Full Text CA-93-022

NATIONAL DES EDUCATIONAL PROGRAM FOR HEALTH PROFESSIONALS AND THE
PUBLIC

NIH Guide, Volume 22, Number 15, April 16, 1993

RFA:  CA-93-022

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Health and Safety Education 
  Hormones 


National Cancer Institute
National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  May 7, 1993
Application Receipt Date:  June 16, 1993

PURPOSE

The Public Health Applications Research Branch (PHARB), Division of
Cancer Prevention and Control (DCPC), National Cancer Institute (NCI)
and the National Institute of Child Health and Human Development
(NICHD) invite cooperative agreement applications to support research
and education to develop a National program to inform health
professionals and the public on the adverse effects of the drug
diethylstilbestrol (DES).  Applicants are encouraged to design,
implement, and evaluate health education strategies in their geographic
regions for increasing health information and improving the early
detection, diagnosis, and treatment for several medical conditions
associated with exposure to DES.

On October 9, 1992, the 102nd Congress of the United States of America
passed an Act, HR4178, cited as the DES Education and Research
Amendments of 1992 stating that the Director of NIH shall establish a
program for the conduct and support of research and training, the
dissemination of health information, and other programs with respect to
the diagnosis and treatment of conditions associated with exposure to
the drug diethylstilbestrol.  In carrying out this program, the
Director of NIH, after consultation with nonprofit private entities
representing individuals who have been exposed to DES, shall conduct or
support programs to educate health professionals and the public on the
drug, including the importance of identifying and treating individuals
who have been exposed to the drug.

The proposed DES educational projects should focus on the development,
implementation, and evaluation of interventions aimed at DES exposed
mothers, daughters and sons, and grandchildren.  In addition, DES
educational programs should be designed for health care professionals,
including primary care physicians, oncologists, pediatricians, nurses,
nurse practitioners, and other relevant allied health personnel.

HEALTHY PEOPLE 2000

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 Request
for Applications (RFA), National DES Educational Program for Health
Professionals and the Public, 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 Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone:
202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit
organizations, public and private, such as universities, public health
departments, hospitals, voluntary organizations, units of state and
local governments, and eligible agencies of the Federal government.
Applications from minority and women investigators are encouraged.
Investigators should be capable of assembling a multidisciplinary team
including health education specialists responsible for DES public
education interventions, trained medical personnel knowledgeable in
DES-associated health risks for professional education interventions,
and associated statisticians, research designers, communication
specialists, etc., for the successful implementation and reporting of
a full-scale research project.  Applications must contain a health
professional intervention and a DES-exposed population intervention.

MECHANISM OF SUPPORT

Support for this program will be through the NIH cooperative agreement
(U01).  The cooperative agreement is an assistance mechanism in which
substantial NCI and NICHD programmatic involvement with the recipients
during performance of the planned activity is anticipated.  The nature
of NCI staff involvement is described in the SPECIAL REQUIREMENTS
section below.  Awardees will be responsible for the planning,
direction, and execution of the proposed project.  The total project
period for applications submitted in response to the present RFA may
not exceed three years.

Except as otherwise stated in this RFA, awards will be administered
under PHS grants policy as stated in the PHS Grants Policy Statement,
DHHS publication No. (OASH) 90-50,000 (rev. 10/01/90).  It is
anticipated that the average direct costs for each award will be
approximately $165,000 per year.  This is a one-time solicitation.
Future unsolicited competing continuation applications will compete
with investigator-initiated applications and will be reviewed according
to customary NIH peer review procedures.  The anticipated start date
for the initial awards will be September 30, 1993.

FUNDS AVAILABLE

It is anticipated that up to five awards will be made under this RFA,
and that the total NCI expenditures for these awards will not exceed
$1.5 million (total costs) for the first year.  In years two and three,
NICHD will contribute an additional $250,000 per year.  Thus, a total
commitment of $5 million for the entire project period is anticipated.
The project period for studies funded through this RFA may not exceed
three years.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  However,
an attempt will be made to achieve funding for the number of awards
noted. Although this RFA is provided for in the financial plans of the
NCI and the NICHD, awards are contingent on the availability of funds.

RESEARCH OBJECTIVES

The following partial review of studies on the medical conditions
associated with DES exposure is provided as background.  These studies
are limited in many cases by small sample sizes of cases, incomplete
follow-up, the lack of recent investigations, and the tendency for
women to delay pregnancy.

Cancer Risks

DES Mothers.  A technical review of studies assessing the risk of
breast cancer in mothers prescribed DES during pregnancy was undertaken
by the 1985 DHHS DES Task Force (DES Task Force Report, 1985); four
studies were reviewed in detail (Beral & Colwell, 1980; Vessey et al,
1983; Hadjimichael et al, 1984; Greenberg et al, 1984).  At this time
the weight of data was felt to support an increased risk of breast
cancer among exposed mothers.  With more than 30 years follow-up, the
increased risk for breast cancer among DES-exposed mothers has
persisted; the adjusted relative risk of 1.35 (95% confidence interval
[CI]=1.05-1.74) for exposed women compared with the unexposed (NIH
Workshop, 1992).

DES Daughters.  The link between in utero DES exposure and clear cell
vaginal and cervical cancer was first published in 1972 (Herbst et al,
1972).  The risk of developing clear cell adenocarcinoma of the vagina
and cervix is approximately 1 in 1,000 from birth through age 34 among
women exposed to DES in utero (Melnich et al, 1987); the risk of
vaginal adenocarcinoma increases rapidly from the onset of puberty
until the late teens and early twenties.  Subsequently, this risk
appears to drop, although cases continue to be reported in women into
their forties (Herbst & Anderson, 1990).  A worldwide registry of clear
cell cases, located at the University of Chicago, was established in
1971.  The registry has documented 589 cases of clear cell
adenocarcinoma since 1971, but the acquisition of information has been
limited by passive reporting (Herbst, 1991).  A recent incidence study
in Connecticut demonstrated that (1) previously estimated incidence
rates for clear cell adenocarcinoma were low, and as many as half of
incident cases were not correctly reported to the local cancer
registry; and (2) incidence rates for clear cell adenocarcinoma have
not declined but have been stable since 1975.  This emphasizes the need
for continued clinical and epidemiological studies of the etiology and
clinical course of clear cell adenocarcinoma (Horowitz et al, 1988).

