Diagnosis - Fainting Spells - NYTimes.com

The middle-aged woman perched on the edge of a plastic chair as the doctor explained his thoughts on why her son was having persistent headaches. Suddenly, she toppled forward, collapsing onto the linoleum floor. Dr. Philip Ledereich hurried over to the woman. "Call 911," he shouted to his nurse. "The patient's mother has fainted."

Ledereich, an ear, nose and throat specialist in Clifton, N.J., first met the mother a couple of weeks before, when she herself came in as a patient. She was fainting several times a day, and no one knew why. Ledereich hadn't been able to figure it out, either. Despite that, she took her son to see him for the treatment of a chronic sinus infection. Ledereich was describing various treatment alternatives when the woman pitched to the floor.

She had been having these spells almost daily for the past several months, she told him at their first appointment. She was 49, a nurse, and she considered herself pretty healthy until one Saturday nearly three months earlier. That day she had just put on her shoes to go to a bar mitzvah, and as she straightened up she felt a fluttering sensation in her stomach. The next minute she was on the floor. Her husband rushed to her side. She could hear him calling her name, but she couldn't answer him; she couldn't even open her eyes.

And then, just as quickly as it started, it was over. She felt just fine. She didn't want to go to the hospital, she told her husband. She wanted to go to the synagogue. And so they did, walking a mile. At the coffee hour following the service she started to feel that fluttery sensation in her stomach. Was she going to faint again? She was almost at the door when she collapsed. Eventually, her husband persuaded her to go to the hospital.

She spent two nights in the cardiac-care unit as doctors looked for any of the irregular heart rhythms that could start as a fainting spell but might end in death. They found nothing. She had a head CT scan and lots of blood tests. Everything was normal, so she went home.

Syncope — the medical term for fainting — is common. Up to half of the population will faint at least once in their lifetimes. Most of the time the cause is benign and transient. The trick for doctors is to identify those cases that are neither. When a heart beats too rapidly, too slowly or too erratically to deliver enough blood to the brain, you faint. If a normal rhythm isn't restored in time, you may never wake up.

Far more often syncope is triggered by dehydration or other causes of sudden low blood pressure. The best way to distinguish among these nonfatal varieties is to witness an attack. And so, before the patient left the hospital, she had a tilt-table test — a study designed to provoke a fainting spell. The patient was hooked up to blood-pressure and cardiac monitors, strapped to a table positioned almost vertically and watched for up to an hour. A test is successful when the patient passes out and the monitors capture the cause. But the patient didn't faint. She went home hoping that whatever caused the two episodes had simply gone away.

But the next day she was driving to work and began to feel that now-familiar flutter in her stomach. She pulled off the highway just in time. When she awoke, she called her husband, who took her directly to her doctor's office. Her internist was as baffled as the doctors she'd seen in the hospital. He sent her to specialists. One thought that these spells might be seizures rather than syncope. But a normal electroencephalogram (EEG) suggested otherwise. A neurologist in New York carefully examined her and her now-thick chart and pronounced definitively that there was nothing wrong with her and that she should try to relax and maybe take up yoga.

That's when she scheduled the appointment with Dr. Ledereich. She thought she might have an inner-ear problem, and he had been recommended by several friends. At that first encounter, Ledereich was not optimistic. He knew she'd seen many specialists. But he listened to her story and examined her. Like the doctors before him, he found nothing. She felt a little tired and had a little asthma, but other than these strange, repetitive spells, she was fine. He would get her records and then have her return. Meanwhile, when her son needed to see an E.N.T., she took him to Ledereich — and now she lay motionless on the floor.

"Don't call 911," the patient called out. She opened her eyes. "This happens to me all the time. I'm fine. Really."

Ledereich watched as the patient calmly sat up. "I know what you've got!" he told her excitedly.

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http://www.nytimes.com/2010/02/28/magazine/28FOB-diagnosis-t.html?ref=magazine&pagewanted=print

Doctors Struggle to Treat Gram-Negative Bacterial Infections - NYTimes.com

A minor-league pitcher in his younger days, Richard Armbruster kept playing baseball recreationally into his 70s, until his right hip started bothering him. Last February he went to a St. Louis hospital for what was to be a routine hip replacement.

