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October 5, 2010 • Volume 7 / Number 19

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An illustration that shows how nicotine attaches to nerve cells in the brain at receptors on the cell membrane. Experts Urge Further Research on Nicotine Reduction to Decrease Tobacco Addiction

Tobacco control experts are calling for additional research on reducing the nicotine content of cigarettes and other tobacco products. Nicotine reduction, they wrote in an article published online October 1 in Tobacco Control, has the potential to profoundly affect smoking rates in the United States, but many outstanding questions remain and will require a focused and collaborative research effort. Read more > >

Science Shots

An image of the vasculature of a tumor grown in a mouse, as seen with a Zeiss LSM 510 confocal microscope. The tumor cells were genetically labeled with Cerulean, and the tumor vasculature was illuminated with Dextran-fluorescein isothiocyanate. What is this? Click on the image to find out.
An image of the vasculature of a tumor grown in a mouse, as seen with a Zeiss LSM 510 confocal microscope. The tumor cells (blue) were genetically labeled with Cerulean, and the tumor vasculature (green) was illuminated with Dextran-fluorescein isothiocyanate. (Image courtesy of Dr. P. Charles Lin of NCI-Frederick)



  • Update

    • NCI Launches Redesigned Science Serving People Web Site
  • Notes

    • NCI to Host Science Writers’ Seminar on Human Papillomavirus
    • NCI Launches Next Phase of Nanotechnology Program
    • NCI Awards Grants to Increase Public Awareness of Pediatric Cancers
    • President’s Cancer Panel Discusses Future of the National Cancer Program

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

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Featured Article

Experts Urge Further Research on Nicotine Reduction to Decrease Tobacco Addiction

An illustration that shows how nicotine attaches to nerve cells in the brain at receptors on the cell membrane. Nicotine attaches to nerve cells in the brain at receptors on the cell membrane, initiating a series of electrical and chemical signals that trigger release of dopamine by other brain cells. Dopamine plays a role in the reinforcing effect of nicotine on the brain. Reducing the amount of nicotine in cigarettes and other tobacco products may reduce their addictiveness. (Source: NIDA Notes Vol. 20, No. 2 August 2005)

Tobacco control experts are calling for additional research on reducing the nicotine content of cigarettes and other tobacco products. Nicotine reduction, they wrote in an article published online October 1 in Tobacco Control, has the potential to profoundly affect smoking rates in the United States, but many outstanding questions remain and will require a focused and collaborative research effort.

Momentum for examining nicotine reduction (a decrease in the amount of legally allowed nicotine per cigarette to levels that do not initiate or sustain addiction) grew with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009. The Act gave the FDA regulatory authority over the manufacturing, marketing, and sale of tobacco products in the United States. This regulatory authority includes setting standards for the ingredients of tobacco products, including nicotine, the main substance responsible for tobacco’s addictive nature.

“Of all the measures that could be taken under the FSPTCA, reducing the addictiveness of cigarettes has the greatest potential to significantly reduce tobacco-related mortality,” said the article’s lead author, Dr. Dorothy Hatsukami, principal investigator of the NCI-funded Transdisciplinary Tobacco Use Research Center (TTURC) at the University of Minnesota.

“If you do that,” she continued, “you could prevent people who experiment with cigarette smoking from becoming dependent, and you would also facilitate cessation among those who are already dependent.”

Two meetings, held in 2007 and 2009 and sponsored by NCI’s Tobacco Harm Reduction Network and the University of Minnesota TTURC, brought together experts from diverse disciplines to review the scientific evidence on nicotine reduction and identify priorities for future research. Their recommendations appear in the October 1 paper. (See the box at the bottom of the page.)

“We wanted to bring people in the field together to identify research needs,” said Dr. Cathy Backinger, chief of NCI’s Tobacco Control Research Branch and a co-author of the paper. “Because it’s not clear yet what the best approach is to reducing nicotine in cigarettes, nor what effects doing so will have, we need a multidisciplinary group to answer the questions we identified.”

To date, research on nicotine reduction has provided some evidence to support the concept that it could reduce the addictiveness of cigarettes. Studies have shown that very-low-nicotine cigarettes can minimize withdrawal symptoms in smokers who switch to these cigarettes and that they also reduce the number of cigarettes smoked in the long term, as smoking ceases to provide the expected rewards.

In one study, 25 percent of participants quit smoking even though they had not enrolled in the study with the intent to quit. (The trial was intended to test the effects of cigarettes with progressively lower nicotine content on the exposure to carcinogens.) And recently published preliminary data from another clinical trial showed that 36 percent of participants given cigarettes containing 0.05 mg of nicotine as a smoking cessation aid remained abstinent 3 months after treatment, compared with 20 percent of participants using a 4 mg nicotine lozenge.

A major unanswered question remains: What is the threshold dose of nicotine associated with addiction? Complicating the question is the likelihood that this dose may be different for adults and for adolescents, whose developing brains may be more sensitive to the addictive effects of nicotine. “Men also may have a different threshold dose compared with women, and it might even differ between races,” explained Dr. Hatsukami. “Clearly we need additional research in this area.”

Researchers also need to determine whether chemicals other than nicotine produce some of the reinforcing addictive effects of tobacco. Chemicals found in tobacco, such as nornicotine, anabasine, and monoamine oxidase inhibitors, may mediate the reinforcing effects of nicotine or have effects of their own.