An increased frequency of vaginal adenosis and/or squamous metaplasia
has also been reported in these women (Robboy et al, 1981; Helmerhorst
et al, 1989).  Robboy et al (1979) reported finding vaginal adenosis
and/or squamous metaplasia in 34 percent of DESAD participants
identified through medical record review.  These pathologic changes
were more common in women exposed to high DES doses and in those with
early gestational exposure.  However, the risk of dysplasia and
progression to squamous cell carcinoma of the cervix and vagina
associated with DES exposure in utero requires more investigation.
While initial data seemed to indicate no relationship (O'Brien et al,
1979; Robboy et al, 1979; Robboy et al, 1981), a more recent study from
the DESAD project indicated a twofold risk of dysplasia and squamous
cell carcinoma in situ of the cervix and vagina among the DES daughters
(Robboy et al, 1984), and a case of invasive squamous cell carcinoma of
the vagina in a woman exposed in utero to DES has recently been
reported (Faber, Jones & Tarraza, 1990).

Most DES-exposed daughters are now in their early forties.  Thus, these
women are just entering the at-risk age for many hormonally related
tumors (e.g., cancers of the breast, ovary, and endometrium).
Increased cancer risk for these sites among DES-exposed daughters has
not been documented.  Continued investigations will determine whether
the risk of vaginal clear cell adenocarcinoma will increase as exposed
daughters approach the age at which this cancer normally occurs in the
unexposed population.  A pattern of late recurrences, 8-17 years after
original cancer, has been recently reported (Herbst, 1992).  In
addition, several complications have been reported among women treated
for clear cell adenocarcinoma of the vagina or cervix, including
vaginal and cervical stenosis, ulceration, necrosis, cystitis,
hematometra, and lymphedema.  These findings have led to the need to
reassess radical surgery, to minimize chronic morbidity and to conserve
function of the bladder, rectum, and vagina (Wharton, 1992).

DES Sons.  The association between in utero DES exposure and the
development of testicular cancer remains controversial.  While several
cases of testicular cancer have been reported in DES-exposed men (Gill
et al, 1979; Conley et al, 1983; Vessey et al, 1983), subsequent
case-control studies have failed to show a significant association
(Schottenfeld et al, 1980; Brown, Pottern & Hoover, 1986; Moss et al,
1986; Gershman & Stolley, 1988).  While an association between DES
exposure and testicular cancer comparable to that which exists for
vaginal clear cell cancer appears unlikely, the small number of cases
studied may preclude the detection of a low to moderate increase in
relative risk associated with in utero exposure.  No other increased
cancer risk has been observed in exposed males.  The recently funded
follow-up studies will determine whether the risk of testicular and
prostate cancer will increase as exposed sons approach the age at which
these cancers normally occur in the unexposed population.

Reproductive Risks

DES Daughters.  DES exposure in utero has long been associated with
abnormalities of the male and female reproductive tract.  Among DESAD
participants at the Baylor College of Medicine identified through
medical record review, 50/282 (18 percent) were found to have gross
anatomical changes of the cervix (e.g., absent pars vaginalis, coxcomb,
hypoplastic cervix collar, or pseudopolyp) (Kaufman & Adam, 1978).
Among DESAD participants originally identified by record review at
Baylor and the Mayo Clinic, and recruited for a fertility study,
154/293 (53 percent) were found to have abnormal hysterosalpingography.
Abnormalities observed included T-shaped and hypoplastic uteri,
constriction of the upper, middle, or cornual regions, and irregular
uterine margins (Kaufman et al, 1986).  While an early study suggested
decreased fertility among DES daughters (Bibbo et al, 1977), this
observation was not confirmed in the DESAD cohort (Barnes, et al, 1980)
where exposed and unexposed daughters were found to be comparable in
the number achieving pregnancy, the number of pregnancies, and age at
first pregnancy.  Individuals exposed prenatally to DES are at
increased risk for poor pregnancy outcome (Rosenfeld & Bronson, 1980;
Stillman, 1982; DeCherney & Naftolin, 1988).  This risk is better
documented for females than it is for males. Congenital abnormalities
of the uterine cavity can be demonstrated in 35-69 percent of women who
were exposed to DES in utero, (vanGils, et al., 1989).  These
structural abnormalities are associated with an increased risk of
ectopic pregnancy, miscarriage, and pre-term birth. Overall, 4.4
percent of pregnancies in DES-exposed women resulted in ectopic
pregnancy compared with 0.5 percent among control women (Barnes, 1980;
Cousins, 1980; Herbst, 1980, 1981; Kaufman, 1980; Liberman, 1988;
Mangan, 1982).  Spontaneous abortion occurred in 23 percent of
DES-exposed women compared with 13 percent of control women.  Virtually
all of the available studies have demonstrated a tendency toward
premature labor with a corresponding increased incidence of perinatal
morbidity and mortality (Barnes, et al, 1980; Berger & Goldstein,
1980).  In addition, it appears that implantation and pregnancy outcome
are impaired in DES-exposed women after IVF (Jones, 1990).

DES Sons.  The effects on in utero DES exposure on the male urogenital
system include epididymal cysts, hypoplastic testis, and cryptorchidism
(Gill et al, 1979; Driscoll, & Taylor, 1980; Leary et al, 1984).
Studies reviewing sperm abnormalities and infertility have been
inconsistent (Andonian & Kessler, 1979; Gill et al, 1979; Beral &
Colwell, 1981; Stenchever et al, 1981; Whitehead & Leiter, 1981).
Although the effects on fertility among DES-exposed males are not well
defined, urologists and infertility specialists should be aware of the
need to ascertain whether the patient has a history of DES exposure.

Other Risks

Animal studies have demonstrated altered T and B cell function in mice
following perinatal exposure to DES.  This has resulted in speculation
that prenatal exposure to DES may have immune sequelae.  Few human
studies have been done.  Two small studies have shown altered T cell
and natural killer cell function in women exposed in utero to DES (Ways
et al, 1987; Ford, Johnson & Smith, 1983).  In review of data from the
DESAD cohort, Noller and colleagues (1988) observed an increased
reporting of lifetime history of autoimmune diseases among
record-reviewed in utero DES-exposed cases compared with unexposed
controls.  While numbers in the subgroup analyses were small, a
lifetime history of Hashimoto's thyroiditis was reported significantly
more often among the DES-exposed than among controls.  Eating disorders
have also been reported more commonly among DES-exposed (Gustavson et
al, 1991).  Animal models have, however, suggested a potential effect
of in utero exposure to DES on the development of the human
musculoskeletal system and in psychosexual development.  These are
active areas of human research.

