions.  In contrast to currently available imaging

methodologies, which rely predominantly on changes in tumor size to

evaluate therapeutic response, MRS can detect early biochemical changes

in tumor composition that precede morphologic changes in response to

therapeutic interventions.  Studies in animal tumors have provided

strong evidence that MRS can readily observe the effects of therapies

on tumor metabolism.  However, it is not entirely clear if MRS could be

used in humans for prediction of therapeutic outcome or as a guide for

treatment planning.  At present, few clinical studies have been done in

this area. More work is required to determine if the changes seen in

animal tumor models are evident in their human counterparts and, if so,

to investigate the underlying biologic mechanisms.  The focus of the

proposed research is to examine proton MRI-guided localized MRS as a

tool for early detection and prediction of tumor response to treatment.

The clinical application of MRS in oncology is in its early stages of

development.  The majority of clinical MRS studies to date have been

performed in a limited number of patients.  In spite of the technical

limitations imposed on early clinical studies, the preliminary

phosphorus-31 MRS results indicate that changes in pH, PME. and PDE

levels may be predictive of response to radiation and chemotherapy.

Moreover, preliminary proton MRS studies in humans indicate the

differences in the levels of choline, N-acetyl aspartate, and, in some

instances, lactate or alanine both between tumor and normal brain and

within tumors.  The developments of the MRS methodology and technology

have progressed considerably in the areas of spatial localization,

spectral editing, data analysis, quantitation, and data presentation.

At a recent NCI workshop, an expert panel identified the need for

carefully planned clinical studies.

The goal of this initiative is to conduct well-focused, prospective

clinical studies using currently available, routinely applicable,

methodology to begin comprehensive testing of the potential for 31P MRS

to predict and/or detect therapeutic response in patients with tumors.

Given the limited resources available at any one institution and the

effort required to perform repeated measurements in each patient for

response predictor studies, it seems prudent to coordinate such studies

among several institutions.  The critical issue in these studies is

quality control, i.e., setting precise standards for performance and

interpretation of spectroscopic studies.

Research Goals and Scope

This new program announcement will stimulate the scientific community

to research, in a centrally coordinated fashion, the utility of

MRI-guided MRS for early detection and prediction of therapeutic

response in patients with tumors.  A consensus-based development of the

experimental design will include data acquisition, presentation and

processing (e.g., standards of MRS performance, well-defined technical

requirements, and method(s) of spectral localization, quantification,

and data analysis).

This announcement seeks to encourage the following research topics in

proton MRI-guided MRS in preclinical and clinical cancer research:

o  Detection and prediction of immediate treatment response

o  Prediction of final outcome

o  Evaluation of the direct effect of drugs

o  Differentiation of viable tumor from treatment-induced necrosis,

edema, and scar

It is also expected that the proposed studies will address the

following needs:

o  In vivo metabolic characterization of human tumors

o  Correlation of metabolic characteristics with histological features

(e.g., tissue types, tumor grade)

o  Correlation of metabolic characteristics with clinical and

biological behavior (growth rate, degree of differentiation,

probability of recurrence, metastatic potential)





NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical

research grants and cooperative agreements will be required to include

minorities and women in study populations so that research findings can

be of benefit to all persons at risk of the disease, disorder or

condition under study; special emphasis must be placed on the need for

inclusion of minorities and women in studies of diseases, disorders and

conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.

The composition of the proposed study population must be described in

terms of gender and racial/ethnic group, together with a rationale for

its choice.  In addition, gender and racial/ethnic issues should be

addressed in developing a research design and sample size appropriate

for the scientific objectives of the study.  This information must be

included in the form PHS 398 in the Research Plan, 1-4, AND summarized

in 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However, NIH

recognizes that it may not be feasible or appropriate in all research

projects to include representation of the full array of United States

racial/ethnic minority populations (i.e., Native Americans [including

American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,

Hispanics).  The rationale for studies on single minority population

groups should be provided.

For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(and preventive strategies), diagnosis, or treatment of diseases,

disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the application will be returned.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to

address these policies.  NIH funding components will not award grants

or cooperative agreements that do not comply with these policies.


