Judy Foreman

Nationally Sindicated Fitness, Health, and Medicine Columnist

Detecting, treating bladder cancer early

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Four years ago, Ellen Pinzur, a Cambridge woman who had been a lifetime smoker, got a most unwelcome surprise.

When she went to her gynecologist for a routine exam, he suspected she had a fibroid, a benign growth in the uterus. He sent her for an ultrasound. Sure enough, she did have a fibroid.    

But that was the good news.The test also showed that Pinzur, now 52, had bladder polyps. She had them removed, then several months later, had a checkup by cystoscopy, in which a urologist inserts a lighted tube through the urethra to see inside the bladder while the patient is under local anesthesia.

The polyps were gone, but they had “seeded” her bladder with cancerous tumors. Unlike many people who get bladder cancer, Pinzur did not have the telltale sign of blood in her urine.

In hopes of boosting the odds of beating her cancer, Pinzur joined a study in which tuberculosis bacteria, of all things, are squirted into the bladder to trigger an influx of white blood cells that attack both the TB and cancer cells. (The risk of TB spreading to other parts of the body is low.)

Perhaps because of this unusual therapy, Pinzur has been cancer-free now for two years.

The therapy she had is but one of a number of new techniques that scientists are working on to improve both treatment and diagnosis of bladder cancer, which will strike 54,200 Americans this year and kill 12,100. Men are four times more likely to get bladder cancer than women because smoking is a major trigger for the cancer, and historically, men have smoked more than women.

If caught early, while the cancer is a shallow spot in the lining of the bladder, the 5-year survival rate is 95 percent; for cancers that have invaded muscle tissue and spread throughout the body, 5-year survival is 50 to 60 percent.

But the most striking thing about bladder cancer is that it recurs in 70 percent of cases, no matter what doctors do. For the 500,000 Americans who have it, this means a lifetime of monitoring – including cystoscopy every three to 12 months.

This is not only unpleasant, it’s expensive – much more so than caring for someone with breast or prostate cancer, notes Dr. Ihor Sawczuk, vice chairman of urology at Columbia University’s College of Physicians and Surgeons.

But nearly a dozen new tests now on the market or under development could lighten this burden.

The goal of all these tests is “to make cystoscopy unnecessary,” says Dr. Kevin R. Loughlin, a urologist at Brigham and Women’s Hospital. So far, he cautions, none of the tests has replaced cytology – a noninvasive exam in which a pathologist looks through a microscope at cells shed from the bladder into the urine. If he or she sees any suspicious cells, the patient must then undergo cystoscopy, the more invasive test.

But cytology, the current “gold standard,” is not a perfect test. In fact, it picks up only about 40 percent of cancers, and is worst at spotting the most common, early stage bladder cancers.

The hope is the new tests can do much better.

Today , for instance, Matritech, Inc. of Newton will present its case to the US Food and Drug Administration, arguing for expanded approval of its already-marketed test, NMP22, which measures a protein made in the nucleus of cells in urine. High levels of NMP22 indicate high turnover of cells, a sign of cancer. The company wants doctors to use the test not just to monitor people who have cancer, as is now the case, but to test those who merely show symptoms, like having blood in the urine. In Japan, the NMP22 test is already approved for wider screening.

Overall, the test is 70 percent sensitive, which means it finds 70 percent of tumors at all stages of cancer combined.

That also means it misses 30 percent. And while that’s better than cytology, it’s still underwhelming to some urologists.

“It’s not the greatest test in the world,” says Dr. Michael O’Donnell, director of the bladder cancer center at Beth Israel Deaconess Medical Center. “I did a 6-month pilot trial at our institution and abandoned it.” The test often said patients had cancer when they didn’t and missed it in those who did have it.

Even if it were 80 percent sensitive, “that just isn’t good enough in my mind,” adds Loughlin of the Brigham.

Still, in one Italian study published last year, NMP22 was a better cancer detector than a marker called BTA. Another 1998 study found NMP22 was just as sensitive as a marker called telomerase, and that both were more sensitive than BTA. A Cleveland Clinic study published in January, showed the test was 100 percent sensitive. And a Spanish study, published this month suggested that NMP22 combined with another marker, CYFRA 21-1, can help reveal whether cystoscopy is needed.

For instance, if a patient scores low on the NMP22 test, it may be safe to postpone the invasive exam for a few months or do it under local anesthesia in the doctor’s office. If a patient scores high, it suggests the procedure should be done in a hospital under anesthesia, so that if the urologist does see cancer, he or she can remove it right then and there.

The NMP22 test may also tip the balance when other tests are ambiguous, notes Dr. Eric J. Sacknoff, a urologist at Cambridge Urological Associates. If the NMP22 score is high and a bladder X-ray is negative, for instance, that may indicate there is indeed a cancer, but higher up in the urinary system.

Ultimately, it’s not just better detection but better treatment that’s needed to turn the tide in bladder cancer.

At the Beth Israel, for instance, urologist O’Donnell is expanding the trial that Pinzur participated in to 70 centers nationwide. It’s already been shown that treating bladder cancer patients with TB seems to prevent recurrence in about 60 percent of cases. O’Donnell hopes that adding alpha interferon may improve those odds. So far, though, his study hasn’t followed patients long enough to tell.

Ultimately, says Loughlin of the Brigham, the best treatment for bladder cancer will probably be gene therapy to correct messages from errant genes on chromosomes 9 and 17. And the best way to prevent it is not to smoke. Scientists believe that bladder cancer begins when genes on one or both of these chromosomes are damaged by tobacco and other carcinogens.

So far, he says, that research is still in its infancy. But “this is where the real, major advance is going to be.”< SIDEBAR

SMOKERS AT HIGHER RISK YOU MAY BE AT RISK FOR BLADDER CANCER IF YOU ARE OVER 50, MALE OR SMOKE. IN FACT, MEN ARE FOUR TIMES MORE LIKELY THAN WOMEN TO GET BLADDER CANCER, PROBABLY BECAUSE, HISTORICALLY, THEY’VE BEEN MORE LIKELY TO SMOKE. MEN ALSO TEND TO URINATE LESS FREQUENTLY THAN WOMEN, WHICH MEANS THAT WHATEVER TOXINS OR CARCINOGENS ARE IN THE URINE STAY IN THE BLADDER LONGER. 

Smoking causes nearly half of bladder cancer deaths in men and more than a third in women. Others at risk include those who are exposed to chemicals called aromatic amines. Painters, as well as people who work in the leather, rubber, dye, and aluminum industries often use these compounds.

In recent years, the incidence of bladder cancer has been rising slowly, for unclear reasons.

One sign of possible bladder cancer is blood in the urine, either enough to see with the naked eye, or traces detected through urine testing. But this doesn’t always indicate cancer. It can also be – in fact, it usually is – a sign of infection or inflammation anywhere in the urinary tract, prostate problems, or a kidney stone. Or sometimes, simply having eaten beets can give the urine a reddish hue.

Still, if you have blood in your urine, you should call your doctor.

E-therapy is hardly a bargain

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We’ve got e-commerce, e-banking, e-pharmacy and of course, e-mail. So why not e-therapy?

Actually, there are lots of reasons why not. But that’s not stopping the latest trend in electronic medicine – virtual therapists, some 150 to 200 of them, who offer assessments, generic advice and even ongoing individual psychotherapy online.

The mere idea of sending private thoughts into cyberspace to someone who may or may not be a qualified therapist, who probably isn’t licensed in the state where you live and who can’t see the tears in your eyes when you talk about your mother is enough to send mainstream therapists around the bend.

And the whole notion might indeed be silly except for two things. One: Some people actually prefer confiding in a computer. And two: There’s a huge unmet need for mental health services in America, and Net-based services might help meet it.

Consider depression. Roughly 18 million Americans suffer from it and only two thirds get treatment. Indeed, a recent Harris poll showed that among 60 million Americans who used the Net last year to search for health information, what they most wanted to know about was depression.

There are several ways computer technology can help, and the least controversial is by offering diagnosis and assessment. At www.mediconsult.com, for instance, you can take a 10-minute test to help interpret your moods. I took it, and it’s not bad – on a par with standard questionnaires in self-help books. In other words, it might help clarify whether you need treatment – but obviously can’t provide warm, supportive feedback.

Another online assessment tool is being developed by Healthcare Technology Systems (www.healthtechsys.com) and is already available by telephone (1-800-813-2364). I took this, too, and for some reason, found it more disconcerting to punch in answers on the phone pad than to click on a computer form.

Still, it’s not assessment that’s really controversial in virtual psychotherapy, it’s the idea of being analyzed by a therapist you can’t see. This drawback might change with the advent of video-audio transmission via the Net.

Many therapists draw a distinction between using e-mail occasionally to stay in touch with patients they already know and conducting therapy between strangers on the Net.

Dr. Russell Lim , a psychiatrist at UC/Davis in California, uses e-mail in the former way. “I’m a pragmatist,” he says, and is quite willing to try “whatever works in real life.”