Need for Education of Health Professionals

Given the numerous debilitating and life threatening conditions that
research indicates are associated with exposure to DES, it is of grave
concern that only half of these exposed individuals may even be aware
of their exposure and possible need for increased surveillance
(Wingard,1993).  One of the reasons for this lack of awareness is that
DES was prescribed under different names, and that DES was prescribed
in many different forms, i.e., pills, shots, suppositories and mixed
with vitamins.  It is not certain whether physicians contacted all of
their DES-exposed clients.  In some cases records were lost.  Other
patients had changed their names or moved.  Some physicians did not
contact their patients because they did not believe the early evidence
that DES could be harmful, or they were concerned about liability.
Most lawsuits, however, have been against the drug companies, not
physicians (Wingard, 1993).

Another area of concern is that many health professionals are unaware
of the complications of DES exposure.  This may reflect their failure
to keep up with the medical literature, a reluctance to consider
iatrogenic effects of treatment, or fears of liability.  This is
compounded by the slowness or failure of science to identify the best
treatment for DES-associated conditions, or to determine whether
standard health care practices (for example, oral contraceptive use or
postmenopausal estrogen replacement) are appropriate for the
DES-exposed.  Finally, there is the ongoing concern that insurance
companies will fail to cover the increased medical costs of DES-exposed
individuals and that drug companies will not be held accountable for
the effects of their product (Wingard, 1993).

Medical care for the DES-exposed needs improvement in three major
areas; screening,education of health professionals and availability of
appropriate treatment information.  Given that only half of all
DES-exposed individuals are aware of their exposure, better DES
screening needs to be instituted.  Since most physicians who prescribed
DES between 1941 and 1971 may be retired, one cannot rely on physician
efforts to contact former patients.  However, all active health
professionals should be encouraged to include questions on personal and
maternal use of DES in their medical history taking, including
indications for such use (i.e. history of or threatened miscarriage).
This information should be collected on all persons born after 1941 and
all women who were of childbearing age between 1941 and 1971 (Wingard,
1993).

The geographic pattern of DES administration is important to consider
in determining the educational needs of physicians.  Heavy
concentrations of DES administration were found in the Boston, New
York, Detroit, Los Angeles, Chicago SMSAs, etc.  Physicians in some
areas ceased administration of DES before November of 1991 when it was
taken off the market for the treatment of miscarriages.  Other
physicians continue to prescribe DES until this date.  Thus some
DES-exposed daughters and sons in their 20's are only now appearing
with DES-associated medical conditions.  Educational efforts for
physicians need to stress the fact that new cases of clear cell
carcinoadinoma may be appearing now, in addition to recurrent clear
cell cases.  Physicians, particularly urologists, need to be alerted to
potential problems in their younger male patients, alerting them to the
fact that new cases of DES-associated medical conditions may be
occurring.  In addition older men should be examined for other cancer
related conditions.

Identifying the DES-exposed is only the first step in improving medical
care for this population.  Health professionals need to be educated
about the known problems associated with DES exposure.  This
information should be updated on a regular basis as new medical
findings become published.  Known information gaps include
misunderstandings about the upper age limit for the development of
vaginal clear cell carcinoma and whether DES-exposed women should use
oral contraceptives or postmenopausal estrogens.  Ongoing education is
needed as well in medical schools, nursing schools, and continuing
medical education courses.  This education could include information on
medical risk of several conditions as well as appropriate treatment and
care for the DES exposed.

Physicians treating DES cancer patients need to have standardized
treatments and procedures incorporated into patient care.  Once
standards for care are developed, then currently existing physician
data bases, such as the NCI funded Physician Data Query system, can be
used to disseminate the standards to physicians treating DES cancer
patients.  Since the presence of vaginal clear cell cancer leads to
isolation and psychosocial distress in many patients, physicians,
nurses, and other health care professionals need to integrate quality
of life concerns into total patient care.  Knowledge and referral to
community sources of social support for DES cancer patients should be
an integral part of health care, along with treatment of the entire DES
affected family.  These efforts should be designed to improve the
sensitivity of health professionals to the psychosocial concerns of
DES-exposed families.

Specific attention should be paid to the encouragement and compliance
of health professionals and their patients with public health
recommendations for the DES-exposed women related to breast cancer
screening, vaginal and cervical cancer screening (pelvic examinations,
pap smears, and colposcopies).  For DES-exposed men, testicular
self-examination, and colorectal and prostate screening are recommended
(Public Health Recommendations, 1992).

Because women prenatally exposed to DES are at increased risk for
infertility and poor pregnancy outcome, respondents to this RFA need to
include reproductive issues in any health education materials
developed.  The message to these women may stress the importance of
pre-conception counseling and early entry into and continued
participation in prenatal care in order to increase the probability of
their delivering full-term, healthy babies.

Likewise, information about these risks and the need for careful
pregnancy monitoring should be conveyed to obstetricians,
gynecologists, family practitioners, and other health care
professionals involved in providing family planning, gynecological, or
obstetrical services to DES-exposed women and their daughters.

Since many of the women who were prenatally exposed to DES are
themselves now parents of children approaching puberty or childbearing
age, messages should be developed for pediatricians, family
practitioners, and other health professionals urging them to ascertain
if there is a history of DES-exposure in children seeking care for
abnormalities in onset of puberty or gynecological concerns.  For those
patients for whom a positive history of DES-exposure in their mothers
is known, appropriate screening or surveillance should be followed.

A wide variety of educational materials are needed for health
professionals including an updated Atlas of Findings for persons
exposed to DES, publications on health risks, clear cell cancer,
psychological concerns, quarterly bulletins on DES research and clear
cell cancer, and videotapes and conferences for health professionals on
the subject (Renick and Sherman, 1993).  Updated materials are also
needed for pathologists, cytopathologists, cytologists, and
cytotechnologists since there are only a handful of specialists
familiar with the procedures for identifying and typing tissue from
DES-associated cancer conditions.

