The Stealth of Pancreatic
Pancreatic cancer’s furtiveness is what makes
it so deadly: Symptoms of the disease rarely emerge
until it is nearly impossible to eradicate. Eight years
ago, Mimi Canto, a gastroenterologist who specializes
in a technique called endoscopic ultrasonography—which
can detect pancreatic lesions as small as 2 millimeters—decided
to find out whether that technique could act as an
early warning system. Her plan would be to study people
most at risk for this cancer, those with two or more
diagnosed relatives, and see if she could pick up precursors
to the disease.
Canto sent out a call to participants in the National
Familial Pancreas Tumor Registry, established here
in 1994, to ask if they wanted to be screened. She
needn’t have worried. Many registrants ended
up spending their own money to fly here. Now, her screening
studies have shown that eight of 78 high-risk people
she examined had precancerous lesions suspicious enough
to warrant removal. “Compared with other screening
tools,” she says, “that’s a high
Seven of the patients she identified successfully
underwent surgery, offering pathologist Ralph Hruban
an opportunity to study the resected tissue. “We
learned,” says Canto, “that there are pancreatic
cancer precursor lesions in large and small ducts that
cause chronic pancreatitis. This explains why we see
chronic pancreatitis-like changes during screening
tests so commonly.” The study has also provided
specimens for biomarker research being conducted by
pathologist Michael Goggins.
“When we began,” Canto says, “we
didn’t know what pancreatic precursor lesions
were. Now we know what to look for so we can intervene.
We offer all out-of-town patients referral to a local
center of excellence or to return here for ongoing
follow-up. As long as they’re being watched,
they feel better about their risk.”
Prince of Polyps
Kantsevoy at work
Flat, huge or hiding, if it’s a nonmalignant growth in the gastrointestinal
tract, there’s a chance it could turn cancerous—and there’s
also every likelihood that Sergey Kantsevoy can snare it. He can coax out masses
the diameter of a fist in two hours or less, and from the patient’s standpoint,
the experience is simply that of an outpatient endoscopy procedure.
Since most polyps, particularly in the colon, arise
on stalks, they’re easily removed during a screening
colonoscopy. But those growing laterally (flat) or
on the colonic fold offer no purchase, increasing the
risk that attempts to “get under” them
will damage the intestinal wall. Large, vascular polyps
also present a higher chance of bleeding and intestinal
perforation. Yet open surgery to excise the polyp requires
the surgeon to also resect a large segment of the colon
or part of the duodenum and pancreas.
Kantsevoy, however, uses endoscopic ultrasound to
see how deeply a polyp has penetrated, then injects
normal saline or hydroxypropyl methylcellulose (artificial
tears) under it, pulls back and lifts, and injects
again into the mass if necessary. With the polyp now
nicely plumped, he encircles it with a plastic loop,
tightens to prevent bleeding and maneuvers his metal
snare around the growth to cut it off. If bleeding
does occur, he’s ready with tiny clips to stop
it quickly. Large or unusual growths—he’s
found polyps under polyps—may require a piece-by-piece
approach, but eventually Kantsevoy gathers the detritus
into a mesh bag and extracts the lot. His final step
is to tattoo the spot so it can be checked later for
signs of regrowth.
Flat polyps growing along the thin-walled cecum don’t
defeat Kantsevoy, nor do polyps hiding behind the colonic
wall. “If I can raise the polyp,” he says, “I
can remove it.”
And if it won’t raise? “It’s probably
malignant; I won’t touch that.”
No Useless Hairball
|> Jef Boeke and his hairball
A poster adorning Jef Boeke’s office looks something
like a blue tumbleweed. It’s not. It’s
a biological network. Of a yeast cell, no less. Boeke,
a professor of molecular biology and genetics, is an
expert in uncovering details in this bramble about
the interactions of integrity genes—those that
keep hereditary material safe. And why should anyone
care about such things? Boeke rephrases the question: “You
mean, is it a useless hairball or is there information
there?” The yeast cell, he explains, has a fully
sequenced genome containing 5,900 genes. Scores of
these are common to other creatures—like humans.
For this reason, geneticists use yeast cells as a model
for studying organisms on a global level.
Boeke looks for genes that have a lot of connections. “Genetic
mutations that result from breakdowns in this DNA integrity
network can cause cancer,” he explains, “so
understanding why these breakdowns occur and how they
might be avoided could have big implications. “Consider
the yeast cell as a radio,” Boeke instructs. “What
we geneticists do is see if the radio still works when
we randomly pull out six different parts one at a time.
Four out of six times it plays on, one time it works
but not well, and one time it’s completely busted.” Boeke
takes this analysis one step further: He pulls out
two parts of the radio at a time and listens for music.