“Eventually, we may not just think about reducing nicotine levels; we may actually think about measuring and reducing the overall addictiveness of cigarettes,” said Dr. Hatsukami. “That would cover a number of constituents or any other chemicals that could be added to a tobacco product to make it addictive.

“One of the main points of this article was to make people aware that we need to be very strategic and comprehensive in this research, in order to either support or refute the concept of nicotine reduction,” she continued. “It’s a call for research and also a call to provide resources to look at this area because of the potentially profound effect it could have on public health.”

—Sharon Reynolds

Nicotine Reduction Research Questions

In an article that appeared October 1 in Tobacco Control, experts in the field identified many outstanding questions relevant to nicotine reduction research and compiled a subset of questions for a proposed research agenda, including:

  • What is the threshold nicotine dose for addiction in different populations (e.g., adolescents and adults)?
  • What other influences (e.g., environmental cues) affect the threshold nicotine dose?
  • What are the effects of reduced-nicotine cigarettes on the brains of both adults and adolescents, including the nicotine receptors?
  • Can reduced-nicotine cigarettes cause compensatory smoking (for example, smoking more cigarettes or inhaling more deeply), and if they do, can such behavior be reduced with concurrent use of nicotine-replacement therapy or other interventions?
  • What effects do reduced-nicotine cigarettes have on vulnerable subpopulations of smokers (e.g., those with mental illness or those severely addicted to tobacco products), and how can potential negative consequences in these populations be safely managed?
  • What tobacco product ingredients and design features influence addictiveness in addition to nicotine or in concert with nicotine?
  • How would the public react to a marketplace containing only reduced-nicotine cigarettes?
  • How could the public health value of reduced-nicotine cigarettes best be communicated to the general population?
  • What are the potential unintended consequences from widespread introduction of reduced-nicotine cigarettes, and how can they be monitored and mitigated?

Cancer Research Highlights

Less-invasive Lymph Node Surgery Safe for Women with Breast Cancer

In the largest randomized surgical trial in breast cancer patients to date, women with biopsies that detected no cancer cells in their sentinel lymph nodes (SLN) who forwent axillary lymph node dissection (ALND) had the same overall survival 8 years after treatment as women who had ALND. The trial results were reported online September 20 in Lancet Oncology.

Researchers led by Dr. David Krag of the University of Vermont enrolled 5,611 women between 1999 and 2004 in the NSABP B-32 trial, which was designed to test whether women with negative SLN biopsies would have the same survival as women who had negative SLNs followed by ALND, a more invasive procedure that carries a greater risk of side effects including lymphedema and nerve damage. The women studied were randomly assigned to undergo SLN surgery plus ALND (group 1), or SLN surgery followed by ALND only if cancer cells were detected in the sentinel nodes (group 2).

A total of 3,986 patients had no apparent cancer cells in their sentinel lymph nodes. After 8 years of follow-up, 54 women in group 1 had a local recurrence of their cancer, compared with 49 women in group 2. Eight women in group 1 had cancer recur in the lymph nodes closest to the site of surgery (the regional lymph nodes), compared with 14 women in group 2. The estimated 8-year overall survival was 91.8 percent in group 1 and 90.3 percent in group 2. These differences were not statistically significant.

In an accompanying editorial, Dr. John Benson of the University of Cambridge in the United Kingdom explained that more than 80 percent of the women in the trial had small tumors (2 centimeters or less in diameter), which tend to have a lower risk of recurrence. Therefore, “the conclusions of this trial in terms of the appropriateness, safety, and effectiveness of SLN biopsy are justified for this population but might not necessarily apply to patients with larger…or multifocal tumors who commonly undergo SLN biopsy,” he cautioned.

HPV Screen-and-Treat Methods Prevent Cervical Cancer Precursors in Low-resource Settings

Women who were treated with cryotherapy immediately after testing positive for high-risk human papillomavirus (HPV) DNA or who had precancerous lesions detected by visual inspection of the cervix had large and statistically significant reductions in high-grade cervical cancer precursors compared with women who did not have immediate treatment, researchers from Columbia University recently reported. The long-term results of the randomized screening trial were reported online September 30 in the Journal of the National Cancer Institute.

A research team led by Dr. Thomas Wright, Jr., followed 6,637 South African women between the ages of 36 and 65. Cervical samples from all women were tested for the presence of high-risk HPV DNA; all women also underwent visual inspection of the cervix. The women were then randomly assigned to one of three study groups: DNA test-and-treat, in which women with an HPV-positive DNA test were treated with immediate cryotherapy; visual inspection-and-treat, in which women with precancerous lesions were treated with immediate cryotherapy; or control, in which further evaluation and treatment were delayed for 6 months. All women had colposcopy with biopsy at 6 months, and a subset of women, including all of those who were HPV positive or visual-inspection positive at study entry, were followed for 36 months.

After 36 months, the cumulative risk for advanced cervical lesions (CIN2+) was 73 percent lower among women in the DNA test-and-treat arm than in women in the control arm. By comparison, the risk of advanced lesions was reduced by 32 percent in the visual inspection arm compared with the control arm.

“These results suggest that cryotherapy may have long-term implications for low-resource settings where it is difficult and costly to re-screen women at regular intervals,” the researchers wrote.

