The Stealth of Pancreatic Cancer

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 yield.”

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.”

Mary Ann Ayd

Prince of Polyps

> Sergey 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.”

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 live.

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?

Erika Gebel

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 benefits?

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 their medications.

What’s next?

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.

Interviewed 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.”

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 brain.”  Psychiatrist 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 the 7-Eleven.

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?

> In 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.”

Ramsey Flynn

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 cancer.”

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

Remaking Hearts

> 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.”

Michael Levin-Epstein

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 procedure.

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 chain” of 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.

Ramsey Flynn