Disease screening is often a delicate balance. Catching a disease in its early stages almost always makes it more treatable, and can prevent permanent damage or even death. But it’s also cost-prohibitive to screen every person for every disease - even if you could convince everyone to show up for their regular doctor’s appointments - and so difficult decisions about benefit vs. cost and risk must be made.

Who actually makes those decisions is one of the key features of the U.S. health care debate. It’s nice to think that they are made by clinicians looking at the latest in medical research, but choices about what screens are affordable enough to be useful often boil down to which are considered acceptable for coverage by health insurance. In theory, insurance companies will follow the recommendations of scientific societies and expert task forces entrusted to analyze available data and make a decision. But what if those experts disagree?

That’s the battle being fought this week as new recommendations about mammograms for breast cancer screening are released by the U.S. Preventive Services Task Force. Published Tuesday in the Annals of Internal Medicine, the recommendations go against the grain of recent practice advising all women to start receiving mammograms at the age of 40, with yearly screening after the age of 50. Now, the task force says women who are not high-risk due to genetic factors or family history don’t need routine mammograms until age 50. Even then, screening every other year is sufficient until the age of 75, the task force concluded.

These new recommendations were not received quietly, as you may have discerned from the media covearge. University of Chicago professor of radiology Robert Schmidt told the Chicago Tribune that the recommendations were “arrogant and irresponsible.” My wife reports that one of the ladies of The View called the decision “gender genocide.”  Some medical societies have come out in favor of the new practice, while others said they will stick to the old guidelines. Ultimately, the decision on whether to be screened (if not the decision on how much screens will cost) lies with patients themselves. So here’s a quick primer on the support and opposition to the new recommendations.

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The Nobel Prize Medal (from nobelprize.org)

The University hasn’t directly won any of the first two Nobel Prizes awarded this week, but one of today’s winners has a UChicago connection: George E. Smith, one of three scientists who will share the $1.4 million prize in physics, received his doctorate at the University of Chicago 50 years ago in 1959. And Monday’s prize has a much more tenuous connection to the proprietor of this very blog, which I’ll explain below.

First, today’s prize rewarded innovations that power technology integral to our daily lives: digital cameras and the Internet. Smith and Willard S. Boyle received the award for the invention of charge-coupled devices, CCDs, the technology put to work in the millions of digital cameras now in use. Charles K. Kao, the third recipient of today’s award, was responsible for improving the use of fiber optic cables, changing the material used in those cables to dramatically extend the distance that light can travel within. Thanks to Dr. Kao, I can quickly research this blog post and you can quickly read it, downloading the information through fiber optic cables that he helped create.

Monday, the award was given to three scientists who made crucial advances in the study of chromosomes, cancer and aging. No, it wasn’t Janet Rowley, but her friend Elizabeth Blackburn was one of the awardees alongside Jack Szostak and Carol Greider. The trio were honored for the discovery of telomeres, repeated sequences at the ends of DNA that prevent genetic material from being damaged and degraded every time a cell is replicated. There really is no better metaphor to explain the function of telomeres than the one used by the Associated Press all day yesterday: “It’s been compared to the way plastic tips on the ends of shoelaces keep the laces from fraying.”

In honor of their award, Scientific American republished an excellent article by Greider and Blackburn that explains why telomeres (and their enzyme partner telomerase, which preserves telomere length) are significant to the study of aging and cancer. As people and their cells age, telomerase works less efficiently, and telomeres and chromosomes shrink, making the cell replication process less accurate. The inability to create new cells could lead to conditions associated with old age, such as artherosclerosis and a weakened immune system. In cancer cells, on the other hand, telomerase is a bad thing, allowing tumor cells to replicate rapidly, grow, and spread around the body. Researchers have thus turned to telomerase inhibitors as a potential cancer treatment.

It is with tongue firmly in cheek that I note my nanoscale contribution to the field of telomere research, from my time at the National Institute of Child Health and Human Development in 2002. I worked in the laboratory of Jeffrey Baron, who studied mechanisms of bone growth in children. As humans grow, a strip of cartilage in the bones of arms and legs called the growth plate produces new cells that lengthen those bones; some time after puberty, those growth plates disappear. With Ben Nwosu and Ola Nilsson, we studied whether the telomeres in those growth plates grow shorter with age - I mostly helped by doing dissections on our chosen animal model, the rabbit, as we bantered about World Cup results. Somewhat unfortunately, we found that the telomere length does not change as a rabbit grows older, suggesting that telomeres are not responsible for the closing of the growth plate after puberty. But disproving a hypothesis is just as important sometimes as proving one, and we were able to publish the results in the journal Hormone Research.