Not until the day Mr. Armbruster died did a laboratory culture identify the organism that had infected him: Acinetobacter baumannii.

The germ is one of a category of bacteria that by some estimates are already killing tens of thousands of hospital patients each year. While the organisms do not receive as much attention as the one known as MRSA — for methicillin-resistant Staphylococcus aureus — some infectious-disease specialists say they could emerge as a bigger threat.

That is because there are several drugs, including some approved in the last few years, that can treat MRSA. But for a combination of business reasons and scientific challenges, the pharmaceuticals industry is pursuing very few drugs for Acinetobacter and other organisms of its type, known as Gram-negative bacteria. Meanwhile, the germs are evolving and becoming ever more immune to existing antibiotics.

"In many respects it's far worse than MRSA," said Dr. Louis B. Rice, an infectious-disease specialist at the Louis Stokes Cleveland V.A. Medical Center and at Case Western Reserve University. "There are strains out there, and they are becoming more and more common, that are resistant to virtually every antibiotic we have."

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http://www.nytimes.com/2010/02/27/business/27germ.html?em

Making the Grade: How Doctor-grading Websites Can Impact Your Practice, and what You Can Do to Lessen the Blow

"Her MA is very rude, uncompassionate. Dr. ABCD doesn't return phone calls. They're not helpful and not good with following up with the care plan for patients. We're new seeing this doctor, but will never go back. I would not recommend this practice at all!!!!!!"

How would you handle a comment like this when found on your patient satisfaction surveys? What if, even worse, this comment was found about you on the Internet. This is an actual comment about a physician found on a website that rates physicians. So, what is doctor grading, how have things changed recently, and what can you do about it?
 

Rating physicians has been part of the "business" for years. In the past, the grading was done formally by utilization review or quality assurance committees at the hospital. It has also been "controlled" by lawsuits and by the various state medical boards. This type of information was maintained "internally" to the medical community.
 

The other method of rating was via word of mouth. This has been the most effective way to market a practice, but it also has been equally effective in losing patients. It has often been stated that one bad experience will be heard by 10 others, whereas one good experience will only be heard by one.
 

As we move into the new decade, the era of public rankings is moving full speed ahead, and the real issue is the online rating sites and what they can do for, or against, you.

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http://www.hcplive.com/primary-care/articles/online_physician_grading_websites

Depression’s Upside - NYTimes.com

The Victorians had many names for depression, and Charles Darwin used them all. There were his "fits" brought on by "excitements," "flurries" leading to an "uncomfortable palpitation of the heart" and "air fatigues" that triggered his "head symptoms." In one particularly pitiful letter, written to a specialist in "psychological medicine," he confessed to "extreme spasmodic daily and nightly flatulence" and "hysterical crying" whenever Emma, his devoted wife, left him alone.

While there has been endless speculation about Darwin's mysterious ailment — his symptoms have been attributed to everything from lactose intolerance to Chagas disease — Darwin himself was most troubled by his recurring mental problems. His depression left him "not able to do anything one day out of three," choking on his "bitter mortification." He despaired of the weakness of mind that ran in his family. "The 'race is for the strong,' " Darwin wrote. "I shall probably do little more but be content to admire the strides others made in Science."

Darwin, of course, was wrong; his recurring fits didn't prevent him from succeeding in science. Instead, the pain may actually have accelerated the pace of his research, allowing him to withdraw from the world and concentrate entirely on his work. His letters are filled with references to the salvation of study, which allowed him to temporarily escape his gloomy moods. "Work is the only thing which makes life endurable to me," Darwin wrote and later remarked that it was his "sole enjoyment in life."

For Darwin, depression was a clarifying force, focusing the mind on its most essential problems. In his autobiography, he speculated on the purpose of such misery; his evolutionary theory was shadowed by his own life story. "Pain or suffering of any kind," he wrote, "if long continued, causes depression and lessens the power of action, yet it is well adapted to make a creature guard itself against any great or sudden evil." And so sorrow was explained away, because pleasure was not enough. Sometimes, Darwin wrote, it is the sadness that informs as it "leads an animal to pursue that course of action which is most beneficial." The darkness was a kind of light.