The research grant application form PHS 398 (rev. 9/91) is to be used

in applying for this program announcement. These forms are available at

most institutional business offices, the Office of Grants Inquiries,

Division of Research Grants, National Institutes of Health, Room 449,

Westwood Building, 5333 Westbard Avenue, Bethesda, MD  20892, telephone

(301) 496-7441, and the NCI program director named below.

The PA number and title must be typed on line 2a of the face page of

the application form.

The use of the IRPG mechanism must be mentioned briefly in form PHS

398, Sections 1-4 of the Research Plan.  The goal of the collaborative

efforts MUST be identified in the specific aims of each application,

with the major rationale and explanation for the use of the IRPG

mechanism to be given in Section 7, Consultants/Collaborators.  A

complete list of applications in the IRPG must be provided in Section

7, as well as an indication of the specific collaborations to be

established for the individual application under consideration.

Requests for limited shared resources, if any, must be proportionally

budgeted in each application based on anticipated use, with a full

explanation given in the budget.  Personnel Time and Effort requests

for management of shared resources are allowable.  If consortium

arrangements between independent institutions are proposed that would

make transfer of funds for required new equipment impractical, the

entire equipment request may be budgeted by the responsible laboratory.

This must be clearly justified.  All PHS and NIH grants policies will

apply to applications received in response to this announcement.

If the applicant has an approved assurance covering the research

(multiple project assurance for human subjects/full assurance of

compliance for animal subjects), the applicant should provide with the

application certification of institutional review board (IRB) approval,

if humans are involved, and verification of the institutional animal

care and use committee (IACUC) approval, if animals are involved.

These reviews and approvals should occur PRIOR TO SUBMISSION of the

applications for award and the certifications and verifications should

be SUBMITTED WITH the applications.  Failure to provide required

certifications and verifications within applications could result in

deferral or rejection of the application.  If animals or humans will be


ORGANIZATION, the applicants must identify, with the application, the

assurance status of each participant.  Failure to provide this

information within applications may result in deferral or rejection.

Submit a signed, typewritten original of the application, including the

Checklist, and five signed, exact photocopies, in one package to the

address below.  The photocopies must be clear and single sided.

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**

Upon receipt, applications will be reviewed by the Division of Research

Grants (DRG) for completeness.  Incomplete applications will be

returned to the applicant without further consideration.  Those

applications judged to be complete will be further evaluated for

scientific and technical merit by study sections of the DRG.  Following

the scientific and technical review, the applications will receive a

second level of review by NIH staff who consider the application in

light of the special needs of the Institute.


Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications will be reviewed for

scientific and technical merit by study sections of the Division of

Research Grants, NIH, in accordance with the customary NIH peer review

procedures. Following scientific-technical review, the applications

will receive a second-level review by the appropriate national advisory



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement


Written and telephone inquires concerning the objectives and scope of

this program announcement and inquiries about whether or not specific

proposed research would be responsive are encouraged and should be

directed to:

Faina Shtern, M.D.

Chief, Diagnostic Imaging Research Branch

Radiation Research Program

National Cancer Institute

Executive Plaza North, Suite 800

Bethesda, MD  20892

Telephone:  (301) 496-9531

Dr. Shtern welcomes the opportunity to clarify any issues or questions

from potential applicants.

Direct inquiries regarding budgetary/administrative issues to:

Joan Metcalfe

Grants Management Specialist

Grants Administrative Branch

National Cancer Institute

Executive Plaza South, Room 242

Bethesda, MD  20892

Telephone:  (301) 496-7800, extension 28


This program is described in the Catalog of Federal Domestic Assistance

No. 93.395, Cancer Treatment Research.  Awards are made under the

authorization of the Public Health Service Act, Title IV, Part A

(Public Law 78-410, as amended by Public Law 99-158,  42 USC 241 and

285) and administered under PHS grants policies and Federal Regulations

42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to the

intergovernmental review requirements of Executive Order 12372 or

Health Systems Agency review.


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