Need for Education of the DES-Exposed

The history of DES education is primarily that of independent,
nonprofit consumer groups carrying out efforts to disseminate
information and provide support to DES-exposed public and health
professionals. The DES Action and DES Cancer Network have been the only
organizations consistently carrying out formal programs of education
(Braun, 1993).  Although the Massachusetts Cancer Information Service
launched a successful public and professional educational campaign in
1982 and 1984, attention to the problem has waned in recent years
(Mazan, 1992; Haynes, 1992).  Currently, three sources of information
on DES exposure are available; information booklets and lecture
materials from the two DES consumer groups and information sheets from
the National Cancer Institute, Office of Cancer Communications.  More
effort is needed to expand these important efforts and to reach the
DES-exposed public through a wide variety of efforts.

Based upon the thousands of calls from DES mothers, daughters, and
sons, there is enormous frustration from these individuals of not being
able to find the simplest information about DES and in many cases
knowing more about DES than their doctors (Braun, 1993).  Their
concerns appear to be minimized or ignored.  The unavailability of
adequate information on screening protocols for DES and treatment
recommendations leads to anxiety and psychological stress.  The current
crisis of information on the medical effects of DES must be corrected.
There must be close coordination between research and education so that
the most current research knowledge is included in the educational
initiatives targeting the DES-exposed and health care providers.

For DES cancer populations, there are special needs to increase
knowledge on the whole range of DES cancer effects, treatment options,
and outcomes. Support groups for DES-exposed cancer populations are
encouraged to create an environment where patient concerns can be
validated, physician referrals can be facilitated, and new medical
information can be shared.  Promotion of recommended early detection
guidelines for breast cancer, cervical cancer, and the like is needed
for all DES-exposed mothers and daughters, and for testicular,
prostate, and colorectal screening for DES-exposed sons.

The following topics are considered priority for health information to
be developed for the DES-exposed public:  reproductive problems of
daughters and sons; breast cancer risk for DES-exposed mothers; cancer
risks for DES-exposed daughters; and other known health risks for
DES-exposed daughters and sons.  As new scientific information becomes
available, health information must also be developed for the
DES-exposed public on clear cell adenocarcinoma recurrence, treatment,
and follow-up and rehabilitation; use of oral contraceptives and
hormone replacement therapy in DES-exposed mothers and daughters;
future reproductive tract abnormalities or dysfunction as DES-exposed
daughters and sons age (Cody, 1992); and immune system disorders among
DES-exposed offspring.

At the current time, a wide spectrum of educational materials are
thought to be needed for the DES general public, including pamphlets on
DES Health Risks, Clear Cell Cancer, DES Exposure, Fertility and
Pregnancy, etc.(Renick and Sherman,1993).  In addition, an 800 hotline
and physician resource directory can be considered.  The creation of a
national DES education program would include production of a wide range
of materials, written and electronic.

Awardees will be expected to participate actively in the development of
a National DES Educational Program whose objectives are to:

1.  Document the barriers and test strategies to improve the
appropriate identification, diagnosis, and treatment of DES-associated
medical conditions among primary care physicians, oncologists,
urologists, other health professionals, and DES-exposed target
populations in defined geographic areas.

2.  Design, implement, and evaluate the DES Educational Program in
several regions of the U.S., to increase health information about DES
exposure and to improve the early detection, diagnosis, and treatment
of several medical conditions associated with DES exposure for the
relevant target populations.

3.  Participate in a working group of medical experts and consumer
representatives to present papers, for publication in a peer-reviewed
journal, on standards for diagnosis and treatment of DES related
medical conditions related to vaginal and cervical cancer, breast
cancer, reproductive problems and issues, infertility, congenital
malformations, and developmental abnormalities.

For the purpose of this RFA, primary care physicians are defined as
family practitioners, internal medicine physicians, obstetricians and
gynecologists, and pediatricians.  Health professionals include
physicians as well as nurse practitioners, physician assistants,
nurses, allied health personnel.  The DES target populations include
DES-exposed mothers, daughters, and sons.  Grandchildren may also be
included as a target population for the physician education programs.

Program Implementation

The goal of this RFA for cooperative agreement is to access as many
DES-exposed families and their health care providers as possible.  With
this goal in mind, interventions should target large, geographically
defined populations with significant numbers of DES-exposed families.
Applicants will be selected for funding based primarily on their
technical merit.  However, an attempt will be made to achieve a
balanced geographic distribution of the three to four awards funded
under this RFA to access the broadest coverage of the DES-exposed
population in the U.S.

Investigators will be required to document that they have access to and
can recruit the targeted population of DES-exposed persons and their
health care providers.  Access to DES-exposed persons can be obtained
through a number of channels, such as, DES consumer organizations and
support groups, DES registries, infertility clinics, family planning
clinics, hotlines, cancer centers, physician's offices, cancer support
groups, health departments, hospitals, etc.

Access to DES health care providers can be obtained through medical
intermediary organizations.  A medical or nursing intermediary
organization is defined as an organization employing, reimbursing,
training, licensing, and/or certifying physicians or nursing
professionals, or an established health professional association.
Examples include ACOG, AAFP, ANA, AHA, etc.

It is of crucial importance that state-of-the-art knowledge about the
detection, diagnosis, and treatment of DES associated conditions be
established by a working group of medical experts and consumer
representatives.  The working group will be convened by NCI during the
first year of the award, so that recommendations for the DES-exposed
and their health care providers can be designed and disseminated during
the subsequent two years.  Applicants will participate in the meeting.

Applicants are encouraged to propose interventions that build
creatively upon the existing research base on DES, on successful
physician/office based education, and on community based health
education programs for women and their families.  Applicants may design
separate but complementary interventions for DES-exposed target
populations and the health care providers who treat these families.
Health professional and community targeted intervention approaches used
in the areas of child health, breast cancer screening, information
hotlines, reproductive health, and the like may be appropriate for this
program.  Experiences from state or local DES educational projects can
be used to justify the approaches taken to reach DES-exposed families
and their health care providers.  Considerable attention should be
given to innovative approaches for reaching the DES-exposed who are
currently unaware of their exposure status.  In addition, interventions
previously demonstrated to be efficacious in changing health
professionals' behavior (e.g., training, practice consultation,
hospital grand rounds, incentives and reimbursements, visual chart
reminders, articles in professional journals, presentations at
professional conferences, patient education, and the addition of DES
queries into health history and patient intake forms) may be
considered.