The mystery of depression is not that it exists — the mind, like the flesh, is prone to malfunction. Instead, the paradox of depression has long been its prevalence. While most mental illnesses are extremely rare — schizophrenia, for example, is seen in less than 1 percent of the population — depression is everywhere, as inescapable as the common cold. Every year, approximately 7 percent of us will be afflicted to some degree by the awful mental state that William Styron described as a "gray drizzle of horror . . . a storm of murk." Obsessed with our pain, we will retreat from everything. We will stop eating, unless we start eating too much. Sex will lose its appeal; sleep will become a frustrating pursuit. We will always be tired, even though we will do less and less. We will think a lot about death.

The persistence of this affliction — and the fact that it seemed to be heritable — posed a serious challenge to Darwin's new evolutionary theory. If depression was a disorder, then evolution had made a tragic mistake, allowing an illness that impedes reproduction — it leads people to stop having sex and consider suicide — to spread throughout the population. For some unknown reason, the modern human mind is tilted toward sadness and, as we've now come to think, needs drugs to rescue itself.

The alternative, of course, is that depression has a secret purpose and our medical interventions are making a bad situation even worse. Like a fever that helps the immune system fight off infection — increased body temperature sends white blood cells into overdrive — depression might be an unpleasant yet adaptive response to affliction. Maybe Darwin was right. We suffer — we suffer terribly — but we don't suffer in vain.

ANDY THOMSON IS a psychiatrist at the University of Virginia. He has a scruffy gray beard and steep cheekbones. When Thomson talks, he tends to close his eyes, as if he needs to concentrate on what he's saying. But mostly what he does is listen: For the last 32 years, Thomson has been tending to his private practice in Charlottesville. "I tend to get the real hard cases," Thomson told me recently. "A lot of the people I see have already tried multiple treatments. They arrive without much hope." On one of the days I spent with Thomson earlier this winter, he checked his phone constantly for e-mail updates. A patient of his on "welfare watch" who was required to check in with him regularly had not done so, and Thomson was worried. "I've never gotten used to treating patients in mental pain," he said. "Maybe it's because every story is unique. You see one case of iron-deficiency anemia, you've seen them all. But the people who walk into my office are all hurting for a different reason."

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http://www.nytimes.com/2010/02/28/magazine/28depression-t.html?hpw=&pagewanted=print

eMedicine - Medical Reference

eMedicine is the most authoritative and accessible point of care medical reference available to physicians and other health care professionals on the Internet. The evidence-based content, updated regularly by more than 8,000 attributed physician or health care provider authors and editors, provides the latest practice guidelines in 38 clinical areas. The eMedicine Clinical Knowledge Base contains articles on over 6,500 diseases and medical topics, and is richly illustrated with some 28,000 multimedia files.

New eMedicine articles undergo several levels of physician peer review plus an additional review by a PharmD prior to publication. Sources for subsequent revisions of articles include the author, a physician or PharmD member of the editorial board, user-driven feedback, and systematically reviewed medical literature.

http://emedicine.medscape.com/

YouTube - Keith Olbermann Special Comment on His Father and Death Panels

"Last Friday night my father asked me to kill him ... to the politicians who go into Blair House for the summit ... Leave your egos at the door. I want, I demand, that you give everybody in this country a chance at the care my father has gotten. And I demand, that you enact this most generous and most kind aspect of the reform proposed: the right to bill the damned insurance company for the conversation about what to do when the time comes, the Life Panel." Keith Olbermann

http://www.youtube.com/watch?v=mWtwvFc842A

In Search of the Best Medicine for Depression - University of Pennsylvania

New research explores why different patients respond better to different treatments.

