February 19, 1999
Radial Scars Join List of Breast Cancer Risk Factors
Pathologists scrutinizing a woman's breast biopsies for signs of
malignancy should add a new feature to their mental list of histological
trouble spots. It is called the radial scar.
This conclusion emerges from a study by Stuart Schnitt,
HMS associate professor of pathology at Beth Israel Deaconess Medical
Center, and four other Harvard scientists. In the February 11 New
England Journal of Medicine, the researchers report that radial
scars constitute an independent histological risk factor for breast
cancer. These scars are abnormalities in which breast ducts and
lobules exhibiting precancerous changes radiate from a central fibrous
Pathologists commonly see radial scars in biopsies taken
from women with benign breast disease, and have noted their morphological
similarity to cancer as early as 1928. Some scientists suspect the
scars may represent an early phase of some types of breast cancer,
yet studies trying to link radial scars to an increased risk of
breast cancer were small and yielded conflicting results.
Schnitt and his colleagues addressed this question by inspecting
breast biopsy slides from 1,396 participants of the Nurses' Health
Study, 255 of whom later developed breast cancer. They found that,
overall, the presence of a radial scar almost doubled a woman's
risk for developing breast cancer. The risk varied depending on
which histological category of benign breast disease a woman fell
into. The scientists also found that the risk increased with the
number and size of the radial scars found in benign lesions.
The researchers recommend that pathologists report the presence
of radial scars, and that affected women undergo the same clinical
and mammographic follow-up as recommended for women with a moderately
In this study, the researchers evaluated mostly scars about
one-eighth inch long. Yet larger scars routinely show up in mammograms,
raising the question whether these also carry the same predictive
Gene Involved in Heart Chamber Specification
How an organ develops and acquires its characteristic shape is
a fundamental question in biology. Now a team of HMS researchers
has gotten to the heart of the problem--literally, that is. They
identified a gene called Irx-4 that will open new doors to
understanding how the heart chambers form. Their findings appear
in the Feb.19 issue of Science.
Scientists knew that some genes were expressed either in the future
ventricles or the future atria of the developing heart, but no one
really knew how these genes remained confined to their respective
chambers or whether their restricted expression reflected a role
in setting up the heart chambers.With Irx4, researchers will
now be able to ask these questions.
As shown by Connie Cepko, HMS professor of genetics,
and colleagues, Irx4--which is specifically expressed in
the ventricle--can induce the expression of a ventricle-specific
gene, ventricle myosin heavy chain-1 (VMHC1), and prevent the expression
of an atrium-specific gene, atrial myosin heavy chain-1 (AMHC1).
These findings suggest that Irx4 works to maintain the boundaries
between the heart chambers.
Looking Beyond Pressure Problems in Glaucoma
Here's an observation that has passed the test of time. In 1622,
the British oculist Richard Banister wrote, "if one feele ... by
rubbing upon the eie-lids that the eye be growne more solid and
hard than naturally it should be ... the humour growne to any solid
or hard substance, it is not possible to be cured." To this day,
most ophthalmologists consider increased pressure inside the eye
a defining factor in glaucoma, and acknowledge that standard therapy
geared toward lowering that pressure is insufficient.
|Normal optic nerve with healthy neural
tissue (left) and glaucomatous optic nerve (right).
A new approach may finally relegate Banister's statement to history,
Stuart Lipton hopes. Lipton, HMS associate professor of surgery
(neuroscience) at Brigham and Women's Hospital, works on amending
standard therapy with neuroprotective agents.
In the January 27 Journal of the American Medical Association,
he discusses recent work on programmed cell death of the retinal
ganglion cells in glaucoma patients, suggesting it provides a new
tack for experimental treatments. For example, researchers led by
Lipton showed that glutamate--an amino acid known to promote apoptosis
by overstimulating so-called NMDA receptors--is elevated to toxic
levels in the vitreous humor of glaucoma patients. Glaucoma is a
leading cause of blindness worldwide.
Lipton suggests that the disease might be treatable with
the experimental drug memantine, which blocks excessive NMDA receptor
activity while sparing physiological receptor activity. This selectivity
gives memantine an edge over other glutamate antagonists that have
failed in clinical trials, Lipton says. Currently in advanced clinical
studies for other neurodegenerative diseases, memantine will soon
be tested in a large trial of glaucoma patients aimed at preserving
vision in people who fail standard therapy.
Designer Drug Safe and Effective Against
Handing physicians a new tool to fight rheumatoid arthritis, researchers
led by Michael Weinblatt, HMS professor of medicine at Brigham
and Women's Hospital, found that a genetically engineered drug called
etanercept is safe and effective in treating the disease.
In the January 28 New England Journal of Medicine, Weinblatt
and scientists from six other medical centers describe a double-blind,
six-month trial in which they administered etanercept together with
methotrexate--the standard treatment for rheumatoid arthritis--to
89 men and women aged 26 to 71. Many patients continue to have active
disease despite receiving methotrexate.
In patients receiving both drugs, the median number of tender
joints dropped by 75 percent; the number of swollen joints decreased
by 78 percent. The corresponding improvements for patients receiving
methotrexate and placebo were 39 percent and 33 percent. Thirty-nine
percent of etanercept patients and 3 percent of control patients
improved by 50 percent using criteria set by the American College
A slight rash at the injection site was the only common side
effect attributable to etancercept, and previous studies have shown
the drug to be safe when given for 18 months, the authors note.
Etanercept is designed to inhibit the inflammatory cytokine
tumor necrosis factor alpha (TNF alpha). Approved by the FDA last
November, the drug is a recombinant protein consisting of two TNF
alpha receptors fused with part of a human antibody. As a protein
drug, however, it comes with certain disadvantages: it is expensive
to manufacture and must be injected twice a week. A similar drug,
infliximab, is awaiting FDA approval.
Knockout Mice Bridge Divide in Diabetes Research
Despite intensive study, scientists still lack a unifying hypothesis
for the development of type 2 diabetes, a disease that afflicts
more than 100 million people worldwide. In a report in the February
5 Cell, HMS researchers now offer such an explanation.
Research into type 2, or non-insulin dependent, diabetes has long
been divided into two camps: those researchers who focus on how
muscle, fat and the liver become insulin resistant over time, and
those who study the pancreatic beta cells' increasing inability
to churn out enough of the hormone to compensate for the peripheral
tissues' numbness to insulin. But it has never been clear how these
two pathological processes are connected.
In this study, researchers led by C. Ronald Kahn,
the Mary K. Iacocca professor of Medicine at HMS and director of
Joslin Diabetes Center, created "conditional knockout" mice, in
which the gene of interest is disrupted only in a specific tissue.
The mice lacked the gene for the insulin receptor only in their
pancreatic beta cells, allowing Kahn's team to look at insulin signaling
apart from its confusing web of body-wide interactions and study
it at the suspected source of the disease, pancreas.
The engineered mice were unable to release an initial burst
of insulin in response to glucose. Like humans with early stage
disease, the mice developed a progressive inability to handle a
glucose challenge. The researchers suggest that a twofold insulin
defect is at play in the pancreas: beta cells themselves become
resistant to insulin, which in turn impairs their ability to secrete
insulin. Coupled with insulin resistance in peripheral tissues,
these defects could result in the classical pathology of this disease,
the authors write.