So on behalf of telomere researchers the world over, I’d like to thank the Nobel Committee for their award. But I’ll happily defer the prize money to Blackburn, Grieder and Szostak.

For information about the grants that the University of Chicago received as part of the ARRA package, click here.

If the scientists you know have an extra spring in their step today, here’s why: over $5 billion in National Institutes of Health funding was announced this week, the scientific portion of the federal stimulus package passed in the spring. In his January inaugural address, President Barack Obama made researchers’ neck hair stand up when he promised to “restore science to its rightful place,” and this was the first installment of that pledge - a much-needed boost of cash after five years of flat NIH budgets put many laboratories in jeopardy.

“We’re announcing that we’ve awarded $5 billion — that’s with a b — in grants, through the Recovery Act, to conduct cutting-edge research all across America, to unlock treatments to diseases that have long plagued humanity, to save and enrich the lives of people all over the world,” Obama said Wednesday at an NIH event announcing the grants.

A $42 million slice of that $5 billion pie was awarded to the University of Chicago, and I’ve spent the day talking to some of the researchers who snagged the biggest awards. They are all, as you might guess, thrilled to have an infusion of money to help finally launch projects that have languished unfunded or undermanned. In all, more than 100 UChicago researchers shared in the $42 million pot, with grants ranging from $10,000 to $5.6 million. After the jump is some information on the day’s big winners and the projects their new grants will fund.

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Sam Volchenboum has his head shaved by Joshua Crosby, Sept. 24, 2009 (photos by David Christopher)

A researcher will do a lot for grant money, the fuel necessary to power a laboratory’s work. Sam Volchenboum, a pediatric oncologist at the University of Chicago Medical Center, took that adage to its follicular extreme last week, volunteering to go bald for funds from the St. Baldrick’s Foundation.

St. Baldrick’s, a California-based organization which raises funds for pediatric cancer research, asks their volunteers and award recipients to shave their heads in solidarity with cancer-stricken children who have lost their hair to chemotherapy. Thursday evening, Volchenboum went under the razor himself, shedding his dark brown hair with the help of Joshua Crosby, a 13-year-old cancer survivor. A small price to pay, Volchenboum said, for a $330,000 award that will help him design faster and more specific diagnostic tools for neuroblastoma.

“It can often take a while and be a little frustrating to get to the diagnosis,” Volchenboum said. “Despite all we know about this disease, even with aggressive treatment - chemo and radiation and surgery - over half of the kids will still die from their disease.”

Despite what its name implies, neuroblastoma is not brain cancer, but rather a cancer of the sympathetic nervous system that connects the spinal cord to organs of the body. Though it’s rare as far as diseases go - with only about 800 new cases a year in the US - it’s nevertheless the most common solid-tumor cancer seen in children and is responsible for about 15% of childhood cancer deaths. But not all neuroblastomas are fatal; in fact, some tumors in infants even regress spontaneously without treatment. That wide variation in prognosis presents a challenge to oncologists, Volchenboum said, who must decide the best course of treatment for a child with neuroblastoma, doing as much as possible to attack the tumor without over-treating with therapies that can be toxic and harmful in an adult, never mind a growing kid.

“We need to be able to sub-stratify the patients to predict outcome better,” Volchenboum said about the goals of his project. “There are probably some patients that will do poorly despite any conventional treatments, so let’s give this patient emerging therapy, let’s try something new. Likewise, there are some patients with apparent high-risk disease who get lots of therapy and are ultimately cured but may not have needed all that therapy.”

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Dr. Funmi Olopade and Dr. Mary Ann Malloy at the Harold Washington Public Library in Chicago, September 22, 2009 (photo by Rob Mitchum)

On Monday we previewed Dr. Funmi Olopade’s public lecture at the Harold Washington Public Library in Chicago titled “Nature, Nurture and Breast Cancer.” For that post, I talked about some recent work from Olopade’s research group that compared the types of breast tumors found in West African women with the tumors seen most often in black and white American women. That research indicated that there likely is a genetic difference between women of African origin and Caucasian, North American women that leads to fewer breast cancer cases but a  higher rate of aggressive, harder-to-treat tumors in black women here and abroad. But the patients from Senegal and Nigeria which Olopade’s group studied also showed different proportions of tumors when compared to African-American women, suggesting a strong role for environmental factors in causing breast cancer as well.