The researchers also observed an increase in HIV infection in women in both screen-and-treat groups compared with women in the control group. However, this increase was not statistically significant. The authors recommended that this association be carefully evaluated in screen-and-treat programs conducted in settings where the incidence of HIV infection is high.

In an accompanying editorial, Drs. Julia Gage and Philip Castle of NCI’s Division of Cancer Epidemiology and Genetics noted that although there is an HPV vaccine, it will be decades before the vaccine will have an impact on cervical cancer rates globally, making screen-and-treat approaches a valuable tool for preventing cervical cancer in some areas of the world.

“Screening women with simpler, more robust technologies and immediately treating those who screen positive can reduce the incidence of cervical cancer in the population,” said Dr. Castle. “That’s the kind of approach we need in a developing country where resources for prevention programs are limited.”

Black Patients with Advanced Cancer Are More Likely to Receive Unwanted Care at End of Life

Compared with black patients who have advanced cancer, “white patients appear to have undefined advantages when it comes to receiving end-of-life care that reflects their values,” concluded the authors of a prospective longitudinal cohort study. Findings from the study, which was carried out at a number of hospitals and major cancer centers in the Northeast and in Texas, were published September 27 in the Archives of Internal Medicine.

The researchers found that, although black patients discussed end-of-life issues with their doctors as often as white patients, black patients were more likely to prefer life-prolonging care and less likely to have do-not-resuscitate (DNR) orders after the discussions. Moreover, black patients with DNR orders were just as likely as black patients without DNR orders to receive life-prolonging end-of-life care.

Between 2002 and 2007, Dr. Jennifer W. Mack of the Dana-Farber Cancer Institute and her colleagues interviewed 71 black and 261 white patients who were enrolled in the Coping with Cancer Study. All of the patients had metastatic cancer and were no longer responding to chemotherapy, and all of the patients died during the course of the study.

Through interviews, the researchers established the extent to which patients had discussed end-of-life issues with their doctors, their awareness of terminal illness, whether they had DNR orders, and whether they preferred life-prolonging care at the end of life, even if it would cause more pain and discomfort, or symptom-directed care (relief of pain and discomfort only). What actually happened at the end of life was gleaned from medical records and caregiver interviews.

The researchers noted that issues beyond patient–physician communication, such as continuity of care or preconceived notions among health care providers about patient preferences, could explain the racial disparity in the translation of preferences into the actual care received at the end of life. “These issues should remain a topic of ongoing research and a priority for physicians who care for patients at the [end of life],” they concluded.

Genetic Study Finds Clue to Gastrointestinal Stromal Tumors

Researchers have identified a gene called ETV1 that may contribute to the development of some types of gastrointestinal stromal tumors (GISTs). Although preliminary, the findings suggest that ETV1 could be a marker for diagnosing the disease and may also be a potential therapeutic target. Drs. Charles Sawyers of Memorial Sloan-Kettering Cancer Center (MSKCC) and C. David Allis of Rockefeller University and their colleagues reported their findings online in Nature on October 3.

The researchers discovered the gene while searching gene expression data sets for GIST-specific genes. Among 11 such genes that appeared in three data sets was ETV1, which is a member of the ETS family of transcription factors—genes that regulate the activity of other genes. This gene was of immediate interest because overexpression of other ETS transcription factors has been associated with prostate and other cancers. ETV1 was highly active in all the GIST tumor samples and cell lines they examined and in the cells where these tumors may originate. Further experiments then showed that ETV1 was essential for the growth and development of GISTs.

In addition, the researchers found that the transcription factor may cooperate with the product of the KIT gene in the development of GIST. Most GISTs harbor mutations that activate KIT, but these mutations alone are not sufficient to cause GIST. The reason could be that KIT mutations promote the development of cancer only in the presence of high levels of ETV1 expression, according to co-author Dr. Yu Chen of MSKCC.

“These findings establish an oncogenic role for ETV1 in GIST,” the authors concluded. Although transcription factors have been considered “undruggable,” recent studies have begun to challenge this idea, they noted.

See: New Drug Blocks “Undruggable” Target in Cancer Cells

Special Report

Studies Provide New Data on Mammography and Breast Cancer Mortality

A woman receiving a mammogram Mammography can reduce mortality from breast cancer, but the magnitude of benefit may differ across age groups and as treatment improves.

Two Scandinavian studies present new information about the extent to which routine mammography in different age groups can reduce the risk of death from breast cancer. However, several researchers cautioned that, because both studies were observational, they have limitations that can affect how the findings are interpreted and are unlikely to resolve the controversy over the extent of mammography’s benefit in reducing breast cancer mortality.

The studies examined the effect of routine mammography in regions of Sweden and Norway where breast cancer screening programs were rolled out over time, county by county. Whereas the Swedish study focused strictly on routine mammography’s impact on breast cancer deaths among women age 40 to 49, the Norwegian study analyzed mammography’s mortality benefit in an older age group and took into account the broader context of changes in breast cancer awareness and improvements in treatment over time. (See the box at the bottom of the page.) The studies came to different conclusions, with the Swedish study finding that routine mammography screening greatly reduced breast cancer mortality in young women and the Norwegian study finding a much smaller reduction in women age 50 to 69.