He uses e-mail with a patient who lives far away and comes in every other week, just as some therapists use the telephone to stay in touch when necessary. “Without the Internet connection,” he says, “the point might be lost.”

Other therapists, like University of Chicago psychiatrist Dr. Robert Hsiung (www.dr-bob.org/tips) haven’t used the Net yet for individual counselling, but do run virtual self-groups. For instance, Hsiung puts patients with similar problems in touch with each other and is excited about the “potential to do something more directly clinical online.”

But when virtual contact is the only or the primary mode of therapy, numerous questions arise, including the issue of online confidentiality.

Hsiung, for instance, acknowledges that “e-mail isn’t totally secure or confidential. You hope people realize that, but maybe not.” E-mail is fine for innocuous things like re-scheduling an appoinment, he says, but patients should “think twice before sending out sensitive information.”

But the “biggest drawback to online versus real life [therapy] is you don’t get the nonverbal cues, which are a big part of communication,” acknowledges psychologist John Grohol, who runs the mental health section of drkoop.com.

That means the therapist can’t detect a telltale whiff of alcohol on a patient’s breath, or the dirty clothes and hair of someone who’s too depressed to bathe, adds Dr. Ronald Pies, a Tufts University psychiatrist.

And if the therapist and patient have never met, it could be downright dangerous to perform therapy online, warns Gerald Koocher , chief psychologist at Children’s Hospital in Boston.

“The difficulty is when you don’t know who you’re dealing with or what the reality of the situation is,” he says, which is particularly crucial for patients who may be suicidal.

“Do you know who they are and where they are? Do you know how to get emergency services to them? If someone is in your office, you can call the police. If you’re on the phone and you know where they live, you can call intervention for them. If they’re on the Net, you may not know who you’re talking to or where they are or what the nearest emergency facility is.”

Patients, of course, are equally “blind” as to who an Internet therapist really is. “Anybody can hang up a shingle on the Net,” says Pies, which raises the risk of both bad therapy and fraud.

Moreover, psychiatrists, psychologists and social workers are licensed state by state. If if you were harmed by online therapy offered by someone in another state, where would you file a complaint or sue for malpractice?

Even www.metanoia.org, a website that offers lists of online therapists and does some checking of credentials, admits on its site that “if something goes drastically wrong as a result of your interaction with a therapist online, at the present time, you probably have little or no legal recourse against the therapist.”

In fact, metanoia concedes that e-therapy is not really therapy, though it says “it can definitely be therapeutic.”

Despite the serious drawbacks, some believe cybertherapy is an idea whose time has come.

“I personally think this technology has the most potential to improve the rates of treatment and overall quality of treatment of any technology since antidepressants,” says Dr. Joshua Freeman , a psychiatrist at UCLA and medical director for mental health at mediconsult.com.

As it is now, he says, “the system is failing if it insists on providing a certain type of treatment that most people don’t get.”

Besides, a number of studies suggest that some people feel more comfortable – and are more honest – when they’re “interviewed” by a computer rather than a human, especially about sensitive issues.

A 1987 study by University of Wisconsin researchers, for instance, examined the scores of 150 psychiatric patients on diagnostic interviews given both face to face with a trained interviewer and on a computer. A significant majority “liked the computer interview better and found it less embarrassing,” the researchers concluded.

Other studies compiled by Dr. John Greist, CEO of Healthcare Technology Systems, suggest that people may feel more comfortable confessing problems with alcohol, drug or sexual function to a computer because they can think before they answer and don’t have to worry about keeping a professional waiting. People with “social phobia” may also prefer a computer.

So where will all this lead? Let’s hope not too far.

Okay, online self-diagnosis tests are fine. And in a pinch, an online shrink might be better than none, though it’s inappropriate if you’re seriously ill or suicidal.

But basically, therapy is a complex, subtle human endeavor that would lose something essential in cyberspace.

In other words, I side with psychologist Barry Schlosser, who runs a consulting firm in New Haven called Clarity Consulting Corp. E-therapy, he says, is not “ready for prime time.”<
SIDEBAR

THERE ARE MANY WEB SITES OFFERING INFORMATION ON MENTAL HEALTH PROBLEMS AND GUIDANCE IN FINDING A THERAPIST. SOME YOU MAY WANT TO VISIT ARE:

www.healthtechsys.com (for information oncomputerized mental healthassessments)

www.mediconsult.com (for mental health assessment – click on depression, then on “mind health tracker”)

www.drkoop.com (for information on depression and other mental health problems)

http://mentalhelp.net (for information on mental health problems)

Trendy pill should be taken with a grain of salt

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She’s a young woman from the South Shore, finally able both to work and to study for an advanced degree.

But for years, she’s been plagued by severe depression that stems, she says, from physical abuse she suffered as a child, and from sexual abuse when she was 17.

She tried Prozac and, by her count, 30 other antidepressant drugs. Nothing worked. Psychotherapy helped some, and still does, but not enough.

She’s been suicidal. She still has nightmares and flashbacks. Until a few months ago, the woman, who did not want her age, occupation or town published, felt she had no options left.

Then she tried SAM-e, the European prescription antidepressant that in recent months has been growing here in popularity, despite its $10-a-day price tag. The preparation is now available as an over-the-counter remedy in US health food stores.

“I haven’t felt as depressed,” says the woman, who has been taking 800 milligrams a day of SAM-e for several months. “It sounds corny, but I just have experienced more joy lately.”

Neither an herb nor a vitamin, SAM-e (pronounced “Sammy”) is a synthetic form of a chemical made in the body from methionine, an amino acid, and an energy molecule called ATP. It helps with dozens of metabolic functions from preservation of cell membranes to DNA replication.

In fact, it’s been studied and used for years in Italy as an antidepressant. In the US, the potential market for it is huge – 18 million Americans suffer from depression.

Because it is sold as a dietary supplement, SAM-e did not have to pass safety or efficacy review by the US Food and Drug Administration. But because it contains a “new ingredient” (S-adenosylmethionine), manufacturers must inform the FDA of their intent to sell it. By law, if the FDA does not object within a defined time period – and it has not with SAM-e – the new ingredient may be sold.

It’s not at all clear how SAM-e might combat depression. It does not work as Prozac-type drugs do, by blocking re-uptake of a brain chemical called serotonin. It may act by improving the elasticity of cell membranes or by stabilizing receptors on cell membranes, but this is unproved.

Still, there’s evidence that some depressed people may be low in SAM-e, and that taking SAM-e supplements may help. In a 1990 study of 30 depressed people, one third had low levels of SAM-e in the cerebrospinal fluid, says Teodoro Bottiglieri, the leader of that research and director of the neuropharmacology lab at Baylor Institute of Metabolic Disease in Dallas.

Several animal studies and one placebo-controlled human study suggest that SAM-e can boost serotonin levels. Other evidence suggests SAM-e may also raise levels of dopamine and norepinephrine, two other brain chemicals often involved in depression.

But the best – albeit flawed – evidence for SAM-e comes from a 1994 Italian analysis of pooled data from 13 clinical trials. Taken together, six studies showed SAM-e was better than a placebo at reducing depression. The other studies suggested SAM-e was equal in efficacy to older, tricyclic antidepressants, which have been shown to be about as effective as newer antidpressants such as Prozac.

Yet even psychiatrists who recommend SAM-e are cautious.

“It is not a good first-line drug. It’s something to consider as a possible alternative when other things have failed,” says Dr. Maurizio Fava, a psychiatrist at Massachusetts General Hospital. So far, he says, most studies are too small to carry much statistical weight and use poorly defined groups of depressed patients.

Dr. Scott Ewing, director of the depression and anxiety disorders clinic at McLean Hospital in Belmont, agrees.

“Every year or so, there’s a new antidepressant du jour. Right now SAM-e is it. A couple of years ago, it was St. John’s wort,” he says. But SAM-e research “is not of the highest quality.”

The studies have typically followed patients for four weeks or less. Since many depressed patients feel better in a few weeks even taking a placebo, these results may be meaningless. A study that followed people for 8 to 12 weeks would be more convincing, say psychiatrists, because the placebo effect often wears off by this point.

Still, Ewing supports the use of SAM-e in his patients who can’t tolerate side-effects of other antidepressants, partly because it appears to have few side effects and to be safe.

It may also take effect sooner than standard antidepressants and may, if taken with them, boost their effectiveness, he says. But this is unproven, warns Ewing, and there are other ways to boost the potency of antidepressants for which there is good evidence.

Dr. Jerry Rosenbaum, associate chief of psychiatry for clinical research at MGH, keeps SAM-e for “situations where I’m striking out with the patient on side effects.” But even when it helps, he says, the benefits don’t always last.

On the other hand, Dr. Richard Brown, associate professor of clinical psychiatry at Columbia University in New York, is an unabashed SAM-e proponent. In his book [see sidebar], Brown calls SAM-e a “breakthrough supplement” and claims that it “begins to relieve depression in seven days.” In a telephone interview, he adds that he’s now treated hundreds of people with SAM-e.