Boeke and his postdoctoral fellow Xuewen Pan recently
published a paper in Cell describing how they used
microarrays (think vast spreadsheets shrunk to the
size of a coaster) to interrogate 74 genes known to
play a role in replicating DNA and keep it free of
mutations. First, they generated 74 yeast cell lines,
each with one DNA integrity gene deleted. For each
of those deletions, they then introduced a second deletion—one
for each nonessential gene in the genome. Then, they
scanned for yeast cell lines that refused to grow.
If a pair of deletions caused cell death, Boeke deduced,
those two genes must have an essential survival interaction.
Alternately, if two genes have a lot of lethal mutation
pairs in common, but their mutual deletion doesn’t
cause cell death, those two genes 1) must be in the
same pathway, and 2) another pathway must exist that
performs the same function and allows the yeast to
Using this method, the researchers defined 17 new
pathways in the DNA integrity network—branches
in the tumbleweed. Now, they hope to map the entire
yeast genome. Pinpointing the major players and their
connections in this network, Boeke says, “could
reveal subtleties about how organisms work”
Who knew a hairball could do that?
Consultation With The Gastric Bypass Whiz
Since the procedure’s quiet debut 40 years ago,
gastric bypass surgery has made heady strides. Michael
Schweitzer, who performs more than a third of the 400
cases here annually, outlines his favored approaches—and
glimpses the future.
Gastric bypass has become common in recent years.
What techniques do you use?
I favor three procedures. I do all of them laparoscopically,
and I’ve found that patients do just as well
as with the long-incision operations.
The laparoscopic Roux-en-Y gastric bypass uses six
tiny incisions to divert the entire food stream past
most of the stomach, and works best for most people.
I also do a procedure where an adjustable gastric
band is placed laparoscopically around the top of the
stomach and a balloon is filled with saline to squeeze
the stomach and slow the emptying of food. It so far
has the lowest mortality rate of all the operations
but does not work well for all patients.
The laparoscopic duodenal switch procedure leaves
a larger stomach pouch than gastric bypass but with
much more malabsorption, so patients can eat more but
also have increased malabsorption that can lead to
more bowel movements.
Do people keep the weight off after the surgery?
Yes. For gastric bypass, patients on average lose
67 to 75 percent of their excess body weight at 1.5
years; lap-band averages between 37 to 50 percent;
and duodenal switch is at 75 to 80 percent.
So besides lightening their load, what are the other
It boosts people’s overall health enormously,
reducing risk of heart disease, stroke, hypertension
and high cholesterol. It also helps with other ailments,
from sleep apnea to heartburn, to diabetes. In fact,
80 percent of our diabetic patients can stop taking
First, hormones. We’re learning that a hormone
called “ghrelin” has a powerful effect
on hunger. When people diet, their ghrelin level rises,
making them hungry. But after gastric bypass, the level
doesn’t rise since the part of the stomach making
the hormone is bypassed from the food stream. In
the future we’ll have medications that prevent
ghrelin’s effect on appetite. Hopefully, this
will help to keep patients on a lower calorie diet.
Second, I expect we’ll see advances in endoscopic
techniques, where the effects of our current procedures
can be achieved through interventions via the throat
so that surgery will be done without a skin incision.
by Ramsey Flynn
Peace of Mind for Expectant Parents
As recently as 15 years ago, couples at risk for passing
on a severe genetic disorder had two early ways to
discover whether they’d conceived a child with
the disease—chorionic villus sampling or amniocentesis.
These tests, performed at 10 and 16 weeks’ gestation,
respectively, could either give peace of mind or present
two nerve-wracking options: continue the pregnancy
or terminate it.
Then, preimplantation genetic diagnosis brought promise
of a way to better the odds. One or two cells could
be removed from each of a woman’s in vitro
fertilized eggs at the eight-cell stage. Each extracted
cell would then be analyzed for the presence
of a specific abnormality, such as cystic fibrosis.
An embryo not found to have the genetic defect could
then be implanted in the woman’s uterus.
But what’s made PGD iffy, says geneticist Garry
Cutting, has been knowing whether you’ve nailed
the single cell’s two potentially defective genes
for a disorder. “In PGD you’ve got only
one chance to hit both of those genes,” he explains. “If
there’s any contamination, if you’re not
working with the cell you think you’re working
with, you’ll get an inaccurate or incomplete
diagnosis.” As a backup, women are usually encouraged
to also undergo CVS or amniocentesis.
To push beyond these sometimes risky checks on accuracy—the
very tests PGD should supplant—Howard Zacur,
director of reproductive endocrinology, and Jairo Garcia,
head of in vitro fertilization, enlisted Cutting’s
genetic know-how. Cutting and his colleagues then spent
more than five years collaborating with their IVF counterparts.
