Move Over, PSA

A simpler, more precise blood test could reduce unneeded treatments.

Prepare for a major leap forward in detecting prostate cancer. If all goes well during ongoing trials, says Robert Getzenberg, “a simple blood test” could vastly outperform the current technique, popularly known as the PSA test. The new blood test could spare more than a million men per year from the pain of multiple biopsy needles. 

In the last several years, Getzenberg and colleagues here have learned how to track a new marker for the presence of prostate cancer. Traditional tracking of prostate-specific antigen (PSA) has helped save lives over the past 25 years, says Getzenberg, but PSA scores are, at best, a very rough gauge for the presence of cancer.

Consider that about 1.3 million men found to have high PSA levels will be scheduled for prostate biopsies this year, but only 19 percent will actually have prostate cancer. Perhaps worse, about 15 percent of men who do have prostate cancer will go undetected because their PSA levels failed to reach the threshold for a biopsy.

The new test screens for a protein known as early prostate cancer antigen-2 (EPCA-2). In a study published in April’s Urology—based on groups of patients with and without the disease—the EPCA-2 test accurately detected prostate cancer in 94 percent of men with the condition, with just a 3 percent rate of false positives. In a smaller sampling of 18 men who had prostate cancer despite low PSA levels, the EPCA-2 assay found it in 14 of them.

This more definitive test could have enormous impact. “We’re probably overtreating many men for prostate cancer today,” says Getzenberg, who directs research at the Brady Urological Institute. The new test could also flag men with prostate cancer whose conditions were missed through PSA screening.

And the EPCA-2 test appears to provide an added value: It can tell when the cancer is confined inside the prostate or has spread beyond its borders; the latter signals a more aggressive form of the disease that calls for more forceful treatment.

In either case, early treatment can help beat the disease, which currently takes more than 27,000 lives each year.

If the new test is approved, Getzenberg expects its early use would be similar to that of the PSA test. He says patients at risk—all men over 40 or those with a family history of prostate cancer—will likely still undergo a digital rectal exam to detect abnormalities in the gland. Tests for both PSA and EPCA-2 levels would follow. But some years from now, Getzenberg believes, the new test will supplant the value of traditional PSA testing. “If our data hold up in the current multicenter trials,” he says, “you would easily throw out PSA."

Ramsey Flynn

“Neurosurgery” on the Pancreas

For benign tumors, the Whipple may be overkill.

>Andersen, with his ultrasonic wonder

When a swollen foot prompted Colorado Springs radiologist Michael Fox to visit his physician, the doctor ordered a CT scan to see if a lymph node abnormality might be the culprit. It wasn’t, but to Fox’s consternation, the imaging turned up a 4-centimeter mass on the head of his pancreas.

Fox spent the next few weeks researching his options and having further tests done. Everyone agreed the tumor looked benign. And with a single exception, his colleagues said his only option was the Whipple procedure. The extensive surgery would remove not only the head of his pancreas but his gallbladder, common bile duct and part of his duodenum as well. Only the surgeon in his group practice, citing “a lot of morbidity and mortality,” advised against the Whipple.

Fox hit the Web in search of an alternative and turned up information about Hopkins’ Dana Andersen, who has pioneered a “less-than-a-Whipple” procedure that spares the duodenum.

Andersen, chief of surgery at Johns Hopkins Bayview Medical Center, understands why most physicians hear pancreatic lesion and immediately think Whipple. Although less drastic operations were introduced in the 1980s for benign and premalignant tumors or chronic inflammation on the head of the pancreas, they’re rarely performed in the United States. Andersen believes that should change. He’s developed a technique for excavating the central core of the pancreatic head and removing the proximal main pancreatic duct while preserving the posterior capsule and neck of the pancreas. Because he’s resecting a smaller portion of the pancreas and none of the small intestine, morbidity is lower and patients are unlikely to have subsequent digestive problems or diabetes.

Still, Andersen says, “the pancreas is very vascular, so coring out the head is technically challenging.” To do that safely, he uses an ultrasonic aspirator and dissector, an instrument more commonly found in the hands of neurosurgeons. “It has a high-frequency pulse at the tip that shakes apart the tissue ahead of it, but in a minute area,” he explains. “The tissue separates before you, like the biblical parting of the waters. You can see the blood vessels before you get to them. That’s why brain surgeons love it, but most pancreatic surgeons are unaware of its utility for ‘our organ.’”

