new england journal of medicine


Rethinking Cancer Research Through ‘Exceptional Responder’ Patients

Grace Silva and her oncologist, Jochen Lorch (Photo: Sam Ogden, Dana-Farber Cancer Institute.)

Grace Silva and her oncologist, Jochen Lorch (Photo: Sam Ogden, Dana-Farber Cancer Institute.)

By Richard Knox

By all odds, Grace Silva should have died more than three years ago. Instead, this 58-year-old grandmother is helping scientists rethink cancer treatment and research.

Silva’s case, detailed in this week’s New England Journal of Medicine, is one of only three recently published accounts of what cancer doctors call “exceptional responses” to a drug called everolimus (brand name Afinitor).

It was approved two years ago to treat certain breast cancers and is also used against some kidney and pancreas tumors. A couple of months after Silva started taking the drug, her thyroid tumors, which had spread to her lungs, melted away to nearly nothing. That basically never happens with this aggressive tumor, known as anaplastic thyroid cancer. “It was a near-complete response,” says her oncologist at Dana-Farber Cancer Institute, Dr. Jochen Lorch. “That in itself is exceptional. When we saw it, it was one of the better days around here.”

Studying The Exceptions

More remarkable still, Silva’s tumor stopped growing for 18 months. We’ll come back to what happened after that. But first, you should understand this story isn’t about everolimus or any particular cancer drug. It’s about how cancer specialists are learning how cancer works at the most basic level — by studying exceptional responders like Grace Silva.

And to appreciate why her case is important, you need to know how researchers figured out why she was an exceptional responder. It’s partly due to a five-year-old technology called next generation sequencing. It’s a cheap and rapid way of spelling out the genetic code of, in this case, individual patients’ tumors. Researchers can then look for gene mutations that are driving the uncontrolled growth that is cancer.

Continue reading

Dr. Arnold Relman, Prominent Medical Editor And Critic, Dies at 91

Dr. Arnold Relman on YouTube in 2009.

Dr. Arnold Relman on YouTube in 2009.

Sad news in The Boston Globe: Dr. Arnold “Bud” Relman, a longtime editor of the New England Journal of Medicine and prominent critic of the influence of money in medicine, has died at 91 of cancer.

We wrote about Dr. Relman just this January:

Dr. Arnold Relman, former editor of the New England Journal of Medicine, has long played a rare role in the health care sphere: He’s an exceedingly senior and authoritative Harvard figure willing to speak out about what’s wrong in American medicine, from financial conflicts to the need for health care reform.

The occasion was his must-read article about the lessons he had recently learned about health care from breaking his neck and nearly dying. It’s in the New York Review of Books here, titled “On Breaking One’s Neck.”

For what it’s worth, at least it sounds like he had a good death. His wife, Dr. Marcia Angell, tells the Globe, ““When he found he had a fatal illness, he said, ‘I just want to die the way I lived, sitting at my desk writing,’ ” Angell said. “He was dignified and brave the whole time. He said, ‘Look, I got 90, maybe 91 years. Not many people get that. I’ve had a wonderful life and I have no regrets.’”

Don’t miss the Globe’s beautifully done obituary here.

Feel As If You, Too, Were Under The Marathon Medical Tent


Medical personnel work outside the medical tent in the aftermath of two blasts which exploded near the finish line of the Boston Marathon in Boston, Monday, April 15, 2013. (Elise Amendola/AP)

Wow. I’ve just read the best description, bar none, that I’ve seen of the medical side of the marathon bombings, and it appears in a publication better known for clinical evidence than literary acrobatics. But if you want to feel as if you were right inside the marathon medical tent, side by side with the personnel who expected dehydration and instead got horrible flesh wounds, do not miss this superb piece by Dr. Sushrut Jangi, a hospitalist at Beth Israel Deaconess Medical Center It’s now online here in the New England Journal of Medicine. From near the beginning:

Sickened and stressed runners poured into our makeshift hospital. A runner stumbled in and vomited into a bag. We helped him onto a cot, where he sat shivering. “You’re OK,” a nurse said gently, wiping his face. But his core temperature had dropped to 96 degrees, and he began having violent rigors. We brought him Mylar blankets and hot bouillon. Nearby, a woman with intense hamstring spasms fell onto a cot; a runner with liver disease trembled with asterixis, his eyes roving in wild saccades.