Although the two studies looked at different age groups and had disparate results, “they both show that fewer women are dying of breast cancer in the presence of screening,” said Dr. Stephen Taplin of NCI’s Division of Cancer Control and Population Sciences. And although it’s been known that mammography can reduce mortality, he continued, “what has been changing is the recognition that the magnitude of that benefit may differ across age groups and that treatment has been making gains.”

Looking at a Younger Population

The Swedish study, dubbed SCRY, came to the conclusion that there was a 29-percent reduction in breast cancer deaths in women age 40 to 49 who underwent screening compared with women who were not invited to undergo screening. Approximately 1,250 women had to undergo screening to prevent or delay one death from breast cancer, reported the study’s senior author, Dr. Hakan Jonsson, at the American Society of Clinical Oncology’s 2010 Breast Cancer Symposium in Washington, DC. The study results also appeared online September 29 in Cancer.

“This report clearly shows a benefit to screening mammograms in this age group,” wrote American Cancer Society Deputy Chief Medical Officer Dr. Len Lichtenfeld, on his blog. But he also acknowledged that there would “be considerable discussion among the experts about what is right with this study and what may be questionable, what questions it answers, and what questions remain open.”

According to Dr. Barry Kramer, associate director for disease prevention at NIH, the way in which the data were analyzed could have led to a substantial overestimation of mammography’s mortality benefit. To calculate the excess number of breast cancer deaths among women in counties without routine screening versus those in counties with it, he noted, the researchers compared only those breast cancer deaths that occurred in women who had been diagnosed with breast cancer (typically via mammography) rather than comparing the overall breast cancer mortality rates in each county. Because mammography can detect nonlethal cancers, “their analysis would not take into account the overdiagnosis associated with screening,” Dr. Kramer explained. “That’s not a subtle issue. It’s an important bias that would favor screening.”

Other methodological issues, Dr. Kramer continued, such as not adjusting the analysis for differences in breast cancer deaths in the counties before routine screening was implemented and socioeconomic and county-level resource differences that likely influenced whether screening was offered, could also have inflated the mortality benefit associated with mammography.

Whether women between the age of 40 and 49 should undergo routine mammography has been a matter of much debate and discussion. In November 2009, the U.S. Preventive Services Task Force (USPSTF) issued updated guidelines on breast cancer screening that recommended that women ages 50 to 74 get a mammogram every 2 years. But the task force did not endorse routine mammography for women in the 40 to 49 age group who have average breast cancer risk, noting that the absolute risk reduction is less in younger than older women and that false-positive results are a greater concern in younger women. Instead, the decision about mammography for these women “should be an individual one and take patient context into account,” the task force recommended. Some cancer organizations, including the American Cancer Society and the National Comprehensive Cancer Network, continue to recommend annual mammography for women age 40 to 49.

Many women in this age group “want unambiguous recommendations regarding whether to undergo mammography,” said Dr. Jennifer Obel from NorthShore University HealthSystem in Illinois during a press briefing on the study results. “I think the critical message is that all women, beginning at age 40, should speak with their doctors about mammography to try to understand the potential benefits and risks of the test and to determine what is best for them as individuals.”

Closer Scrutiny of an Older Population

Meanwhile, Dr. Mette Kalager and her colleagues from Oslo University Hospital in Norway found that routine mammography in women ages 50 to 69 reduced breast cancer deaths, but only modestly. The findings appeared online September 23 in the New England Journal of Medicine.

Based largely on clinical trials conducted in the late 1980s and early 1990s, the mortality reduction associated with routine mammography in this age group has been estimated to be as high as 25 percent. But the Norwegian study found that implementation of a screening program was associated with a 10-percent reduction in breast cancer mortality. Breast cancer mortality was reduced by another 18 percent over the same time period, even in counties that had not implemented the screening program. This component of the reduction was likely due to greater awareness of breast cancer and improvements in treatment, such as adjuvant therapy, the authors concluded.

Dr. Taplin agreed that treatment likely played a role in the mortality improvements. As part of the screening program in Norway, dedicated interdisciplinary breast cancer management teams were also established in each county. “The fact that organized support may have contributed to mortality reduction also suggests that it is needed, so we need to be testing these approaches here [in the United States],” Dr. Taplin said.

The Norwegian study avoided some of the methodological issues seen in the Swedish study, Dr. Kramer explained. Dr. Kalager’s team used population-based breast cancer death rates and compared mortality in each county before and after the implementation of routine mammography; these features “add to the strength and plausibility of the data,” Dr. Kramer said.

The Norwegian findings suggest that it “is quite plausible that screening mammography was more effective in the past than it is now,” wrote Dr. H. Gilbert Welch of Dartmouth Medical School in an accompanying editorial. “If women with new breast lumps now present earlier for evaluation, the benefit of screening will be less. If treatment of clinically detected breast cancer (i.e., tumors that are detected by means other than screening) has now improved, the benefit of screening will be less.”

The average follow-up after diagnosis was 2.2 years in the Norwegian study, which makes it difficult to draw definitive conclusions from it, Dr. Taplin cautioned. Longer follow-up is needed to get a clearer picture of screening’s impact on mortality, he noted.

As part of its ongoing efforts to evaluate mammography, Dr. Taplin explained, NCI is developing a new initiative called Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) to evaluate how to improve the screening processes for breast cancer (as well as colon and cervical cancer) in the U.S. community practice setting. “While we are saving more lives, we are losing too many,” he said. “So we must continue to work harder to improve screening techniques, treatment approaches, and the coordination of care.”