Scientific meta-analysis may not be a typical way to make headlines. But psychology doctoral student Jay Fournier found himself a media magnet last month following the publication of a paper in theJournal of the American Medical Association (JAMA) that examined antidepressant-drug treatment data from studies conducted in each of the last three decades. Fournier and his coauthors, including his mentor, Samuel H. Preston Term Chair in the Social Sciences Robert DeRubeis, reported that for people with mild to moderate depression, medication failed to outperform placebos. The story received wide coverage, nationally and internationally, including a debate about interpretation and methodology that played out in the science pages of the New York Times.

While the JAMA paper received a surprising amount of attention, what is perhaps more remarkable is how little research has been done to date on the effectiveness of antidepressants for people with mild to moderate depression. Thousands of studies have demonstrated that antidepressants work well in treating patients with severe depression. But evidence from clinical trials involving people with less severe forms of depression was, according to Fournier, hard to come by. By including this subset in his analysis, Fournier and his coauthors have provided evidence that not all depression is the same, and that medication may not always be the best treatment.

Fournier cautions that their results do not indicate that medication is ineffective, but they do suggest just how effective placebos are for people with mild to moderate depression. "There are a series of steps," Fournier notes, "that someone needs to take in order to get a placebo in a clinical trial, and these steps alone seem to have a powerful effect. We don't fully understand how placebos work, but it seems that part of the benefit comes from patients taking their depressive symptoms seriously and acting on their concern about their own mental health."

Fournier's dissertation explores this notion—that the decision to take active steps is, in itself, powerful therapy for many people—from a slightly different angle. Rather than comparing medication to placebos, Fournier has compared medication to cognitive therapy. His work builds upon an authoritative 2005 clinical study by DeRubeis and a team of researchers at Penn and Vanderbilt University which found that for moderate to severe depression, cognitive therapy works as well as antidepressants. The focus of Fournier's work is whether there are patient-specific factors that determine which individuals fare better with medication, and which respond to cognitive therapy.

To assess this, Fournier carried out three studies examining the relationship of treatment outcomes with patient characteristics, types of depressive symptoms, and the presence or absence of personality pathology. "Cognitive therapy," Fournier found, "was more effective for patients who are married or cohabit, who are unemployed, who experienced a large number of life events, and with no diagnosis of personality disorder." Further, he found that cognitive therapy was better at treating "atypical vegetative symptoms" of depression, such as sleeping or eating too much. In contrast, medication seems to be the better treatment for patients who in addition to depression have a personality disorder.  Patients with chronic depression, older patients, and patients with lower intelligence experienced poor outcomes with both cognitive therapy and medication.

In demonstrating that different treatments are appropriate for different patients, Fournier's research is consistent with the larger movement toward personalized medicine—a revolution being fueled in many medical specialty areas by the availability of molecular and genetic data. But at this point, according to Fournier, his research might best be considered "informative." To get to the point where it's possible to custom-match treatments to patients with depression, he notes that the first step will be for another study to replicate his findings. Beyond that, Fournier notes, "Whenever we see a subgroup of patients that responds differently to one treatment over another, it tells us that there might be differences in mechanisms of response, and the variables give us clues about the mechanisms." Pursuing these clues will remain Fournier's priority after getting his doctoral degree this May.

http://www.sas.upenn.edu/home/SASFrontiers/fournier.html

“We’ve Got Issues,” by Judith Warner - Review - NYTimes.com

Picture a cupped hand. A capsule and a pill lie in the palm. The hand is extended toward a small child. The caption reads, "Take your vitamins."

It's better than a Rorschach test, that image: most people will erupt with a passionate visceral reaction, especially if they deduce that the proffered medications are not vitamins at all, but strong psychoactive drugs like Ritalin and Prozac.

For some, the picture symbolizes the best kind of parenting, proactive and nurturing. For others, it is an evocative summary of everything that is wrong with our culture, as pushy parents blithely dose hapless children with unnecessary medication in the name of conformity and achievement.

The journalist Judith Warner was a die-hard member of the second camp, and wanted to spread the word. Six years ago, she happily landed a book contract to explore and document the overmedication of American youth.