In her library appearance Tuesday evening with NBC reporter Dr. Mary Ann Malloy, Olopade expanded upon those mysterious “environmental factors” that likely contribute to the higher breast cancer numbers in North America. To a rapt audience, Olopade listed off the most well-known and common risk factors for breast cancer: age, family history and “the most important risk factor,” being a woman.

(Chicago Public Radio’s Chicago Amplified is supposed to post audio from Tuesday night’s event, but it’s not up yet. I’ll add a link when it’s available.)

But even to a crowd that, judging from their questions, was very well informed about breast cancer medicine and science, Olopade inspired gasps of surprise by rattling off some less-publicized environmental factors: breastfeeding, age at childbirth, even height. Many of these factors, in combination with more mundane things like lack of moderation in diet, exercise and alcohol intake, are behaviors more commonly seen in rich countries where women have achieved a more equal status in their work and private lives.

“I think what we’re still struggling with is, as we get more affluent and as people live the good life, then you see the rising incidence of breast cancer,” Olopade said. “We want people to have the good life, but what is it about the good life that is predisposing us to breast cancer?”

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Dr. Funmi Olopade

A fact often lost in the charity walks and commercials that have dramatically raised awareness of breast cancer over the past two decades is that beneath the diagnostic umbrella of  “breast cancer” are numerous types of tumors. Other than the fact that all of these tumors are found in breast tissue, different forms of breast cancer grow at different rates, will express different types of hormone receptors or genes that can act as drug targets, and are more or less likely to become “invasive,” spreading throughout the body. To complicate matters further, not every population experiences these different types of breast cancer in equal proportions - black women in the United States have a poorer survival rate for breast cancer than white women, and women in Africa  have an equal breast cancer mortality rate to North American women despite four times as many diagnoses of the disease in the U.S., Canada and Mexico.

University of Chicago Medical Center researcher Olufunmilayo Olopade (Funmi, for short) has dedicated her career to the study of these discrepancies since moving to Chicago from her home country of Nigeria in the 1980’s. Olopade, a professor of medicine and human genetics, has received several accolades for her work, including the prestigious MacArthur fellowship (known sometimes as the “genius grant”) in 2005. On Tuesday evening, she’ll give a lecture at the Harold Washington Library Center in Chicago titled “Nature, Nurture and Breast Cancer” that will explain what we know about the genetic and environmental factors that cause the disease in more than 200,000 American women each year.

In a recent Journal of Clinical Oncology paper, Olopade and colleagues from Chicago, Senegal and Nigeria looked for physiological reasons to explain the differences in breast cancer rates and outcomes between American and African populations. Learning more about these differences could help direct women into the most effective treatments for their particular type of breast cancer, Olopade said, as well as offer clues as to how genes versus the environment cause breast tumors to arise.

“Breast cancer doesn’t affect all individuals the same way,” Olopade said this past weekend, as she prepared for Tuesday’s lecture. “What we found is that the types of cancer that people get in different populations differ, that’s why when we talk about personalized medicine at an individual level we also have to talk about it on a population level.”

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As you’ve no doubt heard by now, actor Patrick Swayze died yesterday at age 57 after a battle with pancreatic cancer. In March, blog founder Jeremy Manier interviewed University of Chicago Medical Center physician Dr. Irving Waxman about pancreatic cancer, one of the deadliest and hardest to treat cancers. The challenge, as Waxman explains, is twofold - the symptoms of pancreatic cancer typically do not present until the disease is in advanced stages, and the organ’s location deep behind the abdomen makes makes surgical treatment more difficult. The statistics are sobering: even with treatment, only about 5% of those diagnosed with pancreatic cancer survive 5 years.

But doctors are hopeful that the momentum could be shifting in the battle against pancreatic cancer. “Smart chemotherapy” with less severe side effects, new imaging techniques to detect pancreatic cancer in its early stages, and new drug treatments - a study released just yesterday found that an already-existing diabetes medication may be effective in combination with chemotherapy for selectively killing tumor cells.

Here again is the interview with Dr. Waxman where he discusses the clinical challenges of pancreatic cancer and some of the promising frontiers of research to reduce those challenges.