In order for the body to make SAM-e, a person must have adequate levels of folate (which in turn is made from folic acid, a vitamin) and vitamin B-12. (In fact, adding folate to standard antidepressants may increase their benefit.)

Once it’s made, enzymes interact with SAM-e, causing it to give up a part of its chemical structure called a methyl group. In particular, SAM-e donates methyl groups to cell membranes, to big proteins inside cells and to small ones outside cells like the neurotransmitters serotonin, norepinephrine, and dopamine.

For instance, when lipids in cell membranes are well supplied with methyl groups, the membranes remain elastic, says Bottiglieri. This allows receptors in the membrane, including those for some neurotransmitters involved in depression, to move around as they need to, carrying chemical signals.

Still, nobody really understands how SAM-e might work in depression, so if you try it, do so under a doctor’s supervision, assuming you can find a doctor open-minded enough to read what research is available.

Because SAM-e is poorly understood, don’t try it if you have manic-depression, because some antidepressants may make mania worse. It’s also important to take tablets that are enterically coated so they dissolve in the intestines, not the stomach, where they can be absorbed, and that are foil-wrapped so they do not absorb moisture.

Also make sure that your SAM-e product contains 1,4-butanedislfonate, a stabilizer. If not stabilized, SAM-e products can degrade and become useless. In fact, that’s what happened a decade ago when MGH researchers Fava and Rosenbaum did a SAM-e study with 40 patients.

The study was “a bust,” they say, because the tablets they had ordered from Italy sat unrefrigerated over a hot weekend at Logan airport. The pills became discolored, suggesting oxidation, and perhaps because of this, patients who took them did no better than those on a placebo.

There’s also a theoretical possibility that SAM-e might raise levels of homocysteine, an amino acid that can raise the risk of heart disease.

And there’s one final caveat. Several US researchers now at the forefront of SAM-e research have in the past or are now planning to do research supported by Nature Made, which sells a SAM-e product.

This does not necessarily mean the researchers are unethical or their findings won’t be credible. But it’s something to chew on.

The unhealthy side of health concerns

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It’s been years now, but I can still picture the articulate young woman with the mysterious disease who came to the Globe to see me.   She was armed with a stack of medical papers and spoke with the ease of a scientist about possible causes, symptoms, and tests. But what was most striking was how much her identity seemed to be wrapped up in her illness.

I still have no idea what she may have had. She was clearly suffering – and angry. Yet she seemed unable to take comfort in the fact that her doctors could find nothing seriously wrong. In fact, she seemed stuck in what doctors call “the sick role.”      That’s a shame.

Granted, stories abound about people who stick to their guns, resist the bland reassurances of busy doctors and keep fighting until they get the right diagnosis. More power to them!

In fact, that’s what happened to Dr. Martin P. Solomon, a popular Boston internist who works for Affiliated Physicians Group, based at Beth Israel Deaconess Medical Center.

Twenty years ago, Solomon was worried about a mole on his arm. He consulted dermatologists – “the three biggest guys in the city” – and all told him it was nothing. He insisted that it be removed. Sure enough, it was a melanoma, a potentially deadly cancer. “Had I waited, I wouldn’t be here,” he says.

But still, much of the time, contends Solomon in his new, self-published book, “Don’t Worry, Be Healthy – How to Avoid Obsessing About Your Health,” the American fixation on understanding every hiccup has become downright unhealthy.

“Worry displaces joy,” says Solomon, who certainly sees enough patients – 30 to 40 a day – to know. “People push joy out of the way, from fear or from fatigue.”

The bottom line is as simple as it can be hard to swallow: Get yourself checked out if you’re worried about something, and get a second opinion and more tests if you’re really worried. But once you’ve done all that and everything appears fine, get on with your life, including addressing the emotional issues – anxiety, depression or simply stress – that might be causing your troubles, or at least, hampering your ability to cope with them.

The “sick role” is a terrible trap, and oddly enough, people who really have a serious disease may be less likely to fall into it than people who have no documentable illness.

In one study, Dr. Arthur Barsky, a psychiatrist and director of psychosomatic research at Brigham and Women’s Hospital, interviewed people waiting for medical appointments in a clinic, simply asking them to describe themselves.

People who were not deemed by doctors to be hypochondriacs (defined as people who are not faking their symptoms but can’t be reassured when nothing is wrong) tended to talk about themselves as teachers, parents or to describe their hobbies, even if they had cancer. Those who were considered to be hypochondriacs saw themselves as patients.

In a review published in June in the Annals of Internal Medicine, Barsky and Dr. Jonathan F. Borus, chairman of the department of psychiatry at the Brigham, note that it’s normal for healthy people to report physical complaints every few days.

“Significant fatigue” is a problem for more than 20 percent of healthy adults, and musculoskeletal problems, for 30 percent, they note. Indeed, 86 to 95 percent of the general population has at least one symptom such as a headache, dizziness or heart palpitations in any two- to four-week period.

In many cases, Barsky and Borus say, it’s the belief that one is sick that causes distress. In one study they reviewed, people who hadn’t known they had high blood pressure had a threefold increase in days of work lost once they were diagnosed.

In another, telling healthy volunteers they had tested positive for a disease caused them to recall symptoms characteristic of the disease and to think they had acted in ways that could have put them at risk. In yet another, Barsky and Borus note, people who signed informed-consent forms that specified certain gastrointestinal side effects of a treatment were more likely to experience those side effects than those whose forms did not specify those problems.

Sometimes, obsessing about bodily symptoms and conveying this distress to other people is an indirect way of asking for attention. But this can backfire because, to keep getting that attention, you have to stay in the “sick role.”

One way around that is to agree with your doctor that, even though there seems to be nothing wrong at the moment, you’ll come back in a specified number of weeks or months. That accomplishes two things: It allows a window for re-testing, in case you do have a serious disease. And it lets you let go of your need to be “sick” in order to see the doctor again.

Another solution is to tackle the emotional component of hypochondria head-on.

At the Brigham, Barsky is running a study sponsored by the National Institute of Mental Health to see whether six sessions of counselling using cognitive-behavioral techniques helps ease hypochondriacs’ distress. This approach aims at teaching people to spot what things – thoughts, situations, behaviors – make symptoms worse and which make them better.

At Harvard Vanguard Medical Associates, psychiatrist Dr. Steven Locke, chief of behavioral medicine, also runs a 6-week program. It’s geared toward people who have have stress-related symptoms like headaches, or diseases like asthma that are exacerbated by stress; those with chronic diseases like irritable bowel syndrome or cancer who have a hard time coping emotionally with their illnesses; and to those, like the woman who visited me at the Globe, who have persistent symptoms that defy medical explanation.

Dealing more directly with the emotional causes or consequences of illness can not only decrease distress, it can save a health care organization money. In one recent study at Kaiser Northwest in Albany, N.Y., people who participated in a mind-body program cost the system nearly $1,000 less a year than similar patients who were referred to the program but opted out.

But saving money is not the point. Finding contentment is, and that’s important whether you, or someone you love, has a serious disease or not – as Dr. Martin Solomon found out the hard way. For years, he took only two week’s vacation. “I always felt bad when I went away,” he says. “I felt I should be here seeing patients.”

Then, several years ago, his wife was diagnosed with lymphoma. So for their 25th anniversary, they took the trip to Italy they’d planned for their 30th. They bought a bigger house on Cape Cod to accomodate their grown daughters. He now takes six weeks a year off. “We’ve learned to enjoy walks on the beach. We do more things together,” he says.

“I don’t have to tell this to patients with cancer. They know it,” he adds. It’s the worried well who need to hear it.

ILL OR HEALTHY, DON’T ASSUME THE ‘SICK ROLE’

If you and your doctor have appropriately pursued the symptoms that distress you and there still seems to be no cause, take heart. At a minimum, you should know you’re in good company – an estimated 35 to 50 percent of visits to primary care doctors are for problems for which no physical cause can be found.

But that doesn’t mean you’re not suffering, and it doesn’t mean you are powerless, either. Here are some suggestions:

Don’t assume the “sick role.” This means not thinking of yourself as a patient, but instead defining yourself by who you really are – a parent, spouse, worker, friend, gardener, whatever.

If you do have genuine restrictions on what you can do because of pain, disability or fatigue, make realistic concessions to those limits, but focus on what you still can do.

If your doctor does the appropriate tests and does give you reassurance, try not to reject it. If you get angry when the doctor says you’re fine, look deeper into your feelings. Ditto if you find yourself substituting a new worry as soon as you let go of an old one.

Ask yourself what factors other than disease might be contributing to your symptoms. Do you hate your job? Are you fighting with your spouse? Are your kids acting out? Are you fretting about money? If so, the answer may be to focus on the problem that really needs attention, not your aching back.