Suddenly, there was a loud, sickening blast. My ears were ringing, and then — a long pause. Everyone in the tent stopped and looked up. A dehydrated woman grabbed my wrist. “What was that?” she cried. “Don’t leave.” I didn’t move. John Andersen, a medical coordinator, took the microphone. “Everybody stay with your patients,” he said, “and stay calm.” Then we smelled smoke — a dense stench of sulfur — and heard a second explosion, farther off but no less frightening. Despite the patient’s plea, I walked out the back of the tent and saw a crowd running from a cloud of smoke billowing around the finish line. “There are bombs,” a woman whispered. My hands began to shake.

Read the full piece here.

The First Meningitis Patient, And The Medical Mystery Of The Black Mold

Exserohilum rostratum

Exserohilum rostratum (Wikimedia Commons)


The medical detective story of how Vanderbilt doctors figured out the link between tainted steroid injections and life-threatening meningitis came out almost three weeks ago — but now you can read the full (and frightening) clinical details of that “index case” in The New England Journal of Medicine here. 

The authoritative account includes the disturbing details of a man in his fifties who suddenly went into rapid decline a month after he had a spinal steroid injection. He comes in with “nausea, malaise, fatigue, chills, and decreased appetite.” Despite antibiotics, his pain worsens and he becomes “agitated, with incomprehensible speech.” He’s treated with more drugs, but by his sixth day in the hospital, he’s having “intermittent staring spells, and a transient right facial droop.” The next day, the lab identifies the fungus Aspergillus and he is treated for it, but to little avail.

On hospital day 11, the patient abruptly became unresponsive, with rhythmic shaking of the head that was consistent with seizure activity. He was intubated and mechanical ventilation was initiated. A head CT scan showed intraventricular hemorrhage involving the lateral ventricles, subarachnoid hemorrhage in the perimesencephalic cistern, and worsening hydrocephalus.

The man died on his 22nd day in the hospital.

‘It remains a mystery as to why the index case is the sole case in which A. fumigatus was detected.’

The New England Journal also features an informative update on the meningitis outbreak, which points up an oddity of the findings thus far: That first, index case reported finding Aspergillus fumigatus in the patient, but that fungus “has not been detected in any of the subsequent 200-plus cases. The major culprit appears to be Exserohilum rostratum, a plant pathogen that rarely causes human disease. This mold has been cultured or identified by means of a polymerase-chain-reaction (PCR) assay from cerebrospinal fluid in at least 25 patients and has been detected in at least one unopened vial from the implicated lot of methylprednisolone.”

The theory that E. Rostratum, a black mold, is the villain here fits with past cases: Continue reading

Sorry, That Paper Linking Chocolate To Nobels Really Is A Prize-Season Joke

This is so embarrassing, but I have to confess that I had a moment of doubt. Maybe this was a real paper in the august New England Journal of Medicine? Maybe a researcher was seriously arguing that eating more chocolate may lead to winning more Nobel prizes?

I blame my briefly idiotic credulity on the endless parade of really questionable papers that come out all the time (in lesser journals, of course!) linking various foods and behaviors to slightly greater or lesser risks and benefits. Blueberries for brains, raspberries for cancer prevention, gooseberries for weight loss — you know.

So I’m happy to report that I have on very good authority that no, really, the paper “Chocolate Consumption, Cognitive Function, and Nobel Laureates” is in fact utterly tongue-in-cheek, a bit of the New England Journal’s humor. This could prompt great relief in some Latin American circles, where, according to the ever-fascinating Knight Science Journalism Tracker, some reporters took the study seriously:

It’s a mystery why the New England Journal of Medicine published the silliest study correlating a country’s chocolate consumption with chances to win a Nobel prize. The study even suggests that Nobel Panel may have a “patriotic bias” because according to its consumption of chocolate, Sweden should have produced only 14 Nobel prize winners yet it had 32. We’ve seen three different reactions in the Spanish speaking press: 1) the majority of serious outlets have simply ignored the study, 2) Some have joked about it and compared to other associations like sun spots and male depression, and 3) many reporters took it seriously, they bought the flavonoid’s argument, and without any critical spirit they told their readers that “eating chocolate increase the possibilities of winning a Nobel prize”.

Sigh. A little humor can be a dangerous thing. And just for the record, yes, the argument is a joke, but the data — such as they are — and the statistical analysis in the chart below are accurate. Though naturally a bit incomplete; the NPR report on the study prompted this commenter’s query: “My only question: how many Nobel winners have there been from Hershey PA?”

chocolate nobel chart

(The New England Journal of Medicine ©2012.)