Andersen first used his excavation procedure to relieve chronic pancreatitis. He’s since shown that it’s also a godsend for patients like Fox. “By our standard,” Andersen says, “the Whipple is very safe and reasonable for bad disease of the pancreas but it may be overkill for patients without invasive cancers.”

Fox underwent the surgery in Baltimore last fall, and was discharged five days later. (He stayed another week in a local hotel in case of complications—there were none). The 49-year-old still doesn’t know what’s wrong with his foot—but he has developed a mission.

“I teach residents and I’m putting up my case for discussion,” he says. “I’m telling them that there are two treatment paths, not one, and that, unfortunately, they may be the only ones who know about this.”  

Mary Ann Ayd

We Can See Clearly Now

> Tracking the brain’s blood flow

From the outside it may look like any other CT scanner, but thanks to its 256-slice technology, it’s anything but. The latest idea from Toshiba, the prototype scanner spent several months here last spring and has left Hopkins collaborators like Kieran Murphy, director of interventional neuroradiology, anxiously anticipating a permanent version, due later this year.

“This is a major breakthrough,” Murphy says. “It’s one of the most exciting tools I’ve ever seen in medicine.”

The only CT scanner in North America that uses 256-slice technology, it promises to quadruple the volume of tissue viewed in a single take—and give ER physicians a quick and commanding glimpse into the early stages of a stroke, many of which can be successfully reversed with clot-busting drugs if diagnosed within the crucial first three hours.

“We can get the imaging done in less than an hour,” says Murphy. The quicker process also spares patients needless exposure to radiation, he notes.

And the 256 enhances the view into other critical organs, like the heart and liver. Cardiologist Joao Lima, who has headed up cardiovascular testing for the new technology at Hopkins, says the scanner’s speed allows him to take a much quicker shot of a beating heart—down to two seconds or less—valuable in detecting arrhythmias, calcium deposits or other areas of restricted blood flow.

Ramsey Flynn

The Mini Exam with Maximal Staying Power

The most-cited paper in neuropsychiatry grew out of a husband/wife exchange.

As a third-year resident in the fall of 1973, Susan Folstein made daily rounds of the geriatric ward at Cornell Medical Center’s Westchester Hospital. Husband Marshal Folstein was the ward’s attending psychiatrist. Like the other residents, Susan was supposed to assess the mental state of each patient and identify any cognitive impairment. As Marshal remembers it, she’d report, “Mrs. Jones is doing better today, or she’s doing worse.” And he would always reply, “But how do you know she’s better?”

Hopkins’ legendary psychiatrist Paul McHugh, now retired, was then the residency training director at Cornell. “Because Susan was married to Marshal,” McHugh jokes, “she could only put up with this for so long.” One day, exasperated, she finally said, “Why don’t you just write down all of the questions you want me to ask these people?”

So that night, Folstein did. He knew from his previous neurology training the kinds of questions to ask: simple, direct, objective. What day is it? Spell world backwards. Repeat the following. They targeted cognitive function only, rather than moods or perceptions. He called his final product—a 30-point scale based on just 11 questions—the Mini Mental State Examination (MMSE). The test could be given in just 10 minutes.

Susan Folstein immediately began using the MMSE with her patients, and soon the pair set up a trial to see if the exam could differentiate among patients with various cognitive disorders. It could. The MMSE scores of the 206 patients in the trial reliably predicted whether they had dementia, depression or normal cognitive functioning (roughly any score above 24).

“We were just kids; we didn’t have any training. We just needed it to do our work everyday,” recalls Marshal. But the test was revolutionary. “And once we had it,” McHugh says, “it became obvious that nobody else had anything else like it.”

With McHugh’s help, the pair submitted their results to the Journal of Psychiatric Research. The paper was published in 1975, about the time that all three authors moved to Johns Hopkins. It’s since been cited in the scientific literature more than 19,000 times—making it the most-cited paper in neuropsychiatry.

Marshal Folstein attributes some of its popularity to an 18,000-patient epidemiological survey of mental health conducted by Hopkins and four other large medical centers in the early 1980s. The survey’s designers used the MMSE as one of the screening tests, thus validating its effectiveness to the entire field. “And for whatever reason, it has since become the standard test for pretty much any drug study that involves Alzheimer’s or dementia,” says Marshal Folstein, who, with Susan, now serves on the faculty in the Department of Psychiatry and Behavioral Services at Hopkins.