Thalidomide, once a pariah drug, finds a new life in cancer therapy

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The drug thalidomide, which was banned in the United States after it caused serious birth defects in 10,000 babies worldwide four decades ago, can produce dramatic improvements in people with a cancer of the bone marrow, according to a study being published today.The study is a “significant advance” in treatment for myeloma, Dr. Kenneth Anderson, a myeloma specialist at Boston’s Dana-Farber Cancer Institute, said yesterday.   Myeloma, a cancer that arises in the bone marrow and that crowds out normal tissue so that the marrow can no longer make healthy blood cells, is diagnosed in almost 14,000 Americans a year. It is “notoriously difficult” to treat, Anderson said in an editorial accompanying the report in the New England Journal of Medicine. Typically, only 29 percent of people diagnosed with it survive for five years, despite treatment.

The new study, done at the University of Arkansas for Medical Sciences, involved 84 patients who had relapsed despite aggressive treatment, including marrow transplants and high-dose chemotherapy.

When given thalidomide in doses of up to 800 milligrams a day, 32 percent of patients improved at least somewhat, as gauged by lower levels of a myeloma-related protein in blood or urine tests. Two patients had complete remissions, meaning that their cancer was undetectable.

One year after starting treatment, about 22 percent of patients were alive without relapse; a total of 58 percent were alive, although some had progression of cancer. It is not clear how long the responses had lasted, although in some cases, the responses appeared to be “durable,” Anderson and his co-author, Dr. Noopur Raje, said in the editorial.

The lead researcher, Dr. Seema Singhal, formerly in Arkansas and now codirector of the myeloma and lymphoma program at the South Carolina Cancer Center at the University of South Carolina, said in a telephone interview that “the results are extremely encouraging.”

She added:  “You kind of like to believe in magic, and once in a while it happens.”

Magic might be a description of thalidomide, because, at least in myeloma, scientists are less sure now about how it might work than they were when the study began.

Initially, Singhal and her colleagues decided to try thalidomide because it is an angiogenesis inhibitor, meaning it can block the chemical signals that trigger formation of blood vessels around tumors.

But in this study, many patients who responded to thalidomide did not show a reduction in the density of blood vessels that nourish tumors in the bone marrow. That could merely be a sampling problem: Every time a doctor conducts a biopsy on a small piece of bone marrow to study, there is a chance that the section sampled has more, or fewer, cancer cells and blood vessels than the rest of the marrow.

On the other hand, said Anderson of Dana-Farber, it may also be that thalidomide is acting in other ways. For instance, it may directly attack myeloma cells, or the so-called stromal cells of the marrow on which they grow. It might work by keeping myeloma cells from attaching to stroma cells. It might block chemical signals that help myeloma cells grow. Or it might nudge T-cells to attack myeloma cells.

The fact that thalidomide not only seems to work in advanced myeloma but that it also may have several ways of acting is part of the excitement, Anderson said.

After it was banned by the Food and Drug Administration in the 1960s because it caused birth defects in the babies of pregnant women, who took it for morning sickness, thalidomide was approved last year for a type of leprosy.

But the drug, made by Celgene, was approved with severe restrictions, including the stipulation that every person, male or female, who uses it must be enrolled in a government-monitored registry.

In addition, only doctors who have received training may prescribe it. Because it can cause birth defects, women must undergo pregnancy tests before using the drug, and both men and women must agree to use contraception.

In general, however, once a drug is approved for one use, it may legally be prescribed for others as well. In addition to its promise in myeloma, thalidomide is also being studied as a treatment for AIDS-related ulcers and a virulent type of brain tumor called a glioblastoma.

Here’s to your health: the benefits of drinking outweigh the risks, but only within limits

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On Thursday, the French will go nuts.

We know this because they go nuts every year on the third Thursday of November, the day the latest crop of just-off-the-vine wines hit the market.

Wine-lovers will swarm to those cute little bistros, swell with Gallic pride, swill a glass of this fairly flimsy red stuff, and proclaim, “Le Beaujolais Nouveau est arrive!”

(This proves either that the French really do have a better grip on things than the rest of us, as I suspect, or that they, too, can be suckered into a clever marketing ploy. Or both.)

But it’s not just the French who love wine. In recent years, American wine sales have been booming, too. Nobody knows why, but it may be that Americans have come to believe that wine is actually good for them.

And so it is. In the last quarter century, more than 50 studies from around the world have shown that people who drink moderately have up to a 40 percent lower risk of heart disease than those who don’t drink. Because heart disease is such a huge factor in overall mortality in the US, this translates statistically into a lower death rate in any given year for moderate drinkers.

But the whole truth — in vino, veritas — is a bit more complicated, so before you pop that cork, some caveats.

By government estimates, 14 million Americans have an alcohol disorder, which is defined as abuse and dependence (or uncontrolled drinking), tolerance for high doses, and withdrawal symptoms when drinking stops.

In excessive amounts, alcohol raises the risk of heart disease, hypertension, stroke, some cancers, violence, and suicide. It’s also bad for pregnant women because it can cause defects in the developing fetus. It shouldn’t be mixed with certain medications (check the labels). And it clearly doesn’t mix with driving.

For the record, alcohol consumption can also be tough to study because people sometimes lie about how much they drink. It’s especially tough to sort out the relative merits of wine, beer, and liquor because people typically drink different types of alcohol on different occasions.

Beyond that, researchers don’t always agree on what counts as “moderate drinking,” though it’s usually one drink a day for women and two for men, with a drink being 5 ounces of wine, 1.5 ounces of spirits or 12 ounces of beer.

That said, compared to most medical research, the data on alcohol and health are remarkably clear, consistent, and compelling, though things get murky on the finer points, like whether wine, especially red wine, is better than other alcohol.

The first hints that alcohol might carry health benefits came 25 years ago — as a surprise.

With a colleague, Dr. Arthur Klatsky, now a senior consultant in cardiology at Kaiser Permanente Medical Center in Oakland, Calif., was studying factors that predicted heart attacks.

In a 1974 study, Klatsky says, there was no hypothesis about alcohol, but he asked about drinking anyway and found that abstainers were actually at higher risk of heart attack than those who drank moderately. No one knew why.

Now scientists think they do. Alcohol, whether from wine, beer or spirits, raises HDL, or “good” cholesterol, and lowers levels of a blood-clotting protein called fibrinogen and reduces the activity of platelets, which also help form clots. (A recent Stanford University study showed alcohol may also help reduce the damage done to tissue during a heart attack — at least in rats.)

The study that clinched the link between moderate drinking and overall survival came in 1997. Researchers led by Dr. Michael J. Thun, who heads epidemiological research for the American Cancer Society in Atlanta, studied 490,000 people and found that moderate drinkers had a 20 percent lower risk of death in any given year than abstainers.

This holds true for women as well as men, Thun says, though he’s quick to warn that the risk-benefit ratio is trickier for women. That’s because the risk of dying from (not just getting) breast cancer is 30 percent higher among women who have at least one drink a day.

“For breast cancer, not drinking at all would be optimal,” he says. Yet because heart disease kills six times as many women as breast cancer, the benefits of moderate drinking still outweigh the risks for many women.

Here’s another way of looking at it. A huge, 1998 Harvard study of pooled data on 322,000 women found that the risk of getting breast cancer goes up linearly with the amount (though not the type) of alcohol consumed; one drink a day raises risk about 10 percent. Put another way, a woman who lives to age 85 has a 12.5 percent chance of getting breast cancer; adding a drink a day raises this to 13.6 percent. (On the other hand, just to confuse matters, a smaller study published in January and based on data from the ongoing Framingham Heart Study showed that women who drink one alcoholic beverage a day have no increased risk of breast cancer.)

If there is an increased risk, it’s modest and probably due to the fact that alcohol raises blood levels of estrogen, at least transiently, and estrogen can drive some breast cancers.

But this increased breast cancer risk from drinking is less than that from estrogen supplements, which raise risk about 40 percent in menopausal women who take them for five years or more. Even adding together the increased risk from a drink a day to the increased risk from hormone therapy, that’s still only a 50 percent increase in the risk of breast cancer, fairly modest by statistical standards. This may be a crucial difference for women with a strong family history of breast cancer, but for others, the benefits of alcohol may still outweigh the risks.

And what of the notion that red wine has even more health benefits than lowlier forms of booze? That gets tricky.

The theory is that many phenolic compounds in the seeds of grapes and a particular one called resveratrol from grape skins act as potent anti-oxidants, or disease-fighting chemicals. Grape seeds and skins are used in making red wine (and purple grape juice), but not white wine, notes wine chemist Andrew L. Waterhouse of the University of California, Davis.

In a study published in September, Waterhouse showed that a phenolic compound called a catechin shows up in the blood after people drink red wine. Other research has shown that red wine, but not white, causes changes in the blood that make it harder for LDL, or “bad” cholesterol, to be oxidized and thereby perhaps to help form artery-clogging plaques.

Researchers from the University of Wisconsin also reported recently that in 15 people who drank purple grape juice every day, blood vessels were more elastic and LDL cholesterol was oxidized more slowly.

But does this translate into real differences in disease?