Readers of Domestic Disturbances, the online column Ms. Warner wrote for The New York Times until December, will be familiar with what happened next. She sallied forth to interview all the pushy parents, irresponsible doctors and overmedicated children she could find — and lo, she could barely find any. After several years of dead ends, missed deadlines and worried soul-searching, she was forced to reconsider her premise and start all over again.

"We've Got Issues" is the product of that unusual cycle. Journalists who cobble together enough anecdotes to support a preset agenda are all too common, and presumably Ms. Warner could have managed to do just that. Instead, she actually let her research guide her thoughts: it whirled her perspective a full 180 degrees and, as she would be the first to affirm, lifted the scales from her eyes.

"A couple of simple truths have become clear," she writes with the passion of a new convert. "That the suffering of children with mental health issues (and their parents) is very real. That almost no parent takes the issue of psychiatric diagnosis lightly or rushes to 'drug' his or her child; and that responsible child psychiatrists don't, either. And that many children's lives are essentially saved by medication, particularly when it's combined with evidence-based forms of therapy."

How could she have been so convinced otherwise? Half the book is rueful legwork devoted to answering that question.

Ms. Warner points out that she was hardly alone in her previous assumptions: it is accepted wisdom in some circles, including, oddly, liberal-left "moms" and right-wing radio audiences, that the milder variants of attention deficit disorder, bipolar disorder and autism are just different ways of saying "normal, but not good enough."

Both groups share a disdain of parents who buy into those diagnoses, a horror of the medications used to treat them and a deep nostalgia for the simpler childhoods of past eras, when the child in question would definitely have been left alone.

Ms. Warner is sympathetic: "Believing that our toxic world is either producing symptoms in children or classifying them as abnormal when they don't conform is seductive. After all, there is so much wrong with the lives of children today."

She concedes that all the pressures to achieve socially, intellectually and financially can make a toxic brew. "We have to do something about our current social environment," she writes, "because it's creating some pretty big problems."

But she remains immutable on one point: the myth of the overmedicated child is just that — an allegory but not a reality.

Ms. Warner reported out the spectrum of pediatric psychiatric disorders with dozens of interviews. Most of the stories are variations on a theme: well-educated, sophisticated parents, unwilling, at first, to recognize a sick and miserable child who needs professional help.

Once help is finally sought, it is often quite difficult to obtain: there are few child psychiatrists in this country (about 7,000, by most estimates), fewer still good ones, and the usual plethora of dubious alternatives to orthodox medical care. Finally, after a reasonable facsimile of care is obtained, the child is usually better, but nowhere near perfect. "We don't know if he will have an independent life or will be institutionalized for life" is a typical conclusion.

But the big picture is far brighter than its components. Ms. Warner argues that child psychiatry is actually one of the major public health success stories of our time. As one expert tells her, when it comes to mental health, "the horse is out of the barn by adulthood." Treating troubled children is more than symptom management for a calmer classroom: the medications seem actually to change the structure of the brain, helping it develop in what all evidence indicates is the right direction. More children in treatment should spell the beginnings of a healthier adult world.

By her last section, Ms. Warner has worked herself up into something of a lather as she argues passionately for health care reform to ease access to treatment, for more good doctors who understand medications, for better drug research and far tighter reins on the pharmaceutical industry. Much of this has been stated somewhat more expertly and elegantly elsewhere.

But then again, we are all inured to expert voices preaching on these topics. Those who disagree stopped listening long ago, and Ms. Warner's earnest, wide-eyed exhortations will not bring them around. But for the choir, her version of the sermon will make a pleasant change.

http://www.nytimes.com/2010/02/23/health/23book.html?em

A Drug Trial Cycle - Recovery, Relapse, Reinvention - Series - NYTimes.com

On a sunny afternoon last June, Dr. Keith Flaherty stood before a large room packed with oncologists from around the world and described the extraordinary recovery of the melanoma patients in the experimental drug trial he was leading.

It was a moment he had looked forward to for months. Beyond a breakthrough for melanoma, the results were a promising sign for an approach to treatment for all forms of cancer that he and others had championed as more effective and less toxic than standard chemotherapy.