They performed over 1,000 assays to validate the lab
procedures that would prevent contamination and produce
clinically reliable results.
“We were,” says Cutting, “rather
compulsive about this.” As a result, they’ve
whittled their error rate to less than 1 percent, creating
the first method to be posted as a clinical, not a
laboratory test. Even more gratifying, says Cutting,
was their first case—a baby born without cystic
fibrosis to parents carrying the CFTR gene: “All
the genetic markers we predicted were there.”
Now, they’re expanding the test to diagnose virtually
any inherited genetic disease. “This is taking
translation of genetic discoveries to the next level,” Cutting
says. “We can avoid having to tell parents that
their fetus has a life-limiting disorder.”
Look What They’ve Done to Their Brains
Una McCann preps a volunteer for a sleep study.
“I want to see what I’ve done to my
Una McCann doesn’t think twice when people in
her studies say that. She’s heard it before.
But she’s well aware of the anxiety underlying
the remark; it powers her work.
McCann and her neurologist husband, George Ricaurte,
are world experts on the pathology of amphetamines.
Much of their research has targeted MDMA, the chemical
acronym for the drug called Ecstasy. National annual
and lifetime use of the drug now matches that of cocaine.
MDMA is as likely to be used by graduate students at
all-night “raves” as by dropouts behind
For more than two decades, McCann and Ricaurte have
worked like mad to prove what other amphetamine studies have
shown: that, in some users, MDMA causes immediate long-term
harm to the brain’s serotonin-releasing neurons.
Now they’re near the point of settling the question.
Meanwhile, McCann, whose psychiatry training equips
her to evaluate behavior, has been gathering evidence
that MDMA also warps the brain’s activity.
In the 1980s, the first flurry of research worldwide
confirmed that, in animals, MDMA leads to a steep drop
in brain serotonin. Weeks after monkeys received it
orally, the Hopkins team showed that the brain’s
normal thatch of serotonin nerve axons and their endings
had become a lacework of holes. A dozen labs
concluded that MDMA was bad news to neurons. And seven
years after a dose—the longest interval tested—Ricaurte
found squirrel monkeys’ brains hadn’t
returned to normal.
“But the daunting task,” says McCann, “has
been to show that animal studies reflect what happens
in people.” Some detractors say the animal studies
don’t compare, but the Hopkins work suggests
otherwise. And in looking at blood plasma levels of
MDMA, the team may have an index that does apply to
humans. Recently, they tied blood concentrations of
the drug to brain damage in squirrel monkeys dosed
in human-similar ways. Blood levels lowered brain serotonin
weeks later and matched those that other labs reported
in people using Ecstasy. Plus, in both humans and animals,
follow-up PET scans showed corresponding losses of
nerve ending markers.
Do these people act different? “Effects might
not be obvious if you’ve only taken MDMA a few
times,” says McCann. But for heavier users she’s
tested—and labs worldwide confirm—cognitive
troubles, especially in short-term memory, crop up.
“It boils down to the fact that kids are taking
a drug clearly toxic to any mammal you can think of,” McCann
says, “and they think that’s OK.”
Why the Robot?
robotic surgery, the principal surgeon
operates from a console, while assistants
tend the patient.
As surgeons become
ever more comfortable with solving complex problems
through the use of robots (robotic surgery), Stephen
Yang’s biggest question is how far the technology
can go in cancer operations.
Johns Hopkins was the first medical center in the
region to use the da Vinci robot, and Yang has performed
over 25 operations with the device so far. He and his
patients like it for its smaller incisions, reduced
need to spread the patient’s ribs, reduced pain
and quicker recovery time.
As a surgeon, Yang also likes the da Vinci apparatus
for its intuitive qualities, its aid in finer resection
techniques and the way it provides 3-D vision technology
to guide delicate procedures. He says it has turned
the procedure for removing misbehaving thymus glands
into a routine matter, vastly improving on a remedy
for myasthenia gravis first pioneered here in 1941
by Alfred Blalock.
Other surgeons here talk optimistically of the robotic
technology’s prospects for handling a wider range
of procedures, especially those that demand access
to tissues inside the rib cage.
“But what is its ultimate role in thoracic surgery?” Yang
asks, adding that one of his favorite questions is “Just
because we can do it, does it mean we should?”
The current limitation of the da Vinci procedures
is that they are not necessarily the best course when
it comes to removing large masses of tissue, Yang says.
Such operations require larger incisions, not the keyhole-size
openings that allow entry of thin robotic tubes.
Still, Yang says, the robots have proven their worth, “and
the technology is still young.”
Let's Meet Dana Andersen
Bayview Surgery Chief
It’s fun to talk to Dana Andersen about surgery.