Carmen Phillips

Finer Details of the Studies

In 1996, Norway began to roll out, county by county, a breast cancer screening program for women age 50 to 69. Women could receive a mammogram every 2 years and multidisciplinary breast cancer management teams were established in each county before routine screenings were offered.

More than 40,000 women diagnosed with breast cancer between 1986 and 2005 were included in the Norwegian screening study. There were four groups of women: those in counties with established screening programs between 1996 and 2005, those in counties awaiting screening programs between 1996 and 2005, and those in two historical control groups living in the same counties between 1986 and 1995. The comparison of the two “current” groups allowed the researchers to avoid confounding by factors that can change over time, such as treatment and awareness that might be associated with a reduction in breast cancer mortality. The use of the historical groups allowed the researchers to adjust for differences between the counties in factors such as rates of death from breast cancer and to achieve equal follow-up time in each county. The average follow-up duration was slightly more than 2 years after diagnosis, and the longest was nearly 9 years.

Compared with women in the corresponding historical control group, women in the current screening group had a 28-percent relative reduction in breast cancer mortality (breast cancer mortality was 25.3 per 100,000 person-years in the historical control but 18.1 per 100,000 person-years in the screened group, a difference of 7.2 deaths per 100,000 person-years). For women in the current unscreened group, however, breast cancer mortality was also reduced substantially compared with that in the historical control group; in this case, there was an 18-percent relative reduction in mortality (26.0 versus 21.2 deaths per 100,000 person-years, a difference of 4.8 deaths per 100,000 person-years).

As a result, the authors concluded, only “the overall between-group difference [of 2.4 deaths per 100,000 person-years] can be attributed to the screening program alone, representing a third of the total estimated reduction in mortality (2.4 of 7.2).” In other words, the screening program resulted in an absolute 10-percent decline in breast cancer mortality.

The Swedish study was different in that it directly compared breast cancer deaths among women diagnosed with breast cancer at age 40 to 49 in counties that offered routine mammography (the study group) with those in counties that didn’t offer routine mammography (the control group). Beginning in 1986, invitations for routine mammography were mandated for women ages 50 to 69 but were voluntary for the younger age group.

Over the course of the Swedish study, 1986 to 2005, data from more than 1 million women were analyzed. Average follow-up was more than 14 years. There were 803 breast cancer deaths among diagnosed women in the study group (during 7.3 million person-years) and 1,238 such deaths in the control group (8.8 million person-years). There was a 29-percent reduction in breast cancer deaths among women who actually underwent screening and a 26-percent reduction in breast cancer mortality when the analysis was restricted to those women who were invited to receive screening.

A Closer Look

Turning the Immune System against a Childhood Cancer

Jessica Mason performs steps to purify the ch14.18 antibody in the Biopharmaceutical Development Program facility at NCI-Frederick. Jessica Mason performs steps to purify the ch14.18 antibody in the Biopharmaceutical Development Program facility at NCI-Frederick.

In the spring of 2009, Dr. Alice Yu received a phone call from the statisticians monitoring a randomized clinical trial she was leading for children with neuroblastoma. The trial was testing an experimental treatment that stimulates the patient’s immune cells to attack tumor cells, an approach that Dr. Yu had been developing and championing for more than 20 years at the University of California, San Diego Medical Center.

“I knew the phone call was going to be good news or a dead end,” recalled Dr. Yu. The news, it turned out, was good. An interim analysis had shown a clear benefit: 66 percent of patients who received the immunotherapy plus standard treatment were alive and free of the disease 2 years later compared with 46 percent of those who had received standard therapy alone.

Reporting their findings in the September 30 New England Journal of Medicine (NEJM), the researchers concluded that the immunotherapy improved survival in children newly diagnosed with neuroblastoma who were at high risk of developing a recurrence and who responded to initial treatment with standard therapies.

Neuroblastoma is the most common cancer diagnosed during the first year of life. The disease arises in the developing cells of the sympathetic nervous system, often leading to tumors in the neck, chest, or abdomen, along with metastases at the time of diagnosis in high-risk patients. Approximately 700 new cases of neuroblastoma are diagnosed in the United States each year, and nearly half of patients have the high-risk form of the disease, with a likelihood of cure around 30 percent (compared with 50 to 90 percent for patients with intermediate- or low-risk disease).

“This trial was a major landmark for a terrible disease,” said Dr. Yu, who conducted the study of 226 patients with her colleagues in the Children’s Oncology Group (COG). After the interim analysis last year, randomization was stopped and the researchers made the immunotherapy available to all eligible patients.

Testing an Idea

The immunotherapy regimen has gone through many versions since Dr. Yu began testing the concept in the late 1980s. The current treatment uses a monoclonal antibody called ch14.18, which binds to a lipid called GD2 on the surface of neuroblastoma cells. This approach enables immune cells to attack the cancer.

Children who received the immunotherapy had already responded to initial treatment with chemotherapy, radiation, and stem cell transplantation. To enhance the killing of cancer cells, the researchers gave the antibody with two immune-stimulating agents, the cytokines GM-CSF and interleukin-2 (IL-2).