Some researchers think so. In 1995, Danish epidemiologist Morten Gronbaek reported in the Copenhagen City Heart Study of 13,000 men and women that the risk of dying was reduced by 50 percent in people who had three to five glasses of wine a day. He did not find the same benefit for beer or spirits.

But he also found in a 1999 study that people who drank wine were more likely than those who drank beer or spirits to eat a healthful diet, with lots of fruits, veggies, fish, and olive oil.

Klatsky, the Kaiser Permanente cardiologist, has also looked for any special effect of wine and has concluded that if there is a benefit to wine over other forms of alcohol, it’s probably not the wine but the health habits of the people who drink it.

Eric Rimm, a nutritional epidemiologist at the Harvard School of Public Health, puts it this way. About one third of the 50 worldwide studies on alcohol and health look at wine, beer, and spirits separately. Taken together, he says, there’s no compelling evidence that red wine has more health benefits than other types of alcohol.

To which the only decent answer is a raised glass, a Gallic shrug, and a hearty, “C’est la vie!”

SIDEBAR: LABELS CAN’T TELL THE STORY

In February, the government took a long-awaited step toward legitimizing wine consumption when, at the urging of wine manufacturers, the Bureau of Alcohol, Tobacco and Firearms approved a voluntary label for wine bottles that refers consumers who want “to learn the health effects of wine consumption” to the agriculture department’s Web site.

But last month, the agency bowed to political pressure from Sen. Strom Thurmond (R-S.C.), and announced it was re-opening the issue for public comment. Last week, John De Luca, president and CEO of the California-based Wine Institute, an industry-supported group, said, “Far from fearing this, we welcome it. It’s a terrific new forum to share the scientific findings on the subject.”

The new label approved in February did not replace the required label carrying the US Surgeon General’s warning that pregnant women should not drink alcohol because of the risk of birth defects and that drinking alcohol impairs the ability to drive a car or operate machinery and may cause health problems.

It didn’t make outright health claims, either, but did refer readers to the US Department of Agriculture’s statement, which says that in moderation, alcohol is associated with a lower risk of coronary heart disease. The USDA defines moderate drinking as no more than one drink a day for women and no more than two for men.

To read the full USDA statement on the Web, go to http://www.usda.gov/fcs/cnpp.htm

For more information on the health effects of wine and other forms of alcohol, check out the Web site of The Wine Institute at http://www.wineinstitute.org. It’s an industry site, but has done a decent job of pulling together some scientific studies.

Cutting-edge drugs a must in treating rare cancer

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With any serious disease, it’s obviously a good idea to find the best doctor – and the best hospital – you can.

But with ovarian cancer, a rare disease that strikes 25,000 women a year, kills nearly 15,000, and is almost impossible to detect early – it’s absolutely essential.

That’s because there are often no symptoms in the early stages. In three-quarters of cases, by the time ovarian cancer is diagnosed, it’s already spread. Currently, only half of women diagnosed with it are alive five years later.

All of this means it’s crucial to get state-of-the-art chemotherapy and specialized surgery, not from a general surgeon or gynecologist, but from a gynecological cancer surgeon who knows how to probe every inch of the abdominal cavity for tiny tumors.

In ovarian cancer, the primary tumor usually, though not always, begins in the ovary itself. It then spreads quickly throughout the abdomen, scattering mini-tumors all over – on the colon, the spleen, the gallbladder, the diaphragm. Even the walls of the peritoneum – the Saran-wrap like tissue that covers all the internal organs – are studded with sprouting tumors.

“When we see inside the abdomen, it’s like DOTS candies,” says Dr. Linda Duska, a gynecologic cancer surgeon at Massachusetts General Hospital. “It’s not just a mass in the ovary, it’s diffuse miliary cancer – little, teeny things everywhere.” Research shows that the more thorough this initial surgery – which involves a long, vertical incision and can take several hours – the better a woman’s chances of survival.

Historically, those odds have been grim. If the cancer is caught early, while the tumor is confined to the ovary, the 5-year survival rate is more than 90 percent. But few cases are caught early because there’s still no good screening test. Researchers are working on new tests, including a blood test called LPA.

There is already a blood test for a protein called CA125 that can detect some tumors, but it’s notoriously unreliable. It misses some cases and suggests cancer is present when it’s not. Ultrasound can spot some cancers, but it, too, raises many false alarms. Even when these two tests are combined with a standard pelvic exam, ovarian cancer is so hard to differentiate from benign cysts on the ovary that 30 women with suspicious findings may be sent to the operating room for every cancer found.

Barbara O’Brien, 54, an Arlington woman, is one of the lucky ones. She was diagnosed three years ago when her cancer was in the earliest stage. But she says she’s “one of the few in my support group” whose cancers were caught this early.

If cancer isn’t caught until after it has spread to the fallopian tubes, the 5-year survival rate drops from 90 percent to 80 percent. If it has spread to the lymph nodes and abdomen, it drops to 30 percent. Even when symptoms – abdominal swelling, bloating, vague abdominal and pelvic pain, gas – are present, they are so non-specific, a doctor may not suspect ovarian cancer.

Better chemotherapy drugs, however, and equally important, a much better understanding of how best to combine and administer them, are beginning to make a dent in those numbers.

There’s no data yet showing that bone marrow transplantion is more effective than standard chemotherapy. But there are several studies showing that giving chemotherapy intraperitoneally – through a tube into the abdomen, instead of through intravenous injections into the bloodstream – may yield some improvement in survival.

The advantage is that the drugs get directly to the tumor, cause less nerve and marrow damage, and trigger fewer side effects. The downside is this treatment can cause severe abdominal pain and may not work against tiny tumors that travel through the circulation to other areas of the body.

Another emerging strategy is to try new drugs early, instead of waiting until a relapse, as is traditionally done. “The hope is that by utilizing more of the new, active agents in ovarian cancer right at the beginning, it may result in more effective killing of tumors and potentially prolong survival,” says Dr. Ross Berkowitz, co-director of the Gillette Center for Women’s Cancers at Dana-Farber Cancer Institute.

Doctors are also finding new ways to combine drugs so that they attack the tumor through different biochemical pathways and don’t exacerbate each other’s side effects. “The concept of chemotherapy that works in different ways is critically important,” says Dr. Stephen A. Cannistra, program director of gynecological medical oncology at Beth Israel Deaconess Medical Center in Boston.

For instance, platinum-based drugs – either cisplatin or carboplatin – have long been the mainstay of treatment. The drugs insert themselves into DNA and interfere with its replication. Seven out of 10 tumors can be shrunk this way, but the drugs kill only tumor cells that are sensitive to them, and many aren’t.

Adding Taxol to platinum drugs yields significantly better survival, notes Dr. Edward Trimble, a specialist at the National Cancer Institute. In part, that’s because Taxol works differently, by binding to a cellular structure called tubulin. When it binds, the chromosomes can’t pull apart and the cell can’t divide.

Another relatively new drug called Hycamtin (topotecan) works in yet another way, by blocking an enzyme called topoisomerase-1, without which DNA can’t unwind and the cell can’t divide.

Already approved for women whose ovarian cancer has recurred, Hycamtim is now being studied as a first-line treatment. A drug called Doxil works similarly, by inhibiting an enzyme called topoisomerase-2.

Still another emerging strategy is to borrow chemotherapy drugs from other types of cancer. A pancreatic cancer drug called Gemcitabine, for instance, shows enough promise against ovarian tumors that doctors are now designing studies to test it in newly-diagnosed women. Doctors are also trying a lung cancer drug called Navelbine for women with recurrent tumors.

An even more high-tech solution was reported recently by Tayyaba Hasan, a biochemist at the Massachusetts General Hospital Laser Center, and others, in the Journal of the National Cancer Institute. Hasan’s team studied ovarian cancer that was resistant to cisplatin.

The researchers hooked together a drug called a monocloncal antibody (designed to find its way to markers on ovarian cancer cells) with a light-sensitive molecule called a chlorin.

A laser light activates the chlorin, which then destroys the cancer cells – but not normal cells – in the immediate area. “The exciting finding,” says Hasan, is that this approach was 13 times more effective than standard chemotherapy alone. Other researchers, including a team at the University of Pennsylvania, are pursuing a similar approach.

And even that’s just the beginning. In a collaborative effort, researchers at the Dana-Farber, MGH, and Brigham and Women’s Hospital are freezing bits of ovarian cancer tissue in hopes of making individually-tailored vaccines. The idea is to kill the cells, insert genes that make an immune-boosting protein called GM-CSF, then re-inject the cells back into the patient.

Other researchers are trying gene therapy to beef up production of cancer-fighting proteins produced by a gene called p53. Still others are working on SERMS, or selective estrogen receptor modulators, to block hormonally-driven cancers. And others, including researchers at New England Medical Center, are conducting trials of a monoclonal antibody called OvaRex to help the immune system attack ovarian cancer cells.

There is no question that ovarian cancer is still a horribly stubborn disease. But the research is beginning to pay off.