But even as he flashed the slide of his favorite graph, showing tumors shrinking in nearly every patient, his mind was on what had happened to them since.

In the weeks leading up to the annual oncologists' conference here, several of the patients on the trial of the drug known as PLX4032 had relapsed. One had died. Another, Christopher Nelson, who had made what seemed like a miraculous recovery in March, had lost his appetite again. Dr. Flaherty feared what he might see on Mr. Nelson's scan when he returned to his office at the University of Pennsylvania.

The drug's ability to stop the melanoma, on average, he told the crowd, "appears to be approximately six months."

"I was hoping we'd get more time," said Dr. Grant McArthur, one of the six oncologists on the trial team, voicing the thought on everybody's mind when the group met at the conference. None of them had a financial stake in the drug.

Dr. Flaherty, whose perpetual optimism about this kind of treatment, known as targeted therapy, raised eyebrows among some colleagues, declined to dwell on the drug's limitations. However briefly, PLX4032 had held off the cancer by blocking a particular protein in its cells that was spurring them to multiply. If such targeted drugs were ever to provide a lasting benefit, many oncologists believed they would need to be combined with others, much as cocktails of protease inhibitors have worked against H.I.V.

"We just need," Dr. Flaherty said, "to find the right combination."

If they acted quickly enough, they might even be able to help the trial's participants. Many were still in remission. Those who had relapsed were searching for another treatment, acutely aware that their time was running out: most melanoma patients die within a year after the cancer spreads.

The problem, which had bedeviled targeted therapies for other cancers, was that while PLX4032 blocked the protein made by one mutated gene, a second mutation now seemed to be driving the cancer's growth. If that mutation could be identified, they believed, its protein could also be blocked, in a game of biological Whac-a-Mole that just might be possible to win.

The most expedient approach would be to test PLX4032 in combination with other experimental drugs that targeted other mutations, including those seen in Dr. Flaherty's relapsing patients.

But a drug that gave a patient even a few months of life could generate billions in revenue. And the standard practice among pharmaceutical companies, which say they typically invest nearly a billion dollars developing and testing a single drug, is to get each drug approved individually before testing it with others, especially those of competitors that are still experimental. Even small Phase 1 trials can cost over a million dollars. And one drug that was safe and effective, they worried, might be tainted by association with another that proved to have toxic side effects.

As Roche, the pharmaceutical giant that had licensed PLX4032, made plans to test the drug in larger trials in hopes of quick Food and Drug Administration approval, Dr. Flaherty's colleagues in the laboratory would search for the new mutation in the tumor samples of patients who had relapsed, trying to understand why the drug had stopped working.

For his part, the doctor would try to keep his patients alive. And he would work to convince the pharmaceutical industry that the fastest path to finding a combination that really worked would require changing their standard operating procedure.

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http://www.nytimes.com/2010/02/24/health/research/24trial.html?ref=health

After Long Fight, Melanoma Drug Gives Sudden Reprieve - Series - NYTimes.com

For the melanoma patients who signed on to try a drug known as PLX4032, the clinical trial was a last resort. Their bodies were riddled with tumors, leaving them almost certainly just months to live.

But a few weeks after taking their first dose, nearly all of them began to recover.

Lee Reyes, 30, of Fresno, Calif., who had begun using a feeding tube because of a growth pressing against his throat, bit into a cinnamon roll.

Nothing, he told his mother, had ever tasted as good.

Rita Quigley, who had been grateful just to find herself breathing each morning since learning she had the virulent skin cancer, went shopping for new clothes with her daughters at a mall in Huntsville, Ala.

Randy Williams, 46, who drove 600 miles from his home in Jonesboro, Ark., to the M.D. Anderson Cancer Center in Houston to get the experimental drug, rolled out of bed. "Something's working," he thought, "because nothing's hurting."

It was a sweet moment, in autumn 2008, for Dr. Keith Flaherty, the University of Pennsylvania oncologist leading the drug's first clinical trial. A new kind of cancer therapy, it was tailored to a particular genetic mutation that was driving the disease, and after six years of disappointments his faith in the promise of such a "targeted" approach finally seemed borne out. His collaborators at five other major cancer centers, melanoma clinicians who had tested dozens of potential therapies for their patients with no success, were equally elated.