Since there are a significant number of medical specialties responsible
for the detection, diagnosis, and treatment of DES-associated medical
conditions, the use of medical intermediary organizations are crucial
for the education of health care providers currently in practice.
Primary care physicians, oncologists, pediatricians, and other health
professionals can be the focal point for the provider education
program. Barriers that may prevent full participation of health
professionals in the educational program should be addressed by the
intervention to increase participation.  These barriers may include
liability concerns,psychosocial stress of patients, unfamiliar
state-of-the-art treatments, lack of knowledge about DES support
groups, unaware of any DES-exposed patients, etc.

Some persons who are DES-exposed may not have established sources for
health care.  In these cases, special attention should be given to
expediting their access to early detection, diagnosis, or treatment
services.  No funds in the award are to be used to offset the cost of
detection, diagnosis, or treatment.  However, award funds can be used
to stimulate plans for lowering costs.

Comparison of interventions using different innovative strategies is
encouraged, including the effectiveness of different intervention
channels.  A comparison group may be proposed as a means of evaluating
the impact of a particular intervention strategy.  Comparison
populations could receive a standard, less intensive, intervention
rather than no intervention due to ethical considerations inherent in
the health information gap among DES-exposed and their health care
provider.  Applicants may wish to consider testing multiple
interventions, striking the balances between two factors: low
intensity, low cost intervention and a higher-intensity, higher-cost
intervention.  Randomization of the target populations to intervention
and comparison groups is the preferred design, although other well
justified designs will be considered.  If possible a common low
intensity intervention could be used in each geographic area for the
comparison populations.  This will be decided by collaborative
agreement between the NCI Program Director and the Principal
Investigators.

High priority will be given to research designs that ensure
continuation of the intervention beyond the funded period.  This
includes the establishment of an infrastructure that can continue to
inform the DES-exposed public and their health care providers with new
medical findings as they become available.  Applicants should include
a description of the resources and facilities that will enable their
project to continue the educational program after the funding period is
over.

Project Evaluation

Before interventions are developed, gaps in health information about
DES among health care providers and the public should be assessed using
standard survey methodology.  Documentation of barriers to the
appropriate identification, diagnosis, and treatment of DES-associated
medical conditions should be made for both the DES-exposed target
populations and their relevant health care providers.  An evaluation of
the effectiveness of the educational interventions can be undertaken by
the applicant organization or by subcontractors to the applicant
organization.  During the baseline period, before any educational
intervention is undertaken, survey or medical audit data should permit
an assessment of barriers.  Comparable survey or medical audit data
should be collected at the end of the intervention period.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The National DES Education Program will be viewed as a partnership
between the NCI, the NICHD, and the several participating institutions,
with the goal of gaining understanding of this DES-associated medical
problem.  Awardees will be responsible for the planning, direction, and
execution of the proposed project.

Nature of Participation of NIH Staff

The Program Director will be the Chief, Health Education Section,
Public Health Applications Research Branch, CCSP, DCPC, NCI, or
assignee.  The NICHD representative will be the Chief, Office of
Research Reporting, or assignee.

The NCI Program Director and NICHD representative will:

o  Participate in the Steering Committee that oversees study conduct;

o  Assist in the development of educational materials and the
evaluation instrument;

o  Serve as liaison, helping to coordinate activities among the
awardees;

o  Assist in the preparation of questionnaires, medical record
abstracts, and other data recording forms;

o  Assist in the monitoring of field data collection, helping to ensure
standardization in evaluation methods across study centers;

o  Assist in the analysis of the pooled data;

o  Assist in the interpretation and reporting of the collected
information;

o  Approve all key personnel recruitment and changes during the project
period.  Key personnel are the Principal Investigator and principal
project staff who will be identified in the Notice of Grant Award;

o  Provide the awardee with specialized technical assistance essential
to the development and testing of program communication messages and
materials.  These will be common across all four sites;

o  Monitor study progress.  This may include periodic site visits for
discussions with awardee research teams, observation of field data
collection and management techniques, fiscal review, and other matters.
Decisions for continued funding will be based on overall study
progress, as well as sufficient patient and/or data accrual,
cooperation in carrying out the research (i.e., attendance at Steering
Committee meetings, implementation of group decisions, compliance with
reporting requirements), and maintenance of a high quality of research
that will allow pooling of data and comparisons across Cooperative
Agreements for common data elements.  The inability of a cooperative
agreement recipient to meet the performance requirements, or
significant changes in the level of performance, may result in an
adjustment of funding, withholding of support, suspension or
termination of the award;

o  Provide linkages with other NIH programs and grants that are
involved in educational outreach activities, such as the NCI Cancer
Information Service, the Physician Data Query Network, and the DES
follow-up cohort studies;

Nature of Participation of Cooperative Agreement Recipients

The recipients of Cooperative Agreement awards will cooperate with each
other with the assistance of the NCI and the NICHD in the conduct of
this research.  Each awardee will:

o  Designate the Principal Investigator or assignee to participate in
the Steering Committee to oversee conduct of this study.  This
committee will meet periodically during the course of the study.  The
first meeting will be called by the NCI Program Director shortly after
award of agreements.  Subsequent meetings will be planned and scheduled
at this meeting;

o  Cooperate in the development of educational materials and evaluation
strategies.  The study documents may include questionnaires, medical
record abstract forms and field procedures manuals.  Additional
elements could be appended by individual institutions to address issues
of unique interest or capabilities in each center;

o  Organize a working group of medical experts and consumer
representatives during year 1 to develop recommendations for the
detection, diagnosis, and treatment of DES-associated medical
conditions;

o  Establish and maintain quality control in all data and materials
collection and management procedures.  Strategies for the analyses of
the pooled data will be developed jointly by the awardees, and the NCI
Program Director and the NICHD representative;

o  Submit semi-annual progress reports to the NCI Program Director;

o  Cooperate in the reporting of the study findings.  Collaborative
publications among awardees, the NCI, and the NICHD are anticipated,
with plans for joint publication of pooled data to be coordinated by
the Steering Committee prior to the end of year two of the award.
Copies of reports, publications, and major presentations are to be
provided to the NCI Program Director.

o  The NCI Program Director and the NICHD representative will have
rights of access to the data and program materials under this
cooperative agreement.  The awardees will retain custody and primary
rights to the data consistent with current HHS, PHS and NIH policies.

