moderate chronic obstructive pul-
monary disease (COPD). In the first
year after quitting, women’s lung func-
tion improved more than twice that of
the men’s. Among those who quit,
improved lung function remained
greater for women than for men
throughout the study, although the
differences between the genders nar-
rowed over time. The decline in lung
function in those who continued to
smoke was on average similar for men
and women.
Early Diagnosis of UsherSyndrome Type 1 NowPossible
New research findings may help
Ashkenazi Jewish children who
are born deaf and who also experience
a progressive loss of sight due to Usher
syndrome, a genetic dual deficit disor-
der. Deafness in both ears and progres-
sive loss of vision due to retinitis pig-
mentosa are the indicators of Usher
syndrome, a genetic dual deficit disor-
der. There are three clinical subtypes
of Usher syndrome, the most severe of
which is Usher type 1 (USH1). Accord-
ing to researchers writing in the
April 24, 2003, edition of the New
England Journal of Medicine, the iden-
tification of a genetic mutation of an
Usher syndrome type 1 gene,
PCDH15, appears to account for a
large proportion of USH1 in the
Ashkenazi Jewish population today.
Ashkenazi describes those Jewish peo-
ple who came from Eastern
Europe.
In earlier studies, a
founder mutation,
167delT, was identi-
fied in the GJB2
gene, which is car-
ried by 4 percent of
Ashkenazi Jewish
individuals. It’s one
of the major causes
of autosomal-reces-
sive, nonsyndromic hearing loss in the
same population. Researchers hypoth-
esized that at least one USH1 muta-
tion, which arose in an ancestral popu-
lation, is a significant cause of current
USH1. Using DNA contributions from
affected families in the U.S. and Israel,
researchers searched for a haplotype of
genetic markers closely linked to any
of six reported USH1 loci in families
of Ashkenazi Jewish descent.
This approach allowed identifica-
tion of the R245X founder mutation.
They found high carrier frequencies of
R245X in the Ashkenazi Jewish popu-
lation. Carriers are individuals who,
although having no symptoms of the
disorder, transmit their single copy of
the disabled gene to their descendants.
There are no data to indicate that
there is an increased frequency of
Usher syndrome in this population,
only that the inheritance of the disor-
der is more clearly identifiable. There
is indication, through the study’s con-
trols of other non-Ashkenazi Jewish
and non-Jewish populations, that this
mutation may be unique to the
Ashkenazi population.
Uncovering the R245X mutation as
a significant cause of USH1 in
Ashkenazi Jewish individuals means
there are diagnostic and intervention
strategies that can be helpful in amelio-
rating the devastation of this disorder.
“Knowledge is truly empower-
ment in this case,” noted James
F. Battey, MD, PhD,
Director of the National
Institute on Deafness and
Other Communication
Disorders. “Molecular diagno-
sis, carrier screening,
and genetic counsel-
ing all will lead to
earlier intervention
for a child who will
be challenged by
hearing loss and pro-
gressive blindness,
while he or she
can still take advantage of the sensory
input still available in the earlier
years.”
Molecular screening is an impor-
tant tool for use with children in this
population, who are born with bilater-
al, profound hearing loss, not associat-
ed with GJB2 mutations. From these
findings, it has become clear that these
children should be tested for R245X
and have ophthalmologic evaluation,
including funduscopic examination
and electroretinography. These evalua-
tions will detect retinitis pigmentosa at
a presymptomatic state. From this
early identification, the child who is an
appropriate candidate and who has the
ability to see and read lips for some 10
to 12 years pre-onset of the blindness
would be able to benefit from a
cochlear implant.
Carrier screening and genetic coun-
seling will allow parents to prepare for
the educational and social needs of a
child who has Usher syndrome type 1
and for his or her progressive loss of
sight. Parents will be able to focus on
communication skills that will be
needed by their child.
Screening for R245X would allow
additional information to be provided
to individuals who will already be
screened for Tay-Sachs, Gaucher and
Canavan diseases as they seek to have
more information about their genetic
history.