Heart Med Study Cited As Example Of Problematic Financial Ties

Alison Bass

Alison Bass’s past as a crack Globe reporter is showing. Now an author and journalism teacher, she shows on her blog today that she can still do a bang-up super-fast write-up. She reports on a Harvard event last night titled “Dollars For Doctors: Who Owns Your Physician?” and pointed remarks at the forum by Dr. Arnold Relman, former editor of The New England Journal of Medicine.

The issue: how conflict of interest in medicine drives up costs by increasing the use of expensive new drugs when cheaper generics would do. Alison writes:

It was left to Dr. Arnold Relman, professor emeritus at Harvard Medical School, to showcase a fresh-off-the-page example of how studies that are funded by drug makers and conducted by researchers who have financial ties to the industry present skewed research results that favor expensive new drugs over generics.

His case in point: The New England Journal of Medicine published a study last week concluding that a new anticoagulant known as apixiban (brand name: Eliquis) was superior to the generic drug warfarin in preventing stroke and deaths in patients with atrial fibrillation (abnormal heart rhythm). The study was funded by Bristol Myers Squibb and Pfizer, which jointly manufacture Eliquis, and featured a lengthy roster of authors, many of whom have extensive financial ties to the drug industry (in the form of speaking and consulting fees). At least three of the authors were Bristol Myers Squibb employees, as the fine print at the end of the study disclosed. Continue reading

The ‘Oreo Problem’: When Drug Marketers Know Too Much About Doctors

Imagine you’re shopping in the supermarket cookie aisle and a gorgeous, charming salesperson for Nabisco comes up to you and says, “We’ve noticed that you used to buy Oreos, but lately, you’ve switched to Nutter Butters instead. We’d really like to get you back to Oreos. May I offer you these free samples?”

I don’t know about you, but I’d feel a pretty deep sense of offensive intrusion. Yet that is pretty much how it works with prescription drugs: salespeople have immensely detailed information on the prescriptions written by each doctor, and they can use it to make their marketing as specific and effective as possible. Only in the drug industry, it’s much more concerning than the cookie industry.

Prof. Kevin Outterson, co-director of the health law program at Boston University School of Law, points out: “If it’s Oreos, it’s only a snack and I’m buying them for my family. What we worry about for physicians is that they’re making an important medical decision for somebody else. We’re trusting the physician to make the right decision, without inappropriate influence from drug companies.”

In the latest New England Journal of Medicine, online today, Kevin writes here about Vermont’s recent attempt to fix what we could call “the oreo problem” in drug sales. Vermont passed a law that barred pharmacies from selling doctors’ prescribing data to data miners and drug companies — unless the doctors themselves opted in. (Names of patients are protected by HIPAA, the federal medical privacy law, but names of doctors are not.)

The Supreme Court recently shot down that Vermont law, so drug companies remain free to buy information that helps them market their drugs better to each doctor. Kevin’s article analyzes that decision and looks ahead at its implications. We asked him to explain.

Q: Why is this issue important enough to merit inclusion in a top medical journal?

The medical profession has been interested for a while in how pharmaceutical companies are marketing to doctors. They’ve devoted a lot of articles and commentary over the years to whether doctors are making correct clinical decisions or whether they’re being inappropriately influenced by advertising and marketing and promotion.

Being able to identify prescribing patterns is very powerful to the companies. If they send in a drug detailer with a certain tactic, or if they meet with the doctor at a convention, or if they hire the doctor to give speeches, the company can track in real time, every day, the impact of all these activities. If a certain doctor is given free samples of a drug, they can then track over the next weeks or months whether the doctor has written new prescriptions for the drug. If the doctor doesn’t, they can go in and try to modify their behavior. They can ‘punish’ doctors who are not writing the scripts and reward those who do. If they know a doctor has recently switched and is prescribing more of a rival drug, they can go in and say something negative about the rival drug. Continue reading

Those Pernicious French Fries, And Other Weight-Gain Wisdom

The New England Journal of Medicine study came out last week, but we continue to, shall we say, digest it. We linked to this Los Angeles Times story Friday, but just got word of the above helpful L.A. Times chart today. And the Boston Globe’s g section sums up the findings nicely here; it, too, fingers the spuds:

Potato chips. Increasing consumption of potato chips was the single biggest factor associated with weight gain through the years. For every extra daily serving that study participants ate, their weight increased by nearly 1.7 pounds over each four-year period in the study.

Other potato products. Everything from baked potatoes, to mashed potatoes, to French fries contributed to weight gain, an average of nearly 1.3 pounds over four years.

It also offers a lively Deb Kotz piece about how wearing a pedometer helps Blue Cross Blue Shield chief Andrew Dreyfus — and many others — get moving.