Other

A Steering Committee will be the main oversight body of the study and
will be composed of the Principal Investigators or assignees from the
awardee institutions, the NCI Program Director or assignee, and an
NICHD ex officio representative.  The Committee likely will meet three
times the first year and approximately twice yearly thereafter in the
Washington, DC area.  Major scientific decisions regarding the core
data will be determined by the Steering Committee.  All investigators
selected will need to be able and willing to implement the core data
collection method and educational strategy collaboratively decided upon
by the Steering Committee.  Additionally, the investigators must be
able to implement the strategy specifically designed for their study
population.  An organizational meeting of the Steering Committee will
be convened early after award by the NCI Program Director to design the
educational intervention and evaluation instruments.  A Chairperson,
other than the NCI Program Director or NICHD representative, will be
selected by a vote of the members.  Research results will be
disseminated by means of peer-reviewed publications that will be
planned and prepared by award recipients, with assistance as needed
from NCI and NICHD program staff.

Arbitration Procedures

In the event of a major scientific/programmatic disagreement between
NCI, NICHD, and the awardees that cannot be resolved by appropriate
negotiations, an ad hoc arbitration panel will be assembled to consist
of one awardee nominee, one NIH nominee, and a third member with
appropriate expertise chosen by the other two.  This NIH arbitration
process in no way affects the awardees' right to appeal an adverse
determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR
Part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH 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
people at risk of the disease, disorder, or condition under study.
Special emphasis should be placed on the need for inclusion of
minorities in studies of diseases that 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 and compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial or ethnic group.  In addition, gender and
racial or 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 on grant application form PHS
398 (rev.9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5 (Human Subjects).

Applicants are urged to carefully assess 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 or 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 includes human
biomedical and behavioral studies or 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 to enable results of the study to be applied
broadly.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will specifically address 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 a 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
that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are requested to submit, by May 7, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of this RFA.

Although a letter of intent is not required, is not binding, and does
not enter into the review of the subsequent application, the
information that it contains is helpful in planning for the review of
applications.  It allows NCI staff to estimate the potential review
workload, and helps to avoid conflict of interest among reviewers.

The letter of intent is to be sent to Dr. Suzanne G. Haynes at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying to this RFA.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grant Inquires, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone 301/435-0714.

The RFA label available in the PHS 398 application kit must be affixed
to the bottom of the face page of the application.  Omission of this
label could result in delayed processing of the application and its
failure to reach the review committee in time for review.  In addition,
the number and title of this RFA must be typed on Line 2a on the face
page of the application, and the YES box must be marked.

Respondents must request sufficient travel funds within the submitted
budgets to accommodate expenses for two to three participants at these
meetings.

A signed, typewritten original of the application, including the
Checklist, and three signed copies must be sent or delivered in one
package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 626
Bethesda, MD  20892

Applications must be received by June 16, 1993.  An application
received after that will be returned to the sender.  The Division of
Research Grants (DRG) will not accept any application in response to
this RFA that is essentially the same as one currently pending initial
review, unless the applicant withdraws the pending application.  The
DRG will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the NCI and the NICHD
staff for completeness and responsiveness.  Incomplete applications
will be returned to the sender without further consideration.  If the
application is not responsive to the RFA, NCI staff return the
application to the applicant.

Applications may undergo triage by an NCI peer review group on the
basis of relative competitiveness.  The NCI will withdraw from further
competition those applications judged to be non- competitive for award
and notify the application's Principal Investigator and institutional
official.  Those applications that are judged to be complete and
responsive will be evaluated in accordance with the criteria stated
below for scientific or technical merit by an appropriate peer review
group convened by the NIH.  The second level of review will be provided
by the National Cancer Advisory Board and the National Advisory Child
Health and Human Development Council.

The applications will be evaluated on the basis of the following
criteria:

1.  Extent to which the overall goals and objectives of the RFA are
addressed by the applicant;

2.  Scientific merit of the research design and intervention approach:

o  Soundness of the rationale for the choice of interventions, target
populations (mothers, daughters, sons, health professionals) and
approaches,

o  Quality and rigor of outcome evaluation designs,

o  Quality of methods for identifying DES-exposed persons, particularly
those unaware of their exposure;

3.  Feasibility of interventions chosen and commitment of intervention
communities/health professional organizations:

o  Feasibility of the proposed interventions,

o  Commitment of communities/health professional organizations with
adequate sample sizes to attain the proposed statistical power,

o  Extent of interaction with nonprofit DES groups involved in the
planning and implementation of interventions,

o  Adequacy of plans for building capacity within the community,

o  Transferability of the interventions to other geographic areas;

4.  Qualifications and time commitment of the proposed research team:

o  Qualifications and competence of the proposed research team for the
intervention components chosen,

o  Demonstrated previous relevant experience of the research team in
DES health education, physician interventions, community interventions,
and the like,

o  Adequacy of time commitments of key personnel,

o  Adequacy of the plans to cooperate with other awardees with NCI's
assistance;

5.  Adequacy of resources and facilities:

o  Adequacy of well-described target populations (demographics, data on
DES-exposed populations in geographic area, health education programs
available for the DES-exposed in geographic area),

o  Adequacy of resources available to implement the interventions
including personnel, equipment, and data processing capacity,

o  Adequacy of data management and data quality control,

o  Adequacy of the capacity of the lead organization for managing the
project;

o  Inclusion of minority subjects.

The review group will also critically examine the submitted budget and
will recommend an appropriate budget and period of support for each
approved application.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.  Availability of
funds, geographic distribution of awards, characteristics of study
populations, and other programmatic priorities are important criteria
in making grant awards.

INQUIRIES

The NCI Program Director and the NICHD representative welcome the
opportunity to clarify any issues or questions from potential
applicants.  Written and telephone inquiries concerning the objectives
and scope of this RFA, whether or not specific proposed research is
responsive, the scientific content and objectives of an application,
the size and focus of a research program, and the organization of an
application, are strongly encouraged and may be directed to:

Suzanne G. Haynes, Ph.D.
Health Education Section
National Cancer Institute
Executive Plaza North, Room 218
Bethesda, MD  20892
Telephone:  (301) 496-8577

Michaela P. Richardson
Office of Research Reporting
National Institute of Child Health and Human Development
Building 31, Room 2A32
Bethesda, MD  20892
Telephone:  (301) 496-5133

Requests for information on NCI fiscal policies may be directed to:

Eileen Natoli
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext 56

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.399.  Grants will be awarded under the authority 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 Parts
74 and 92.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.