Carolyn Mostecki, 54, a professional gardener in Gloucester, appears to be in remission after six years of treatment. She took an experimental drug called Taxotere, a cousin of Taxol, but thinks Tibetan herbs have helped, too.

Alice Rouff, 60, a restaurant hostess from Ashland who was diagnosed 10 years ago, is also optimistic. “I’m totally fine now,” she says, though she’s scared to use the word “cure.”

“And every day, I make a good day.”

SIDEBAR:FIGURING A WOMAN’S RISK FOR CANCER OF THE OVARIESThere are no definitive ways to prevent ovarian cancer, but some factors may reduce or increase risk.

Last week, for instance, Italian researchers reported in the Journal of the National Cancer Institute that taking a drug related to vitamin A (fenretinide) may protect against ovarian cancer, in part by triggering apoptosis, or cell death.

In general, scientists believe that the more ovulatory cycles a woman has in her life, the greater the risk, and the fewer cycles she has – whether they are interrupted by pregnancy, birth control pills or breastfeeding – the lower the risk.

Every time a woman ovulates, there is microscopic damage to the surface of the ovary where the egg pops out. Usually, this damage is quickly healed, but cells must work overtime to repair it. During this repair, researchers theorize, there is an increased risk of genetic mutations, which may lead to cancer.

Studies show that a full-term pregnancy, during which there is no ovulation, reduces the ovarian cancer risk by 50 percent; subsequent pregancies offer additional protection. Breast feeding, which can also inhibit ovulation, reduces ovarian cancer risk, too, but this data is less convincing.

There is good evidence, though, that oral contraceptives, which keep the pituitary gland from triggering ovulation, decrease ovarian cancer risk by about 50 percent if they’re taken for a total of five years, not necessarily continuously.

And what of the interplay between infertility and ovarian cancer? That’s dicey. If infertility means there’s no full-term pregnancy, that increases risk just as it would in a fertile woman who never had a baby. On the other hand, if infertility is caused by lack of ovulation, as it can be, that could reduce risk, though this hasn’t been proved.

Fertility drugs such as Clomid and Pergonal have been suspected in some cases of ovarian cancer. Some evidence suggests that ovulation-inducing drugs may increase risk, particularly if the drugs don’t work and a woman never gets the risk-reducing benefits of pregnancy. On the other hand, a recent California study found no such association.

Curiously, tubal ligation, in which a woman’s fallopian tubes are tied to prevent eggs from getting from the ovaries to the uterus, may reduce the risk of ovarian cancer by 30 percent, for unclear reasons. One theory is that ligation blocks potentially carcingenic substances from travelling from the vagina, cervix or uterus up to the ovaries.

In support of this, scientists point to several studies suggesting that talcum powder, which some women put on diaphragms or on genital skin, can raise ovarian cancer risk.

Some women, including some Ashkenazi Jews, also have mutations in BRCA1 and BRCA2 genes that increase risk of both breast and ovarian cancer. In general, women have about a 1.4 percent chance of getting ovarian cancer over a lifetime; in women with one close family member who has had the disease, the risk rises to 5 percent. If more close family members are affected, it rises more.< Doctors suggest that women who test positive for the mutations or have a strong family history of the disease consider having their ovaries removed surgically in hopes of preventing ovarian cancer. Even after such surgery, however, it may be possible to develop a related cancer in the peritoneum, the tissue that lines the abdomen.

Site has all the research that fits

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In the elite world of medical research, Dr. Harold Varmus is at the top of the heap. He runs the government’s biggest health research engine, the National Institutes of Health, and won the 1989 Nobel Prize for his groundbreaking work on cancer genes.

Yet Varmus, 59, has proposed such a radical, power-to-the-people idea involving Internet publishing that the rest of the medical establishment is at his throat – partly out of self-interest, but partly out of genuine concern that Varmus’ plan would add dramatically to the chaos of medical information and misinformation already on the Net.

Aided and abetted by computer whizzes at the National Library of Medicine, Varmus wants to do the unthinkable: Put the full text, not just abstracts, of research papers on the Net in an expedited way, and – here’s the grabber – in some cases without the peer review that journals like the New England Journal of Medicine and the Journal of the American Medical Association have long used as a way to weed out solid studies from schlock.

This is cage-rattling stuff – not just because it might mean scooping journals on medical news, but because some scientists might choose to bypass the traditional journals altogether in favor of speedier publishing – with less rigorous review – on the Net, all under the NIH imprimatur.

Speaking by phone from New York City last week, Varmus, who will leave NIH at the end of the year to head Memorial Sloan-Kettering Cancer Center, said he is and always has been a believer in peer review. This is the process by which, before accepting an article for publication, medical editors send it to outside experts who pore over the data looking for errors in methodology, science or interpretation.

And initially, all of the research that Varmus envisions for the new site, to be called PubMed Central, just posted last Thursday and scheduled to be operational in January, will indeed be forwarded from journals that have vetted the work.

This research – in biology, medicine, agriculture, and plant sciences – could be posted after publication in a major journal, which nobody objects to. Or before it appears in print, which critics say could make mainstream medical journals obsolete.

“This would be a surefire method of killing ourselves,” says Dr. Marcia Angell, interim editor-in-chief at the New England Journal of Medicine. If the Journal took the time and care to review articles, then handed them right to PubMed Central, by the time the Journal published the work “it would be just an archive. . .we would be committing suicide.” As it is now, the Journal posts its new research on its own Web site the night before the print publication becomes available.

And then there’s the even more controversial, back-door route to getting research in the public domain fast that Varmus has developed with David Lipman, director of the national center for biotechnology information at the National Library of Medicine.

The idea, still a work-in-progress, is to have a “screening” process in which papers that might never be submitted to a mainstream journal would be posted on the Net if they were forwarded by a “certifying group.” This non-peer-reviewed material would be clearly labelled as such.

A still-to-be-created committee would figure out who would qualify as a certifying group, but initially, this would be any organization with at least three members who are principal investigators on research grants from agencies such as the NIH, the National Science Foundation, the Department of Energy, etc.

The point is to “develop a way to disseminate research results in a way that allows anyone access any time, any place,” says Varmus, who dislikes the “gatekeeper” role that major journals now play.

The goal, he says, is fast, “barrier-free” access to medical research. No passwords, no need to “register” on a Web site to read a research study, no fees to Web surfers. In fact, in PubMed Central, the costs of publishing could be picked up by the authors of papers – whose funding often comes from taxpayers anyway – instead of those who want to read the work online.

Some people love this idea. Among them is Barbara Lackritz, a St. Louis, Mo. cancer patient and patient advocate who says that to keep up with the latest research, she needs more than the abstracts most Web sites offer. “The more information we can get out there for people to read and understand, the better off we are all going to be,” she says.

Dr. Helga E. Rippen, a physician-engineer who runs a health information think tank at Mitretek Systems in McLean, Va., agrees. “I’m into as much information as somebody wants,” she says, though she adds there’s also a need to teach consumers how to evaluate and interpret complex, raw medical data.

But Dr. Sidney Wolfe , director of Public Citizen’s Health Research Group, a health research-based advocacy organization in Washington, D.C., is leery about rushing unreviewed research into the public domain. “Needless to say, the sooner people get information, especially information with public health impact, the better. But it’s only better if it’s accurate.”

Biased, incomplete or incorrect medical information can do serious damage, he notes. Though physicists have posted preliminary research results on the Net, there’s considerably more risk when medical researchers do so, he adds.

And Angell, of the New England Journal, is appalled. “I believe in the marketplace of ideas,” she says. “But you can’t just throw up everything – advertising, old wives’ tales, research studies – on the Net and hope people can figure out what’s valid and what isn’t.”

For his part, though, Dr. George Lundberg, former editor of the Journal of the American Medical Association, is gloating.

Now editor of Medscape, an online health information service with access to 25,000 research articles, and its spinoff, Medscape General Medicine, an electronic medical journal, Lundberg says it is possible to put peer-reviewed medical information on the Net without the long delays in standard medical publishing. (At the New England Journal, for instance, it takes seven months from the time a paper is submitted to the time it is published.)

In fact, in a way, he’s beaten Varmus to the punch. Medscape, he says, does peer review its articles, but fast – in three to five days, not the 28 that print journals take.

So far, only a handful of existing journals have agreed to supply material to PubMed Central, including the National Academy of Sciences, the Journal of the American Society of Cell Biology, the Canadian Medical Association Journal, and a British entrepreneur who publishes biomedical journals.

But that should change as scientists realize the potential for getting work out quickly, says Jo McEntyre, a fellow at the National Library of Medicine. “Scientists love it,” she says, “because they are the ones who do the research.”

Because of the sheer volume of medical research, many scientists can’t get their work published in high-profile journals, she says. This may be especially true for “negative” studies that find that a cherished hypothesis doesn’t hold up.

Angell, the New England Journal editor, disputes this, noting that when a truly important hypothesis yields negative findings, those results are likely to be published.