Donor Immune CellsAttack Metastatic Breast Cancer
In patients with metastatic breast
cancer, immune cells from a geneti-
cally matched donor can attack and
shrink tumors, researchers from the
National Cancer Institute (NCI)
announced at this year’s Annual Meet-
ing of the American Society of Clinical
Oncology. This is the first time
researchers have clearly demonstrated
this type of immune response, known
314 AWHONN Lifelines Volume 7 Issue 4
as a graft-versus-tumor effect, acting
against breast cancer.
“Graft-versus-tumor effects have
been shown to be useful in treating
cancers of the blood, such as leukemia
and lymphoma. Breast cancer, howev-
er, has generally been resistant to
immune-based therapies,” said
Michael Bishop, MD, of NCI’s Center
for Cancer Research, the lead author
on the study. “Although the tumors of
patients in this study were not com-
pletely eliminated by the treatment,
the responses we saw provide hope
that immunotherapies for breast can-
cer are worth pursuing.”
Tumor regression has been
observed in the past in some patients
with metastatic breast cancer who
received stem cell transplants, but it
was unclear whether immune cells had
attacked the tumor or the tumor was
shrinking in response to chemotherapy
drugs administered prior to the trans-
plant. The design of this clinical trial,
however, allowed researchers to attrib-
ute tumor regression to a true graft-
versus-tumor effect.
Each of the 13 patients in the Phase
I trial had received multiple previous
treatments for metastatic breast can-
cer. In the study, patients first received
conventional doses of chemotherapy
to kill cancer cells and reduce the cells
in their immune system so that donor
cells could replace them. They then
received stem cells from the blood of
HLA-matched siblings. HLA-matched
donor cells, which have the same set of
proteins (known as human leukocyte-
associated antigens) on their surface as
the patient’s own cells, are much more
likely to be accepted by the patient’s
body.
T cells, specialized immune cells
that recognize and kill foreign cells
that have invaded the body, were
removed from the pool of donated
stem cells prior to transplant. These T
cells were given to patients later, in an
initial infusion 42 days after stem cell
transplant, then in two follow-up infu-
sions over the next two months.
Because T cells were not given imme-
diately following chemotherapy,
researchers were able to attribute any
tumor cell death to the transplanted T
cells rather than to antitumor effects of
the chemotherapy drugs.
In four patients, tumors shrunk at
least 50 percent in response to the
treatment. A minor response was seen
in three of the other patients.
Although not all patients in the study
responded to treatment, and none of
the tumors was eliminated entirely, the
results of the trial provide evidence
that transplanted T cells can attack
tumors in patients with metastatic
breast cancer. Researchers are opti-
mistic that further study could lead to
effective immunotherapies for these
patients.
Study Estimates MoreThan 2 Million WomenCould Benefit FromTamoxifen
More than 10 million women in
the U.S. have a high enough
risk of developing breast cancer that
they could consider taking the breast
cancer chemoprevention drug tamox-
ifen, according to Andrew N. Freed-
man, PhD, and his colleagues at the
National Cancer Institute (NCI).
When the scientists examined this
group of women using a risk-benefit
analysis of the drug, they found that
more than 2 million women would be
likely to derive overall benefit from the
drug without undue risks. The results
were reported in the April 2, 2003,
issue of the Journal of the National
Cancer Institute.
Tamoxifen was approved five years
ago as the first drug to prevent breast
cancer. It can halve the incidence of
breast cancer in women who are most
likely to develop the disease. As with
all medicines, tamoxifen has side
effects that may affect some women
and not others. In this case, the effects
are rare, but serious—endometrial
cancer, stroke, deep vein thrombosis
and pulmonary embolism. The deci-
sion to take tamoxifen will depend on
a woman’s age, breast cancer risk fac-
tors, family history, how she weighs
the benefits and risks and her specific
medical situation, lifestyle, personal
values, and preferences, said one of the
co-investigators on the NCI study.
“Tamoxifen therapy may not be appro-
priate for all women who are at
increased risk for breast cancer.”
Tamoxifen was approved as a
chemoprevention drug for breast can-
August | September 2003 AWHONN Lifelines 315