“To see the best antitumor effect of the therapy, we wanted to activate as many immune cells that could kill tumor cells as possible,” said co-author Dr. Paul Sondel of the University of Wisconsin, Madison. “The immunotherapy is providing a clear benefit, but it’s not yet the complete answer. Forty percent of patients who are eligible for the therapy are relapsing and dying, so we need to do better.”

To understand why some patients recur within 2 years and others don’t, the researchers are studying the tumors and immune responses of patients, hoping to identify biological markers of response and clues that could make the therapy more effective.

Another challenge is to reduce the side effects of the immunotherapy, such as the pain caused by the antibody and the cytokines. “The side effects are substantial, but we have learned how to manage the pain so that the treatment can be given safely without severe pain,” said Dr. Yu, who noted that less-toxic versions of the immunotherapy are in development.

Persistence and Cooperation Pay Off

The ch14.18 antibody is filled, stoppered, capped, and sealed prior to labeling and distribution to the NCI Clinical Trials Evaluation Program. The ch14.18 antibody is filled, stoppered, capped, and sealed prior to labeling and distribution to the NCI Cancer Therapy Evaluation Program.

The fact that the ch14.18 antibody remained in development as a neuroblastoma treatment is a testament to the persistence and cooperation of Dr. Yu and her COG colleagues. Twice, the small pharmaceutical company that was producing the antibody for early-stage trials was bought by a bigger company, and the second time the producer stopped making the antibody.

A turning point came in 1996, when Dr. Yu flew to Washington, DC, her luggage packed with x-rays and pathology slides from patients in the early-stage trials. A panel of experts examined this evidence and recommended that NCI support the continued development of the antibody-based immunotherapy.

“I’m very grateful for the committee’s decision, because otherwise this antibody would have died,” said Dr. Yu. When no pharmaceutical company was willing to manufacturer ch14.18 for the phase III COG trial, NCI began to produce the agent for the study. 

“So much of the credit for the success of this study goes to researchers like Dr. Alice Yu and Dr. Paul Sondel, who laid the groundwork and showed that the use of cytokines can make the antibody more active when [these are] given together,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program (CTEP).

But the antibody’s history also illustrates the unique role NCI can play in developing more effective treatments for rare diseases such as childhood cancers, he added. NCI supported research from the discovery stage through the phase III study that proved the treatment’s efficacy. NCI then ramped up production of the antibody to have enough for every patient eligible for the therapy, he noted.

The Silver Spring, MD-based United Therapeutics Corp. will take over the manufacturing of ch14.18 and be responsible for obtaining FDA approval for its use in treating high-risk neuroblastoma patients.

25 Years in the Making

Dr. Ralph A. Reisfeld identified GD2 as a potential target for immunotherapy in 1985, and it took nearly 25 years to prove the concept in the clinic. But the researchers point out that the current study could now be a model for testing monoclonal antibodies such as rituximab, trastuzumab, and cetuximab in combination with cytokines as part of therapy for other cancers.

“Based on our results, we think that it might make sense to test these monoclonal antibodies in combination with GM-CSF and IL-2 in the appropriate patients who do not have bulky tumors,” said Dr. Sondel. Most of the responders in the current trial were in remission or had minimal evidence of cancer following the extensive first-line therapy.

“Although it took 25 years to get an answer, neuroblastoma is a rare disease, and it was terrific that we were able to get an answer,” Dr. Sondel noted. He attributed success largely to cooperation among the COG investigators and NCI support and involvement.

Despite the many challenges along the way, Dr. Yu always believed in the approach after seeing patients improve in the early-stage trials. “Some patients in those early trials were supposed to be doomed, and yet they are still alive today,” she said. “A patient from Tennessee came to see me when he was 2 years old, and he is now 22.”

—Edward R. Winstead

See also: "An Experimental Treatment Improves Survival for Patients with Neuroblastoma"

Also in the Journals: Reduced Doses Effective in Lower-risk Neuroblastoma Patients

Substantially lower doses and duration of chemotherapy were as effective as more intensive treatments for neuroblastoma in patients with an intermediate risk of recurrence, researchers reported last week in the New England Journal of Medicine. The patients in the prospective, nonrandomized trial received reduced doses of chemotherapy and no radiation therapy, which had been used in the past. The goal was to determine whether a 3-year estimated overall survival of more than 90 percent could be maintained with reductions in chemotherapy dose and duration and with biologically based treatment assignments.

The average 3-year overall survival of patients in the trial was 96 percent. “We maintained outstanding survival rates for these patients by dramatically reducing the amount of chemotherapy and by eliminating radiation therapy,” said co-author Dr. John Maris of the Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine.

Taken together, this trial and Dr. Yu's trial show that researchers may need to consider the risk levels of patients when developing therapies, according to Dr. Maris. For the intermediate-risk group, the goals were to reduce doses and achieve a cure without toxicity. But for the high-risk patients, the goal was to use more targeted approaches because the standard treatments for this group had already reached the maximum levels of tolerable toxicity for patients.

Featured Clinical Trial

Preventing Chemotherapy-related Hearing Loss in Young Cancer Patients

Name of the Trial
Phase III Randomized Study of Sodium Thiosulfate in Preventing Ototoxicity in Young Patients Receiving Cisplatin Chemotherapy for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy (COG-ACCL0431). See the protocol summary.