REFERENCES

Adonian RW, Kessler R:  Transplacental exposure to diethylstilbestrol
in men.  Urology 13:276-279, 1979.

Apfel RJ: Long-Term Emotional Effects of DES Exposure. NIH Workshop,
Long-Terms Effects of Exposure to Diethylstilbestrol (DES). ORWH, NCI,
NICHD, NIEHS, April 22-24, 1992:60-62.

Barnes AB, Colton T, Gunderson J, Noller KL, Tilley BC, Strama T,
Townsend DE, Hatab P, O'Brien PC:  Fertility and outcome of pregnancy
in women exposed in utero to diethylstilbestrol.  N Engl J Med
302:609-613, 1980.

Beral V, Colwell L:  Randomized trial of high doses of stilboestrol and
ethisterone therapy in pregnancy:  long-term follow-up of the mothers.
Br Med J 280:1098-1101, 1980.

Beral V, Colwell L:  Randomized trial of high doses of stilbestrol and
ethisterone therapy in pregnancy:  long-term follow-up of the children.
J Epidemiol commun health 35:155-160, 1981.

Berger MJ, Goldstein DP:  Impaired reproductive performance in
DES-exposed women.  Obstet Gynecol 55:25-27, 1980.

Bibbo M. Gill WB, Azizi F, Blough R, Fang VS, Rosenfield RL, Schumacher
GFB, Sleeper DK, Sonek MG, Wied GL:  Follow-up study of male and female
offspring of DES-exposed mothers.  Obstet Gynecol 49:1-8, 1977.

Braun ML:  Educational/Outreach Research and Implementation.  DES
Cancer Network.  Personal Communication, 1993.

Brown LM, Pottern LM, Hoover RN:  Prenatal and perinatal risk factors
for testicular cancer.  Cancer Res 46:4812-4816, 1986.

Cloitre M, Ernhardt NP, Meyer-Bahlbury V, and Meyer-Bahlburg HFL:  The
psychological impact of prenatal DES exposure in women:  A comparison
of short-term and long-term effects.  J Psychosom Obstetrics and Gyn
8:149-168, 1988.

Cody, N.  DES Action.  Personal Communication, 1992.  Conley MD,
Grannum R, Sant MD, Ucci AA, Mitcheson HD:  Seminoma andepididymal
cysts in a young man with known diethylstilbestrol exposure in utero.
J Am Med Assoc 249:1325-1326, 1983.

Cusins L, Karp W, Lacy C, Lucas WE:  Reproductive outcome of women
exposed to diethylstilbestrol in utero.  Obstet Gynecol 56:70-76, 1980.

DeCherney AH, Noftolin F:  Diethylstilbestrol--Effect on fertility.  In
Behrman SJ, Kistner RW and Patton CW (eds).  Progress in Infertility,
3rd edn. Little, Brown, and Co., Boston, pp. 227-236.

Driscoll SG, Taylor SH:  Effects of prenatal maternal estrogen on the
male urogenital system.  Obstet Gynecol 56:537-542, 1980.

Ford CD, Johnson GH, Smith WG:  Natural killer cells in in utero
diethylstilbestrol-exposed patients.  Gynecol Oncol 16:400-404, 1983.

Gill WB, Schumacher GFB, Bibbo M, Straus FH II, Schoenberg HW:
Association of diethylstilbestrol exposure in utero with
cryptorchidism, testicular hypoplasia and semen abnormalities.  J Urol
122:36-39, 1979.

Greenberg ER, Barnes AB, Resseguie L, Barrett JA, Burnside S, Lanza LL,
Neff RK, Stevens M, Young RH, Colton T:  Breast cancer in mothers given
diethylstilbestrol in pregnancy.  N Engl J Med 311:1393-1398, 1984.

Gustavson CR, Gustavson JC, Noller KL, O'Brien P KL, O'Brien P KL,,
Melton LJ, Pumariega AJ, Kaufman RH, Colton T:  Increased risk of
profound weight loss among women exposed to diethylstilbestrol in
utero.  Behav Neural Biol 55:307-312, 1991.

Hadjimichael OC, Meigs JW, Falcier FW, Thompson WB, Flannery JT:
Cancer risk among women exposed to exogenous estrogens during
pregnancy.  J Natl Cancer Inst 73:831-834, 1984.

Haynes SG: Demographic characteristics to the NCI Cancer Information
Service, 1983-1990, NIH Workshop, Long-Terms Effects of Exoisure to
Di(DES). ORWH, NCI, NICHD, NIEHS, April 22-24, 1992:56-58.

Helmerhorst TJM, Wijnen HJA, Kenemans P, Tijoe GSTD, Dijkhuizen HH,
Calame JJ, Stolk HG:  Colposcopic findings and intraepithelial
neoplasia in diethylstilbestrol-exposed offspring.  The Dutch
experience.  Am J Obstet Gynecol 161:1191-1194, 1989.

Herbst AL, Anderson D:  Clear cell adenocarcinoma of the vagina and
cervix secondary to intrauterine exposure to diethylstilbestrol.  Semin
Surg Oncol 6:343-346, 1990.

Herbst AL, Kerman RJ, Scully RE, Poskanzer DC: Clear cell
adenocarcinoma of the genital tract in young females. N Eng J Med
287:1259-1264, 1972.

Herbst AL, Scully RE:  Adenocarcinoma of the vagina in adolescence.  A
report of seven cases including six clear cell carcinomas (so-called
mesonephromas).  Cancer 25:745-757, 1970.

Herbst AL, et al: A comparison of pregnancy experience in DES-exposed
and DES0-unexposed daughters.  J Reprod Med 24:62-69, 1980.

Horowitz RI, Viscolli CM, Merino M, Brennan TA, Flannery JT, Bobbay SJ:
Clear cell adenocarcinoma of the vagina and cervix: Incidence,
undetected diseases, and DES. J Clin Epid 44:593-597, 1988.

Jones HW, et al:  Are implantation and pregnancy outcome impaired in
diethylstilbestrol-exposed women after in vitro fertilization and
embryo transfer?  Fertility and Sterility 54:287-291, 1990.