In a kind of "pinch me" exercise, the six doctors sent one another "before and after" CT scans of their patients.

One was of Mark Bunting, 52, an airline pilot in Sandy, Utah. His initial scan in early October showed the cancer in his bones, an incursion considered virtually impossible to reverse. After two months on the drug, it had all but disappeared.

"Holy Cow!" Dr. Flaherty typed in reply to the slide from Dr. Antoni Ribas at the University of California, Los Angeles, that Dec. 17.

"Are you sure it is the same patient??" added Dr. Jeffrey A. Sosman at the Vanderbilt-Ingram Cancer Center in Nashville.

From New York, Dr. Paul B. Chapman of Memorial Sloan-Kettering Cancer Center, perhaps the most determined skeptic of the group, acknowledged, "This looks impressive."

The trial of PLX4032 offers a glimpse at how doctors, patients and drug developers navigate a medical frontier as more drugs tailored to the genetic profile of a cancer are being widely tested on humans for the first time.

Throughout the fall, the only two patients on the trial whose tumors continued to grow were the ones who did not have the particular gene mutation for which the drug had been designed. They were removed from the trial. By late December, tumors in the 11 patients who did have the mutation had shrunk. Those involved in the trial held their collective breath waiting to see how long the remissions would last.

It was a far cry from where they had been a year earlier, when a previous incarnation of the drug had no effect. Urged on by Dr. Flaherty and Dr. Chapman, the companies that owned it had spent months devising a new formulation that could be absorbed at higher doses.

But the new drug, still in the earliest phase of testing, had to pass several more hurdles before federal regulators would determine whether it was safe and effective enough for widespread use.

In December, as the doctors added more patients to the Phase 1 trial, looking for the highest dose they could give without intolerable side effects, they scrambled to prepare slides with graphs and statistics to convince the Food and Drug Administration that the drug should be tested in a larger Phase 2 trial. The agency required a summary of any and all side effects — there had been only a few — and any deaths of patients on the study; thankfully, there had been none since the drug was reformulated. In a matter of days they needed to submit their findings for a prestigious meeting of clinical oncologists in June.

First, though, Dr. Flaherty, 39, needed to respond to a desperate phone message from a patient named Christopher Nelson. It came the day after Christmas.

"Dr. Flaherty," the message said, "I need to get onto your trial."

Hoping for a Match

The doctor had expected the call.

Mr. Nelson, 42, and his wife, Sharlene, had come to see him just before Thanksgiving. They were planning to travel to Bethesda, Md., so Mr. Nelson could enroll in a trial for a different melanoma drug. But the couple, from Jackson, N.J., had learned of Dr. Flaherty's trial, and wanted to cover all their bases.

He liked them: Sharlene, a real estate broker who peppered him with questions, and Chris, a furniture installer around his own age with a penchant for low-stakes poker and the Grateful Dead. Both were quick to make light of a grim situation.

"I've gained the 60 pounds he's lost from the cancer," Mrs. Nelson observed. "Stress eating."

They had met after high school, at Levitz, the furniture store where they both worked. Like Dr. Flaherty, they had two children.

"He was never sick a day in his life," Mrs. Nelson told Dr. Flaherty. "Never had a headache, never took a sick day. I mean, can't you give me the common cold first? It had to be cancer?"

The trial in Bethesda, run by the National Cancer Institute, involved coaxing immune cells to grow in a test tube in a procedure that worked for only a small fraction of patients, Dr. Flaherty knew.

But there would be no point in Mr. Nelson taking PLX4032 if his tumor did not carry the right mutation. For now, the doctor had a slot for only one more patient on the trial, and he and his collaborators had agreed it was almost unethical to give the drug to people without that mutation.