“Every psychiatrist in training knows what a Mini Mental score of 24 means,” McHugh says. “They know 24 like we all know 98.6.”

Virginia Hughes

A Gentler Fix for Broken Aortas

It’s the sort of injury that smart trauma teams look for whenever they receive the survivors of a high-speed car crash. Though the patients’ broken bones might be instantly obvious, the deadliest culprit may lurk within—a torn aorta, either actively leaking blood into the chest or about to come apart. The complication typically propels surgeons into an urgent open-chest procedure that involves sawing through the ribs and replacing the torn portion of the vessel with an artificial graft.

But what happens when a patient is too fragile to survive heavy surgery and further blood loss? Such a case presented itself when 72-year-old Raymond Sheffler was brought into the Emergency Department at Johns Hopkins Bayview Medical Center bleeding heavily from five cracked ribs and other injuries sustained in a head-on collision minutes earlier. A sharp-eyed radiologist then detected the torn aorta next to Sheffler’s heart, accompanied by a telltale bulge in the great vessel.

Sheffler’s age and other injuries made him a high-risk candidate for open-chest surgery, yet his stars had clearly aligned—Bayview’s chief of endovascular surgery, Mahmoud Malas, is an expert in precisely this type of injury.

Malas decided Sheffler was the perfect candidate for a minimally invasive approach much like the one used in common cardiac stenting procedures. The surgeon made a 2-inch incision into the femoral artery in Sheffler’s groin, deployed a delivery sheath into the artery to smooth the way, and threaded it up close to the aorta’s injury site. He then inserted a catheter through the sheath. The tip of the catheter was equipped with a 4-inch self-expanding stent. Using intraoperative imaging to guide placement of the endograft, Malas triggered its expansion after it straddled the aorta’s rupturing section.

Once the endograft was deployed, blood again flowed securely through Sheffler’s biggest blood vessel. Sheffler was sent home three days later. An open-chest procedure would have easily required a weeklong hospital stay and extensive rehab.

Malas says about 8,000 Americans suffer from ruptured aortas annually—mostly from high-speed collisions—and that up to 90 percent die at the scene. Of the remaining 10 percent who make it to the ED, he says, half die because their condition isn’t recognized. He is bullish about the endograft procedure because it’s proving safer than open-chest techniques—and it also reduces the risk of diminished nerve function to the limbs that can accompany open procedures. “This procedure only took two hours,” he says of the Sheffler case. “He only lost 10 ounces of blood, about one-tenth of what he would have lost in an open-chest procedure.”

Ramsey Flynn

Averting Sudden Cardiac Death

A new genetic test could offer an early warning for dangerous arrhythmias.

In their quarter-century campaign to accurately diagnose one of the most mysterious causes of sudden cardiac death, scientists are closing in on their quarry with the aid of improved genetic screening. “In many cases,” says cardiologist Hugh Calkins, “we can now pin it down.”

One of every 5,000 people has arrhythmogenic right ventricular dysplasia, or ARVD. Tragically, it’s responsible for 5 percent of sudden cardiac deaths in young people in the United States—and is often the culprit behind the abrupt collapse of athletes on the playing court and field.

But the process of diagnosing ARVD has always been vexing, says Calkins, who has been immersed in the chase for eight years and now heads a team of 10 specialists at Hopkins. ARVD’s presence too often becomes clear only after an autopsy reveals telltale signs of the condition, such as a severely dilated right ventricle whose walls are thinned and replaced with fibro-fatty tissue.

While a family history of ARVD is obviously a strong indicator (a third of an afflicted person’s children will get it), Calkins, who serves on a task force charged with revising the condition’s diagnostic criteria, says one genetic mutation has recently come to the fore—in a protein known as plakophilin-2. This PKP2 error is associated with up to 45 percent of ARVD patients.

What’s more, Calkins adds, is that patients with PKP2 are also more likely to develop ARVD at an early age, which hints at the condition’s disproportionate toll on young athletes.

If ARVD can be caught in advance—PKP2 can be detected through a blood test with genetic screening—patients can be advised against strenuous activity and their arrhythmias can be temporarily relieved with ablation therapy. The more optimal long-term solution: implantation of a defibrillator, which can detect and correct dangerous arrhythmias whenever they strike.

Ramsey Flynn