The shortened "Philadelphia chromosome" seen in certain leukemias (picture from nature.com)

The big science news of the day was the announcement of the Lasker Awards, informally thought of as the American version of the Nobel Prize for physiology and medicine. This year’s clinical medical research award went to a trio of researchers from Oregon Health & Science University, Sloan-Kettering Cancer Center and drug company Novartis, but you could just as easily say it was awarded to a drug: the cancer treatment Gleevec. And Gleevec’s roots stretch back to the campus of the University of Chicago and a very familiar face on this blog: Janet Rowley.

This year, Rowley has already received the Presidential Medal of Freedom, the Gruber Genetics Prize and stood at President Obama’s shoulder as he repealed federal limitations on stem cell research. Oh, and she’s already won the Lasker Award herself, in 1998. So it’s okay that she’s not mentioned among today’s winners.

As with most stories of scientific discovery moving from the laboratory bench to the pharmacy, it’s simplistic to pin the achievement on one, three, or even ten people. The path to Gleevec’s discovery go back beyond Rowley to the 1950’s when Peter Nowell and David Hungerford - working at the University of Pennsylvania in Philadelphia - found an odd, shortened chromosome in patients with a form of cancer called chronic myelogenous leukemia (CML). They called that stubby piece of DNA, appropriately enough, the Philadelphia chromosome.

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In each cell of the body is a busy factory, containing all of the elements needed for that cell to develop and perform its unique function. A neuron sprouts a long extension and develops the ability to conduct electrical impulses. A liver cell secretes bile and can absorb toxic substances to neutralize them. Muscle cells elongate, form multiple nuclei and build long fibers that contract powerfully when stimulated.

But as different as the end product may be, the machines that make up the inner workings of these cells are largely the same, built from the identical set of genetic instructions that all cells share. Indeed, all of the body’s hundreds of cell types originate from one ambitious type of cell with the potential to become almost anything – the pluripotent stem cell to which so much scientific attention has been recently paid. What destiny that neutral cell follows is largely determined by how it organizes its factory, placing its machines in various orders that can have dramatically different outcomes.

Charting those interactions in specialized cells is a frequent goal of scientific research, as understanding a cell’s inner workings will help doctors make repairs when something goes wrong. The laboratory of Dr. Marcus Clark, chief of the Section of Rheumatology at the University of Chicago Medical Center, has devoted itself to the machinery of the B cell, the immune system cells responsible for producing antibodies that fight off disease. In a paper published this week in the journal Nature Immunology, Clark’s group fills in much of the story of what signals are involved in a crucial step of early B cell development, and shows that one of those signals, called Ras and typically associated with cancer in other cells, is surprisingly a key component in the healthy formation of a B cell.

“Ras is one of the best described oncogenes out there, it contributes to cancer in a variety of different formats.” Clark said. “It’s always seen as this pro-proliferative thing: if you put Ras in, the cells start dividing autonomously, and that’s cancer. In our hands, Ras turned off proliferation, it was very unexpected.”

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As reported everywhere today, Sen. Ted Kennedy died Tuesday night after a year-plus fight with malignant glioma, a type of brain cancer. The condition, in which tumor cells arise from glia cells of the brain, is known to be especially deadly and hard to treat - only about 16 percent of patients diagnosed with the condition survive five years. Treatment involves radiation, surgery and chemotherapy, but long-term survival is a challenge.

“In some cancers, the brain or pancreatic cells are multiplying at such a rapid rate,” said Dr. Maciej Lesniak, director of neurosurgical oncology at the University of Chicago Brain Tumor Center.  ”When you have a cancer that grows that rapidly, the prognosis can usually be measured in months or years at most. It’s always a battle between how quickly the cancer is growing and the available therapies.”

Those grim numbers have inspired many researchers to look at improved ways of treating brain tumors, employing some of the latest technologies available in biomedicine. One promising tool, currently being tested by Lesniak and scientists at Argonne National Laboratory, is the use of nanomaterials to target and kill tumor cells with minimal damage to nearby healthy tissue. A laboratory demonstration of this method was published last month in the journal Nano Letters.