Dr. David Freyer Dr. David Freyer

Principal Investigator
Dr. David Freyer, Children’s Oncology Group

Why This Trial Is Important
The chemotherapy drug cisplatin is a key part of treatment for many children and adolescents with cancer. However, treatment with cisplatin carries the risk of serious side effects, including irreversible hearing loss (ototoxicity). Although this drug can cause hearing loss in patients of all ages, children younger than age 5 are especially susceptible to cisplatin-induced ototoxicity. Hearing loss among young children is a particular concern because it interferes with their ability to learn language skills and acquire other knowledge and can result in lifelong disability and impaired quality of life.

Cisplatin-induced ototoxicity usually develops in both ears and typically progresses from losing the ability to hear high-frequency sound to losing the ability to hear low-frequency sound as the total cumulative dose increases. Some children develop high-frequency hearing loss with as little as one dose. As hearing loss progresses, the frequency range for understanding human speech is commonly affected.

Unfortunately, the cisplatin doses needed to treat many pediatric cancers often exceed the total dose at which hearing loss typically develops, and hearing loss is frequently the dose-limiting factor in their treatment. Without a way to protect hearing, patients, families, and physicians may be required to choose between optimal tumor treatment and preserving the ability to hear.

A drug called sodium thiosulfate may help prevent or lessen the degree of hearing loss in people undergoing cisplatin treatment. In animal studies, sodium thiosulfate protected hearing across several frequency ranges and did not interfere with the effectiveness of cisplatin or a similar drug, carboplatin, when given several hours after chemotherapy. A clinical trial in adults with brain tumors demonstrated that the drug could delay or prevent hearing loss in patients treated with high-dose intra-arterial carboplatin, and a pilot study in pediatric brain cancer patients showed that sodium thiosulfate was well tolerated by children undergoing similar carboplatin chemotherapy.

In this clinical trial, children and adolescents with cancer who are scheduled to receive cisplatin will be randomly assigned to receive sodium thiosulfate intravenously 6 hours after each cisplatin infusion or no additional treatment after each cisplatin infusion. All patients will have their hearing assessed at study entry, before each chemotherapy infusion, and at 4 weeks and 1 year after their last cisplatin treatment to determine whether sodium thiosulfate can prevent or reduce hearing loss in these patients. They will also try to determine whether sodium thiosulfate can prevent or reduce several other toxic effects of cisplatin, see if the drug affects event-free or overall survival, and examine the association of certain genetic mutations with the development of cisplatin-related hearing loss.   

“We really feel that it’s important to achieve not only long-term survival for these patients but also a good quality of life, especially for young children, for whom hearing is so critically important,” said Dr. Freyer. “Our current standard of care with cisplatin is that we treat the child until the hearing loss is so severe that it requires a discussion between the physician and parents about stopping treatment. We’re hopeful that we may now have a means of preventing this very serious side effect.”

For More Information
See the lists of entry criteria and trial contact information or call the NCI Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The call is toll free and confidential.

An archive of "Featured Clinical Trial" columns is available at

Profiles in Cancer Research

Dr. Pier Paolo Pandolfi

Dr. Pier Paolo PandolfiDirector of Research for the Cancer Center
and Director of the Cancer Genetics Program
at Beth Israel Deaconess Medical Center

As an undergraduate student at the University of Rome in the early 1980s, Pier Paolo Pandolfi studied philosophy and appeared to be heading into the family business––his parents were both University professors of literature (French and Russian). Approaching his senior year, however, he suddenly realized that he wanted to be a scientist and transferred to the medical school. “My parents weren’t thrilled, to say the least,” he said, “but at least I was still at the University of Rome.”

At least for a while. But then he left Rome a few years later to finish medical school at the much smaller University of Perugia, in a beautiful town 100 miles away in the countryside. His parents, he joked, “were tearing their hair out for a while.”

These hairpin turns on the road to where he is today could be seen as the vagaries of youth, but looking back over his career in cancer research, he admits these abrupt changes in direction may be a character trait.

“At a certain point I can get distracted and even bored if I’m only working on one single thing. If you do that in science 24/7 for 10 years, you become an utmost authority,” he observed. “That is not me, I’m afraid. I need to follow many leads simultaneously and jump from one to the other, maybe until I drop dead of exhaustion. But, meanwhile, it’s tremendously exciting.

“Cancer is a complex disease. The ability to make connections between various disciplines is an essential component of cutting-edge cancer research,” Dr. Pandolfi explained. “This ability to make unexpected connections is perhaps our distinctive trait as a research team.”

Dr. Pandolfi’s colleagues see him as a brilliant cancer researcher who has already done a career’s worth of work and whose prolific laboratory at Beth Israel Deaconess Medical Center, continues to make important discoveries. Two of his breakthroughs may never have happened had he stayed in Rome.

Finding the APL Gene

Acute promyelocytic leukemia (APL) is a fast-growing blood cancer that affects both children and adults. In the late 1980s, only one in four patients survived.

During this era of ambitious gene-hunting expeditions, Pandolfi applied to work with Dr. Pier Giuseppe Pelicci, a prominent geneticist who had recently returned from the United States and was looking for APL-causing genes. When Pandolfi arrived in Perugia he met and began working with another young researcher, Letizia Longo, and within a year they were first authors on a paper that identified and described the identification of the primary gene driving APL. They also fell in love.

