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