“This paper overcomes a potential challenge in nanomedicine,” Lesniak said. “While nanotechnology is very interesting in terms of applications, targeting nanoparticles to specific parts of the body is a problem. They are so small, they can go anywhere.” read more

University of Chicago molecular geneticist Janet Rowley received her Presidential Medal of Freedom Wednesday along with 15 other honorees, including Stephen Hawking and Sen. Edward Kennedy. Here’s video of the ceremony, courtesy of C-SPAN…President Obama’s warm introduction is at 15:50, and he presents Dr. Rowley with the medal at 35:00:

Here is President Obama’s introduction:

“After graduating from the University of Chicago School of Medicine in 1948, Janet Rowley got married and gave birth to four sons, making medicine a hobby and making family a priority. It was not until she was almost 40 that she took up serious medical research, and not until almost a decade later that she discovered, hunched over her dining room table examining small photos of chromosomes, that leukemia cells are notable for changes in their genetics — a discovery that showed cancer is genetic and transformed how we fight the disease. All of us have been touched in some way by cancer, including my family, so we can all be thankful that what began as a hobby became a life’s work for Janet.”

Two Chicago TV stations have also done profiles of Dr. Rowley since the Presidential Medal honor was announced, which you can watch online:

WTTW, Ch. 11

ABC-7 Chicago

Gina Kolata has an interesting story in the New York Times today about the lack of volunteers for cancer research trials, but she left out a facet that has puzzled me: Even though few adults enter cancer studies, the vast majority of kids with cancer do get enrolled in trials. Why?

Kolata offers many possible reasons for the shortage of adult volunteers, including anxiety and a reluctance to make the extra office visits that a trial often requires. But those are factors in pediatric cancer too. And yet at least 75 percent of kids with cancer get enrolled in trials, compared with just 3 percent for adult patients. We did a piece recently for the University of Chicago Medical Center magazine describing how clinical trials have transformed pediatric cancer care for the better. Among other things, the studies probably raise adherence to treatment regimens because each center must document that participants follow the required course of therapy.

One likely reason for the adult-pediatric gap, as Kolata mentions, is that many adult patients are satisfied with existing treatments, especially for types of cancer with a good prognosis. If a regimen of surgery plus chemotherapy is likely to work, and patients can get the chemo at a local cancer treatment center, they’re less motivated to make the trip to a major research center conducting a trial.

But once again, the same factors could affect pediatric trials. Many pediatric treatments are highly successful, and parents would seem to have less incentive to enter their children in trials. Yet they do enter those trials, time after time.

Could one answer be that we adults are sometimes more hyper-vigilant about our children’s health than our own? Are we just more willing to suffer inconveniences for the sake of our kids? Perhaps entering a study that could result in extending the lives of other adult patients by a few months or years seems like insufficient payoff. But give those same months or years to a pediatric patient, and the calculus starts to look better, the time gained somehow more precious.

Maybe recruiters for cancer trials should try an experiment with prospective patients: Imagine you were making this decision not for yourself, but for your child. Would you be satisfied with the standard of care, or would you want to try something that might improve your child’s outcome, if only by a little? And if you would do it for your child (and most people do), why not do it for yourself?

You could say that Janet Rowley is having a pretty good year. In March, the University of Chicago molecular geneticist stood at President Barack Obama’s right arm as he signed an executive order clearing the way for federal funding of embryonic stem-cell research. Earlier this month, she was declared the winner of the 2009 Peter and Patricia Gruber Genetics Prize, which comes with a $500,000 cash award and a gold medal.

Today, another tremendous honor was announced for the still-active 84-year-old: the Presidential Medal of Freedom, the highest award an American civilian can receive from the White House. Among the other 15 recipients are Stephen Hawking, Sen. Edward Kennedy and Desmond Tutu; very prestigious company indeed.

In typical fashion, Rowley downplayed being recognized for her important research in the early days of cancer genetics.

“I felt very humbled, but also as though I didn’t deserve it,” Rowley said yesterday about her initial reaction to the honor. (You can watch the video interview with Dr. Rowley here: Janet Rowley talks about winning the Presidential Medal of Freedom)

With all due respect to Dr. Rowley, she’s wrong. When Rowley began to investigate the mysterious relationship between chromosomal abnormalities and leukemia in the 1960’s the scientific jury was still out on the relationship between genes and cancer. It was known that patients with certain types of leukemia had unusual chromosomes — notably the shortened “Philadelphia Chromosome,” associated with chronic myelogenous leukemia (CML) — but scientists debated whether that was the cause of the cancer or the result.

After starting a laboratory at the University of Chicago with help from legendary hematologist Dr. Leon Jacobson, Rowley used the newest chromosome-staining techniques to discover that the genetic segment missing from the Philadelphia Chromosome had not disappeared, but instead traded places with a segment from another chromosome in a process called translocation. This swap was not merely cosmetic; the gene for a particular protein that promotes cell division was separated from its natural genetic brake, causing the uncontrolled cell proliferation characteristic of cancer.