He can home in on his specialty, pancreatic disease,
at the molecular level and then project out 50 years
into the future. “I think the names medicine
and surgery and radiology will all have vanished,” says
the new chief of surgery at Bayview Medical Center. “We’ll
be looking at specialists who focus on diseases, not
on the tools of their trade.”
Andersen, who arrived last fall from the University
of Massachusetts Medical School, started his research
career at Bayview 30 years ago. “The pancreas
is a marvelously smart and complicated organ that makes
all sorts of hormones that help regulate our metabolism,” he
says. “We now know that some of these gut hormones
can act like insulin. And if we can find a way to capture
them, then we’ll be on our way to replacing the
pancreas in someone at risk for developing pancreas
But until the day arrives when a drug can be given
to simulate those hormones, pancreatic surgery will
still carry risks. At Bayview, where big-incision operations
of yesterday have given way to minimally invasive,
catheter-based technology aided by image-based techniques
like CT scanners inside the OR, Andersen is recruiting
surgeons in nearly every specialty. “This is
a campus where there’s room to expand and build
new programs,” he says.
Already, Bayview is adding four new operating rooms,
for a total of 14. “We probably need 20,” says
Andersen, who expects the medical center’s surgical
volume, now at 10,000 cases a year, to double over
the next five years.
Andersen also envisions Bayview as a center for clinical
research. “The history of progress in medicine
has been to figure out why surgical operations achieve
the goals they do and then see if you can replicate
the same response in a safer way and provide the treatment
to lots more people. Our patients represent a great
source of information for us.”
Mary Ellen Miller
Eduardo Marbán may have discovered a way to repair hearts using patients’ own adult stem cells.
Just a few months after beginning the first clinical
trial in the United States using donor stem cells to
repair muscle damaged by a heart attack, researchers
have shown that one day damaged heart tissue could
be regenerated with a patient’s own stem cells.
Led by cardiology chief Eduardo Marbán, the
scientists reported on two stem cell studies using
cardiospheres, multicellular spherical structures that
behave like primitive heart tissue. In the first, they
biopsied heart tissue from 10 patients of different
ages and grew the tissues in the lab for two weeks.
They then collected cardiac stem cells from the cultivated
tissue and reproduced them as cardiospheres that were
similar to either heart muscle cells (with the ability
to contract) or cells that could develop into smooth
muscle or blood vessel lining.
The team then induced heart attacks in 19 mice and
injected eight of them with 100,000 stem cells (grown
from cardiospheres) adjacent to where the heart attack
had caused damage. The rest of the mice they gave placebo
cells. To test their results, they measured the muscular
contraction and blood pumping in the hearts of both
groups of mice. What the scientists discovered was
that the hearts treated with the stem cells performed
on average 15 percent to 20 percent better than those
in the control groups.
“Those findings are dramatic,” Marban
says, “because they open up a whole new vista
for heart repair and muscle regeneration. Most important,
by using a person’s own adult stem cells instead
of those from a donor, there’s no risk of rejection.”
The Ease of Sweat-Reduction Surgery
In a scene from the
film “Broadcast News,” comic actor Albert
Brooks portrays an anchorman suffering an attack of “flop
sweat” on the air while a make-up woman scurries
about with tissues that are quickly supplanted by towels.
The scene is uproariously comical, but it captures
a medical condition that real-world sufferers consider
a daily nightmare. It’s also a condition that
thoracic surgeons can halt with a simple outpatient
The condition is known as “hyperhidrosis,” and
it typically afflicts 1 percent of the population with
excessive bouts of sweating in the armpits, palms,
face, neck or groin. Many sufferers have silently endured
hyperhidrosis for years, often devising ways to thwart
the affliction’s ability to cause social embarrassment.
Some sufferers have learned to wear extra undershirts
to soak up the excess sweat; others sport thick sweaters
that hide the appearance of stains. Job applicants
dread giving “wet fish” handshakes to potential
employers. Afflicted guests at cocktail parties confess
to keeping a cold drink in their right hands to explain
their wet handshakes.
Stephen Yang describes one recent patient from Bermuda,
a hotel manager who required three to four shirt changes
every day. Such coping strategies can become unnecessary,
according to Yang, who assures sufferers that hyperhidrosis
is not the result of emotional or nervous states; It ’s
a hereditary condition of unknown origin that has haunted
populations around the world.
Malcolm Brock explains
that hyperhidrosis results from overactivity in the “sympathetic
the nervous system. He says his division has mastered
the procedure to flip the “off switch” in
this system by severing the nerve through a pair of one-inch
incisions just below each armpit. Brock calls it “a
simple operation that provides an instant response.” He
adds that his division’s patients, including the
once-distraught hotel manager from Bermuda, are typically “very
happy” with the procedure’s results.