The real problem, Angell contends, is that everybody assumes that “we live in a sea of good research,” much of which never sees the light of day. In reality, she says, there’s not a lot of good clinical research out there.

The New England Journal, accepts only 10 percent of the articles submitted. “And we’re not weeping as we reject what we reject,” she says. “We sometimes weep [ about] what we have to accept.”

But Varmus is undeterred. “It will take time,” he says of the new venture. But “in the first year, we’ll show what we can do.”

To read about the government’s new health Web site, go to (http://www.PubMedCentral.nih.gov) or to www.nih.gov/welcome/director/pubmedcentral/pubmedcentral.htm. To read a critique of the proposed site, read a June 10, 1999 editorial in the New England Journal of Medicine at www.nejm.org.

Evaluating health data on the Net

When the government’s new health research Web site, to be called PubMedCentral, goes online in January, it will join thousands of medical sites already available to Web surfers.

Roughly 45 million American households now have online access and half of all US adults use the Net to search for health information, says Dr. Helga E. Rippen, a physician-engineer who tracks such things for Mitretek Systems, a think tank in McLean, Va. Health-related Web sites are constantly being created and abandoned. An estimated 10,000 to 25,000 are up now.

But the quality of information on these sites varies widely, from peer-reviewed articles posted by medical journals such as The New England Journal of Medicine to thinly-disguised advertisements for pharmaceuticals to utterly unsubstantiated claims by quacks or shysters.

A growing numbeer of health information specialists, including the Internet Healthcare Coalition (www.ihc.net), are concerned about the glut of misinformation on the Net. Here are some tips that may help:

  • Look to see who wrote the information, checking the “about us” section of the site. If there’s no author listed, or no credentials for the author, be suspicious.
  • Check attribution of the information. Research that has been published in a mainstream journal has been reviewed by experts; so has most information from big government agencies such as the National Institutes of Health or the Food and Drug Administration. Information from drug companies may be reliable, but remember, these companies are selling products.
  • Try to determine whether the authors have a potential financial or ethical conflict of interest. Ideally, authors are upfront about this, but many aren’t. A more subtle bias can occur with information put out by patients’ groups, which may be so wedded to one point of view that they exclude others.
  • Beware of anecdotal information. Emotional testimonials can be convincing – but also misleading or irrelevant to you.
  • When you read a study, check the methodology. Was there a control group? How many people were in the study? How long were they followed? Was the study “double-blind”? (This means neither doctors nor patients knew until the study was over who was taking the real drug and who, the placebo.)
  • Just as you’d get a second opinion from a doctor, don’t rely on one Web site. Read many sites and cross-check what you find.
  • If a treatment seems too good to be true, it probably is.

Chocolate’s not so dark secret

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I slip it reverentially into my mouth. Luscious, gooey, it melts on my taste buds, caresses my tongue. I stop talking, thinking, even breathing. I have but one sense: Taste. I have but one love: Chocolate.

Nanoseconds later, the guilt sets in. I imagine my arteries seizing, my weight soaring. Yet I am powerless: I want more.

What the hell, the voices whisper. Have another piece. After all, chocolate is a “health food.”

Could it be?

A slew of studies – eagerly embraced, not surprisingly, by the American Cocoa Research Institute, the research arm of the Chocolate Manufacturers Association – suggest that chocolate may not only be less sinful than people used to think but may even have some health benefits, taken in moderation, of course.

It’s loaded with disease-fighting antioxidants. It doesn’t cause acne. It’s not addictive. It’s less likely to cause cavities than stickier stuff – including starchy food – that clings to teeth for hours.

It may have no adverse effect on cholesterol. And it’s fairly low in caffeine – you’d have to eat a pound of chocolate to get the amount in a cup of coffee.

The trouble is, even if you believe all that – and I do (though I’m no role model: my four food groups are pasta, wine, chocolate, and Advil) – it’s packed with calories. That’s because, in the form in which we eat it – cookies, fudge, and cakes, though not most candy bars – chocolate is loaded with butter and sugar as well. And while all this may not stick to the teeth, it does stick to the hips.

Chocolate comes from the cacao tree, or theobroma cacao, which grows in tropical regions 20 degrees north and south of the equator. Cacao pods are harvested, then split open to reveal the pulp and beans. After fermentation, the beans are roasted and the shells and seed germ removed to leave the essence, or nib. Nibs are then ground into the goo called chocolate liquor (which is not alcoholic).

Cocoa butter is the fat that’s removed from the liquor. It’s saturated fat, but is composed mostly of the relatively safe stearic acid, not the nasty stuff, palmitic acid. What remains after the cocoa butter is removed is cocoa powder.

To a food chemist, chocolate is complicated stuff. It contains hundreds, maybe thousands, of “phyto,” or plant chemicals, including polyphenols (rings of carbon, hydrogen, and oxygen atoms), which act as antioxidants because they sop up destructive molecules called free radicals.

Among the polyphenols, the most important to chocolate chemists are the flavonoids, which contribute the chocolately flavor.

The fact that scientists are even studying chocolate is interesting, says Larry Lindner , executive editor of the Tufts University Health & Nutrition Letter. “This is a food that’s loved in Western culture, so it’s logical that we’d work backwards to attach good benefits to it. . .In Japan, they’re not studying it. We study it in countries where we like to eat it.”

And the study results are tantalizing. “The chemicals found in chocolate, when isolated, do have pharmacological properties,” notes Mindy Kurzer, a nutritionist at the University of Minnesota who has reviewed most of the published studies.

“However, there are no data to my knowledge to show that, at the low levels these compounds are found in chocolate, that they exert any of the hypothesized effects.”

So what do we really know? Here are the tastiest tidbits:

  • People do crave it – in fact, chocolate is the most-craved food in America. But it is not truly addictive, even though it does contain pharmacologic, or drug-like, chemicals such as phenylethylamine, tyramine, caffeine, theobromine and the mineral magnesium.

In a study by University of Pennsylvania psychologists, chocolate cravers were given a chocolate bar, a serving of “white chocolate”( which did not contain the drug-like compounds), cocoa capsules (which did), placebo, nothing, or white chocolate plus cocoa. If cravings were physically based, the researchers reasoned, they should be assuaged as readily by cocoa, alone or with white chocolate, as by the real thing.

But only the real chocolate bars reduced cravings, suggesting, says Kurzer, that people crave it “because it tastes great, not because it has any biological effect.”

It’s also suspicious, she says, that while women often say they crave chocolate around their periods, perhaps because of its magnesium, they never crave leafy green veggies, which are also rich in magnesium. The data are mixed on whether chocolate produces consistent improvements in mood.

  • Unlike other saturated fats, the stearic acid in cocoa butter seems relatively benign. In fact, it may not affect LDL or “bad” cholesterol at all and may possibly raise HDL, or “good” cholesterol, according to a 1994 study in which Pennsylvania State University scientists followed 15 young men who ate a 1.6 ounce bar of milk chocolate a day.

On balance, chocolate “doesn’t raise cholesterol as much as butter or palm oil. . .You won’t have a heart attack as soon as if you eat butter, but you might have one sooner than if olive oil is your only fat,” says Dr. Scott Grundy, director of the center for human nutrition at the University of Texas/Southwestern Medical Center in Dallas.

  • And the antioxidants in chocolate may be actively beneficial. At the University of California at Davis, researchers have shown that, in the test tube at least, the antioxidants in cocoa powder are powerful blockers of the oxidation of LDL. (When the LDL on blood vessel walls is oxidized, scientists think, the result is atherosclerosis, which can lead to strokes and heart attacks.)

In the Netherlands, researchers reported recently that dark chocolate may be richest of all in antioxidants, though it’s too soon to conclude that it’s is better for you than milk chocolate, says Harold Schmitz a food chemist who heads the analytical and applied science labs at Mars, Inc., makers of M&Ms and Mars bars.

So far, Schmitz cautions, no one has proved that the antioxidants in chocolate get into the body in high enough doses to help. But there are hints.

 Last year, Harvard School of Public Health researchers led by epidemiologist Dr. I-Min Lee studied food questionnaires answered by nearly 8,000 male Harvard graduates and found that those who ate a “moderate” amount of candy – one to three candy bars a month – lived a year longer than those who didn’t.

The study isn’t perfect, as Lee acknowledges. The researchers didn’t separate out sugar candy, which presumably has no redeeming nutritional value, and chocolate. (They’re doing that now.) But she speculates that if the effect is real, it’s probably due to the antioxidants in chocolate.

So, the jury is still out, as it usually is in science. But I’d bet my editor’s salary that as the mythical jurors pore over the studies, they’re munching on M&Ms. I certainly am.