Rowley’s landmark paper on CML was published in 1973, but only after rejection by at least two scientific journals unconvinced of her findings. Eventually, chromosomal translocations were found to be responsible for several different cancers, and the concept of cancer as a genetic disorder became widely accepted in medicine. Her research also led to the development of the anti-cancer drug imatinib, aka Gleevec, which acts by inhibiting the protein that is excessively activated after the translocation.

For much of the past decade, Rowley served on President George W. Bush’s Council on Bioethics, advising the White House on controversial scientific topics such as embryonic stem-cell research. Having long opposed Bush’s limitations on federal funding for such studies, Rowley celebrated Obama’s loosening of those restrictions, writing for US News & World Report that the decision “has removed a key barrier to research and discovery.”

Rowley continues her research at the University of Chicago, and is an avid swimmer, sailor, cyclist and gardener. When I interviewed her for a Chicago Tribune article on the Gruber prize in late June, she said, in her understated way, that she was flattered to receive such awards and surprised that her work was still being acknowledged.

“It’s a great honor to have one’s colleagues still recognize one’s accomplishments,” Rowley said. “I suppose it’s a great pleasure to be around to be recognized.”

This announcement from the National Cancer Institute could be very big news at cancer research centers like this one. The increase, which NCI director John E. Niederhuber described in a speech at the meeting of the American Association for Cancer Research, will be part of the economic stimulus package.

Here’s an interesting passage from the story in The Scientist:

In 2009 the agency will be able to fund the top 16% of grant applications instead of only the top 12%–last year’s payline–based on budgetary increases alone, Niederhuber said. The NCI may be able to fund 25% of applications with the added $1.3 billion that the agency is set to receive as part of the $10 billion in stimulus funding for the National Institutes of Health. 

But raising the payline is only half the story. “Economic stimulus funds give us the chance to be visionary,” Niederhuber said, adding that the NCI will seek to fund more young, first-time investigators, and will emphasize prevention and early diagnosis in the research it supports in the future. “Patients still need better treatments, better prevention, and better early detection,” he said. “We must recommit ourselves to answering that call.” 

Neuroblastoma patients recently got some of the best research news they’ve had in a while - but the news wasn’t perfect for everyone.

Word of the advance came in an announcement last month from the national Children’s Oncology Group. A Phase III trial of an antibody-based treatment for neuroblastoma (protocol ANBL0032) had found that the treatment significantly increased patients’ chances of survival. The trial was immediately halted - standard procedure in cases where a trial is so successful that it would be unethical to deny patients the treatment.

The antibody treatment yielded a striking survival gain of about 20 percent for children with the deadly form of cancer. Neuroblastoma researchers such as Susan Cohn, M.D., were elated.

“This is as successful a story as we’ve had in neuroblastoma treatment in many, many years,” Cohn told me in a recent interview. “We hope to be able to incorporate this as part of our standard approach.”

The protocol is on hold to study toxicity issues that arose in some patients, but experts hope the treatment will be available soon for more patients. The March 19 statement from COG concluded, “We now expect that this immunotherapy may eventually become a standard part of high-risk neuroblastoma treatment after stem-cell transplant.”

So what’s the downside? It’s simply the nature of such clinical trials, in which not everyone can get the superior treatment.

Patients are randomized at the start of a trial like this one; some get the new treatment, some get the standard, established protocol. Some families opt out altogether. No one knows at the outset whether the new protocol will be better, the same or perhaps worse than the existing treatment.

But it’s clear now that in this case, patients who got the new protocol stood a markedly better chance of surviving their cancer than those who stayed with the old form of treatment. A 20 percent improvement is no guarantee, of course; some patients on the new protocol died, and many who got the existing treatment did fine. Yet an outcome like this can raise a tantalizing “what-if” question in the minds of some parents. Might a child have had a better chance at survival if randomization had placed him or her in the new treatment group? What about parents who may feel guilt over not taking part in a trial that could have improved their child’s outcome?

Such doubts may be impossible to resolve. It’s difficult to imagine replacing randomized trials as the gold standard for gathering scientific evidence that a treatment works.

“You just never know until you do the study,” Cohn said. “We are so grateful to the families who are willing to participate in these trials.”