He wished, not for the first time, that he could snap his fingers and know the genetic profile of his patient's cancer cells. But getting a hospital that had operated on a patient months earlier to retrieve a tumor sample from storage could take days or weeks; the test for the gene mutation could take even longer. To speed the process, Mr. Nelson drove his tumor sample himself fromRobert Wood Johnson University Hospital in New Brunswick, N.J., where it had been removed from his lymph nodes, to the laboratory at the University of Pennsylvania.

Dr. Flaherty agreed that while they waited, Mr. Nelson should proceed with the trial in Bethesda, which first required the removal of his tumor-laden spleen. Either way, that needed to go.

Mrs. Nelson thought her husband had died when she saw the stricken look on the face of the surgeon after the operation. Normally 2 pounds, the spleen had weighed 10. Mr. Nelson's liver was so enlarged that maneuvering around it had been almost impossible. And then, on Dec. 23, Mr. Nelson learned that the doctors running the trial had been unable to grow his immune cells.

On the phone, Dr. Flaherty assured him he would let them know his genetic status as soon as he found out. "If it's positive," Dr. Flaherty told him, "the spot is yours."

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http://www.nytimes.com/2010/02/23/health/research/23trial.html?em=&pagewanted=print

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A Roller Coaster Chase for a Cure - NYTimes.com

His patient, a spunky Italian-American woman in her 60s, was waiting in an exam room down the hall for the answer: Was the experimental drug stopping her deadly skin cancer?

But as Dr. Keith Flaherty read out the measurements of her tumors from the latest CT scan, he could not keep the distress from his voice.

“She’s worse,” he said to the clinical trial nurse at the University of Pennsylvania’s melanoma clinic.

Like the 17 other patients on the drug trial — the corporate lawyer, the receptionist with young children, the Philadelphia philanthropist — the woman known in the trial as Patient 18 was going to die, most likely within months.

In the exam room, her gratitude for his failed efforts to save her tore at his heart.

He had been so optimistic. A radical departure from standard chemotherapy, the drug was designed to reverse the effect of a genetic mutation particular to the patient’s tumors. The approach represented what some oncologists see as the best bet for attacking all types of cancer.

And as he returned to his office that autumn afternoon two years ago, Dr. Flaherty was already calculating the next step: he wanted to test the drug at a more potent dose before giving it to more patients in a larger trial. It would require retooling the drug in a costly and complicated task that might not work, and he would have to make his case to two companies that had already poured hundreds of millions of dollars into the drug and were eager to move it forward.

“This,” he insisted to colleagues, “is the best drug we’re going to get.”

Dozens of such “targeted” drugs are emerging from the laboratory, rooted in decades of research and backed by unprecedented investment by pharmaceutical companies, which stand to profit from drugs that prolong life even by weeks.

But putting them to their truest test falls to a small band of doctors committed to running experimental drug trials for patients they have no other way to heal.

At a time when cancer still kills one in four Americans, it is a job that requires as much hubris as heart. To chronicle the trial of the drug known as PLX4032 is to ride a roller coaster of breakthroughs and setbacks at what many oncologists see as a watershed moment in understanding the genetic changes that cause cancer.

Over three tumultuous years, Dr. Flaherty saw patients who drove hundreds of miles for their monthly dose, and one who arrived barely able to walk. Some took 32 pills a day. When it became clear they were not absorbing the drug, he asked them to take the pills with high-fat foods like hamburgers and eggs, which might help dissolve them.

At academic conferences, he clashed with other oncologists who warned that targeted therapy had almost never had long-lasting results. At Penn, he badgered laboratory researchers whose animal tests might provide early clues for how a drug would behave in his patients.

And always, he ended up on his BlackBerry, e-mailing, calling, cajoling the drug makers to commit even more resources to the new category of drugs he so deeply believed in.

A five-and-a-half-foot streak of outsize energy, Dr. Flaherty, 39, seemed buoyed by an innate optimism and a faith in the scientific logic underlying the approach.

But at his clinic, where he gave vials of pills to patients whose tumors were often erupting, black and bumpy across their arms and legs, he told them only what he believed to be true.

“This,” he said, “is our best shot.”

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http://www.nytimes.com/2010/02/22/health/research/22trial.html?th=&emc=th&pagewanted=print