Kaufman RH, Adam E:  Genital tract anomalies associated with in utero
exposure to diethylstilbestrol.  Israel J Med Sci 14:353-362, 1978.

Kaufman RH, Adam E, Noller K, Irwin JF, Gray M:  Upper genital tract
changes and infertility in diethylstilbestrol-exposed women.  Am J
Obstet Gynecol 154:1312-1318, 1986.

Kaufman RH, Adam E, Binder G, Gerthoffer E:  Upper genital tract
changes and pregnancy outcome in offspring exposed in utero to
diethylstilbestrol.  Am J Obstet Gynecol 137:299-308, 1980.

Leary FJ, Ressenguie LJ, Kurland LT, O'Brien PC, Emslander RF, Noller
KL: Males exposed in utero to diethylstilbestrol.  J Am Med Assoc
252:2984-2989, 1984.

Linn S, Lieberman E, et al:  Adverse outcomes of pregnancy in women
exposed to diethylstilbestrol in utero.  J Reprod Med 33:3-7, 1988.

Long-Term Health Effects of Exposure to DES--Background. Office of
Cancer Communications, National Cancer Institute, August, 1992.

Mangan EE, et al:  Pregnancy outcome in 98 women exposed to
diethylstilbestrol in utero, their mothers, and unexposed siblings.
Obstet Gynecol 59:315-319, 1982.

Mazan KD: The Role of Massachusettes Cancer Information Service in the
Massachusetts DES Educational Program. NIH Workshop, Long-Terms Effects
of Exoisure to Diethylstilbestrol (DES). ORWH, NCI, NICHD, NIEHS, April
22-24, 1992:55-56.

Melnick S, Cole P, Anderson D, Herbst AL:  Rates and risks of
diethylstilbestrol-related clear cell adenocarcinoma of the vagina and
cervix.  N Engl J Med 316:514-516, 1987.

NIH Workshop:  Long-term effects of exposure to Diethylstilbestrol
(DES).ORWH, NCI, NICHD, NIEHS, April 22-24, 1992.

Noller KL, Blair PB, O'Brien PC, Melton LJ, Offord JR, Kaufman RH,
Colton T: Increased occurrence of autoimmune disease among women
exposed in utero to diethylstilbestrol.  Fertil Steril 49:1080-1082,
1988.

O'Brien PC, Noller KL, Robboy SJ, Barnes AB, Kaufman RH, Tilley BC,
Townsend DE:  Vaginal epithelial changes in young women enrolled in the
National Cooperative Diethylstilbestrol Adenosis (DESAD) Project.
Obstet Gynecol 53:300-308, 1979.

Public Health Recommendations for the DES-Exposed. NIH Workshop:
Long-term effects of exposure to Diethylstilbestrol (DES).  ORWH, NCI,
NICHD, NIEHS, April 22-24, 1992;93.

Questions and Answers about DES.  Office of Cancer Communications,
National Cancer Institute.  August, 1992.

Renick K and Sherman A:  Proposed Budget for DES Education and Outreach
to Health Professionals and the General Public.  Personal
Communication, 1993.

Robboy SJ, Kaufman RH, Prat J, Welch WR, Gaffey T, Scully RE, Richart
R, Fenoglio CM, Virata R, Tilley BC:  Pathologic findings in your women
enrolled in the National Cooperative Diethylstilbestrol Adenosis
(DESAD) Project. Obstet Gynecol 53:309-317, 1979.

Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richart RM,
Gaffey TA, Prat J, Virata R, Hatab Pa, McGorray SP, Noller KL, Townsend
D, Labarthe D, Barnes AB:  Dysplasia and cytologic findings in 4,589
young women enrolled in Diethylstilbestrol-Adenosis (DESAD) Project.
Am J Obstet Gynecol 140:579-586, 1981.

Robboy SJ, Welch WR, Young RH, Truslow GY, Herbst AL, Scully RE:
Topographic relation of cervical ectropion and vaginal adenosis to
clear cell adenocarcinoma  Obstet Gynecol 60:546-551, 1982.

Rosenfeld DL, Bronson RA:  Reproductive Problems in the DES-exposed
Female. Obstetrics and Gynecology 55:453-456, 1980.

Schottenfeld D, Warshauer ME, Sherlock S, Zauber AG, Leder M, Payne R:
The epidemiology of testicular cancer in young adults.  Am J Epidemiol
112:232-246, 1980.

Stenchever MA, Williamson RA, Leonard J, Karp LE, Ley B, Shy K, Smith
D: Possible relationship between in utero diethylstilbestrol exposure
and male fertility.  Am J Obstet Gynecol 140:186-191, 1981.

Stillman RJ:  In utero exposure to diethylstilbestrol:  Adverse effects
on the reproductive tract and reproductive performance in male and
female offspring. American Journal of Obstetrics and Gynecology
142:905-921, 1982.

Tedeschi C: Communicating Epidemiologic Risk to the DES-Exposed
Population. NIH Workshop, Long-Terms Effects of Exoisure to
Diethylstilbestrol (DES). ORWH, NCI, NICHD, NIEHS, April 22-24,
1992:58-59.

vanGils A, Tham R, Falke T, Peters A:  Abnormalities of the Uterus and
Cervix after Diethylstilbestrol Exposure:  Correlations with Findings
on MR and Hysterosalpingography.  American Journal of Radiology
153:1235-1238, 1989.

Vessey MP, Fairweather DVL, Norman-Smith B, Buckley J:  A randomized
double-blind controlled trial of the value of stilbestrol therapy in
pregnancy: long-term follow-up of mothers and their offspring.  Br J
Obstet Gynaecol 90:1007-1017, 1983.

Ways SC, Mortola JF, Zvaifler NJ, Weiss RJ, Yen SSC:  Alternations in
immune responsiveness in women exposed to diethylstilbestrol in utero.
Fertil Steril 48:193-197, 1987.

Whitehead ED, Leiter E:  Genital abnormalities and abnormal semen
analyses in male patients exposed to diethylstilbestrol in utero.  J
Urol 125:47-50, 1981.

Wingard DL:  DES Policy Paper.  Personal Communication, 1993.

Wingard, DL:  Educating Health Professionals about DES Exposure.  In
NIH Workshop:  Long Term Effects of Exposure to Diethylstilbestrol
(DES). ORWH, NCI, NICHD, NIEHS, 1992.

.

Return to RFAs Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.