Product
A
B
C
D
Dark chocolate bar (1.4 oz.)
200
100
7
0
Milk chocolate bar (1.4 oz.)
210
120
7
11
Milk chocolate covered raisins (35 pieces)
160
50
3.5
2
Semi-sweet chocolate chips (30 pieces)
70
35
2.5
0

Columns Headings:

A = Total CaloriesB = Calories from fatC = Saturated Fat (grams)D = Cholesterol (mg)

SOURCE: Chocolate Manufacturers Associationhttp://www.chocolateusa.org/Science-and-Nutrition/nutrient-profiles.asp

Treatments improve, but hepatitis C still a threat

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For decades, hepatitis C, a potentially fatal liver virus harbored by 3 million Americans, was a virtual black box.

Scientists knew there was some kind of nasty virus afoot in the land – and in the nation’s blood supply. In fact, they knew that one in five people who got a blood transfusion came down with infections caused by it. But they couldn’t find the virus itself. In fact, they didn’t even have a name for the disease it caused, dubbing it simply non-A, non-B hepatitis.

By 1988, they had found the virus and given it a name. By 1990, they had a detection test with which to screen blood donors. A year later, they had a treatment. By 1998, the number of new infections was cut by 80 percent and the risk of catching hepatitis C from donated blood was down to 1 in 100,000.

Today, treatments have progressed to the point where some people have not just experienced temporary remissions but may be cured.

Yet hepatitis C is still a huge threat. It has become the leading reason for liver transplantation. Granted, there’s now a two-drug regimen to treat it, but it makes many people feel worse than having the disease. The regimen, called Rebetron, has also generated fury among patients because of the controversial way the manufacturer, Schering-Plough, markets it.

Worse, many of the 3 million Americans who are infected with hepatitis C don’t even know it yet, because infection can smolder for years without causing symptoms. Eventually, more than 80 percent of people who come down with the virus end up with chronic infections. Of these, 20 percent go on to get cirrhosis, the destruction and scarring of liver tissue; of those, 20 percent develop liver cancer after 10 years and another 20 percent, end-stage liver disease.

Because so many people are infected and because of the long course of the disease itself, the death toll, now 10,000 a year, is likely to triple in coming years.

The first step toward combatting that, health officials say, is testing, especially for anyone who had a blood transfusion or organ transplant before 1992, when a new detection test made the blood supply safe. People who’ve used intravenous drugs are also at risk. Like the AIDS virus, hepatitis C is spread through blood contact, and, to a lesser extent than AIDS, through sex.

But luckily, testing just got easier. In the last few weeks, a $70 home test kit made by the Home Access Health Corp. began reaching stores. You prick your finger at home, put a few drops of blood on a piece of filter paper and mail it to the lab. You get the results, confidentially, in 10 days. You can also be tested at a doctor’s office or hospital, though the test is not part of a routine physical and may not be covered by insurance.

If the test comes back positive, you need more blood tests – for levels of enzymes that show whether you have liver damage. If you need it, your doctor will recommend a liver biopsy to see how much inflammation and cirrhosis (scarring) you have.

If the scarring is mild, some people postpone treatment on the grounds that the disease progresses slowly, and treatment with Rebetron, the “bundled” or pre-packaged combination of two drugs – interferon and ribavirin – can be long and miserable. Interferon causes intense flu-like symptoms such as fever, chills and joint aches; ribavirin can cause severe anemia.

Indeed, after discussion of the pros and cons, says Dr. Fredric Gordon, medical director of liver transplantation at Lahey Clinic Medical Center in Burlington, 25 percent of his patients decide not to be treated. For some, it’s “just too early” in the disease. Others “want to wait for better drugs.”

Many patients, however, do grit their teeth and go for it; among them, a 47-year old Malden man, who asked that his name not be used. He felt fine before treatment, he says, but now feels like he’s got the flu whenever he gives himself an injection of interferon. So far, he’s been taking Rebetron for four months now and has eight to go. But his liver tests already show improvement, and he’s determined to stick it out.

That makes sense, because while interferon alone yields a sustained response 10 percent of the time, interferon plus ribavirin can quadruple that. (A sustained response is defined as undetectable levels of virus six months after the end of treatment.)

“I tell patients that if by six months after treatment they’re free of the virus, there’s a 90 percent chance they’re cured,” says Dr. Sanjiv Chopra, director of clinical hepatology at Beth Israel Deaconess Medical Center.

But Rebetron, or more precisely, its manufacturer, Schering-Plough, nonetheless draws ire from many patients.

In June, 1998, the US Food and Drug Administration approved Rebetron as a bundled product. That means it’s sold – for $1,440 a month – as a package containing Schering’s interferon, called Intron A, plus ribavirin, an antiviral drug discovered by ICN Pharmaceuticals and now made by Schering.

The catch is that ribavirin is only FDA-approved as part of the Rebetron package. “Ribavirin by itself doesn’t work. The only thing that works is the combination. What’s not known is whether combinations [ of ribavirin] with other interferons work as well as with Schering’s,” says Dr. Bruce Bacon, a liver specialist at Saint Louis University in Missouri.

That irks patients who want to combine ribavirin with interferon made by other companies, notably Amgen and Roche Laboratories, in the hope, so far unproved, that the other interferons might be less toxic or more effective.

“It’s outrageous,” says Brian Klein, a founding member of HAAC, the Hepatitis C Action and Advocacy Coalition, based in San Francisco and New York. Not only does bundling prevent other researchers from testing their interferons with ribavirin, “the bundling hides the outrageously inflated cost of the little pills because you can’t buy them separately.”

Some patients resort, perfectly legally, to asking “compounding” pharmacies, notably Fisher’s Specialized Pharmacy Services in Pittsburgh, to convert bulk ribavirin powder into capsules for them, which they then take with other companies’ versions of interferon. Betty Stein, a pharmacist-owner at Fisher’s, says the pharmacy fills orders every day for hepatitis C patients and charges only $225 for a month’s supply.

Other patients, including a 25-year old Roxbury woman, have gotten ribavirin through patient-organized buyer’s clubs. “It’s a good thing I did, because Shering-Plough monopolized the drug,” says the woman, who used ribavirin with “consensus” interferon, a rival product to Schering’s that combines several components of interferon and which, she hopes, may have a “better track record.”

But Schering is “not going to unbundle” Rebetron, says company spokesman Bob Consalvo. Cost is not an issue because insurers usually pay, he says. And if patients are poor and have no insurance, the company provides the drugs free, he adds.

Recently, some patients have been adding other drugs to the regimen, notably a flu medicine called amantadine. According to research presented at a recent conference, Italian scientists found that by six months after treatment, 43 percent of patients on this triple-drug therapy had a sustained response versus 5 percent with two drugs.

Dr. Thomas Najarian, a Belmont internist, says he’s encouraged by such findings. So is one of his patients, William Bochicchio, 43, a contractor from W. Ossipee, N.H., who used the triple therapy for nine months. It was “pretty rough,” but he’s been virus-free for two years and says, “I’m cured.”

And there could be even better treatments in the near future, including “pegylated” interferon – interferon hooked to a chemical called polyethylene glycol. This compound would be injected just once a week. Now in clinical trials, pegylated interferon alone may be as effective as Rebetron, says Dr. Ray Chung, medical director of liver transplantation at Massachusetts General Hospital in Boston.

Also in the pipeline are protease and helicase inhibitors, which could combat replication of the virus directly. Anti-fibrotic drugs to reduce scar tissue in the liver may also help.

Some patients also take an herbal remedy called milk thistle, sold as a dietary supplement. This may improve scores on liver tests, but there’s no evidence it eradicates the virus.

The bottom line is that if you think you’re at risk, get tested. And if you test positive, at least take common-sense steps, like not exacerbating liver damage by drinking alcohol. And of course, talk with a doctor about what treatment, if any, to have.

“This is a pretty stubborn, insidious disease,” says Bochicchio, the New Hampshire contractor. “The virus eats away at your liver, slowly but surely.”

Living with hepatitis C

He’s only 31, still on the verge of a blossoming career as a DNA researcher at Harvard Medical School. But this biochemist, who for professional reasons asked that his name not be used, has been plagued his entire life with hepatitis C.

He was “an Rh baby,” he says, meaning that because of a blood abnormality, he was vulnerable as a fetus to a potentially fatal anemia caused by antibodies in his mother’s blood. Indeed, his mother had lost a previous baby this way.

So he was given transfusions while he was still in the womb – in the 1960s, before tests became available to monitor the blood supply. He often felt, growing up, that he was “getting older faster than I should have been,” but he still played softball, went skiing, hiking and studied. “I had no idea I was sick,” he says.

By the time he was diagnosed with hepatitis C – at 27 – his liver was severely scarred. By 28, he had liver failure. At 29, he had a liver transplant. (Hepatitis C is so prevalent, in fact, it is now the leading cause for liver transplantation.)

To prevent the virus, which still lingered in his body, from attacking the new liver, he underwent therapy with interferon and ribavirin for a year. That treatment, which causes intense flu-like symptoms, was “worse than the disease.. . .You get really depressed and hopeless,” he says.

But “it is something you can get through and I think treatment is worth it, even though it’s horrible,” he says. He urges anyone who may be at risk to get tested and treated.

After all, he’s now virus-free for the first time in his life. And that, he says, is “pretty cool.“