“Call it luck, determination, fate, whatever you will,” said Dr. Pandolfi, “but if I hadn’t quit Rome for Perugia, I certainly wouldn’t have discovered the [promyelocytic leukemia] gene , and I probably would not have met my wife.”

Having cloned the APL gene, the newlyweds headed to the University of London to continue working on the disease using what was then the new rage in molecular biology—the knockout mouse. Researchers inactivate specific genes in these animals to learn more about the role those genes might play in cancer and other diseases. The challenge before them was not trivial, said Dr. Pandolfi, because no mouse had ever naturally developed APL.

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Dr. Pier Paolo Pandolfi discusses his involvement in identifying the primary gene that causes acute promyelocytic leukemia, and his continued work on the disease using mouse models—research that has led to improved survival for patients with the disease. (Video produced and edited by Sarah Curry)

Pioneering the Knockout and Transgenic Models

In parallel with his research on APL, Dr. Pandolfi was developing other interesting ideas and results on gene expression. He had not even finished his Ph.D. when researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) recognized his potential and brought him to New York, gave him his own lab, and made him an assistant professor.

In those early days, most people trying to eliminate genes in a mouse were developmental biologists studying the role of specific genes in embryogenesis, according to Dr. Pandolfi. “But MSKCC was ahead of the curve, looking hard at how this new approach could be applied to cancer,” he said. “The turning point for us came when Dr. Raymond Warrell, head of the clinical leukemia program, kept coming back to our lab meetings and began to believe in the results we were having with our genetically engineered mice.”

These genetically engineered mice faithfully developed APL in a manner very close to the way that people do, something Dr. Pandolfi refers to as “phenocopying” the disease. Even better, the mice mimicked how humans responded to specific drugs.

Dr. Pandolfi’s mouse-engineering expertise brought him into contact with many people who were interested in this approach; one that is now being used to study other forms of cancer, such as breast, prostate, and lung. Then-NCI Director Dr. Richard Klausner asked him to join a group that eventually formed the Mouse Models of Human Cancers Consortium (MMHCC).

Dr. Cheryl Marks, program director of the MMHCC, calls Dr. Pandolfi’s body of work on APL “profound." Over the course of 15 years, using his evolving expertise with the mouse, "Pier Paolo has been a driving force in saving the lives of countless patients and raising the APL cure rate to more than 90 percent,” she remarked.

“He’s energetic, incredibly inquisitive, and a lot of fun—at times exuberant, always passionate about helping patients,” she said. “But he’s also a powerfully convincing scientist, backing his observations with clear-cut, well-designed experimental data, and able to bring others around to his views by force of a compelling vision. And he has an uncanny ability to discover connections that many people miss.”

Exploring a Pathway

This portrait of Dr. Pandolfi as a keen observer and dogged researcher is reinforced by a colleague and director of the cancer center at Beth Israel Deaconess Medical Center, Dr. Lewis Cantley, whose biochemistry lab studies cell signaling, including the role of PTEN in cancer development. In the late 1990s, Dr. Cantley was in New York to talk about his latest grant on prostate cancer, and—knowing that the PTEN gene was down-regulated in some 70 percent of cancer patients—started a conversation with the young assistant professor who had been trying to engineer a PTEN mouse model.

“From the first, I was impressed by his openness, willingness to share unpublished data, and his enthusiasm,” remembered Dr. Cantley. “We agreed to use his PTEN knockout mice, and I’ve been collaborating with him ever since.” At a meeting on mouse models held in Bethesda, MD, last month, which Dr. Pandolfi organized, Dr. Cantley spoke about the progress his lab has made using these PTEN knockout mice to test drugs that inhibit the PI3 kinase pathway in prostate cancer.

“The problem is that cancer is not one but many diseases,” explained Dr. Pandolfi. “We are curing APL because it has only six subtypes, and we found a drug combination for each one. But prostate cancer looks like it has five to 10 times that many subtypes. This is certainly the case for any major cancer type.” His lab has engineered more than two dozen animals that they hope will successfully phenotype those prostate cancer subtypes.

Exploding the “Junk” Paradigm

This summer in the journal Nature, Dr. Pandolfi published findings that could have tremendously important implications for the central dogma of molecular biology.

Genes make messenger RNAs (mRNAs), mRNAs make proteins, and the proteins within and around a cell determine its fate. However, only 2 percent of the human genome consists of protein-coding genes, and for many years much of the rest was labeled “junk.”

Then it was discovered that another type of RNA, microRNAs (miRNAs), can bind to certain mRNAs and disrupt their ability to produce proteins. “We’ve learned over the last few years that miRNAs can have a significant impact on which genes are expressed and blocked, and thus on the development of cancer,” said Dr. Pandolfi.

His lab has now found that some RNAs that encode for proteins, as well as some that do not, can bind to and regulate miRNAs.

“We call them competitive endogenous RNAs, or ceRNAs, and they can regulate whether PTEN and other important cancer genes are turned up or down,” said Dr. Pandolfi. “This is quite simply a radical change of perspective on how genes operate, and I think the real breakthrough is that we can use it to predict how specific genes function.”

Dr. Cantley said that this is typical of Dr. Pandolfi’s vision as a scientist. “ceRNA makes a lot of sense now that we see it, but nobody else was thinking about it,” he explained. “Pier Paolo dove into it and showed how it worked and opened up an entire area of regulation that everybody had missed.”

“We’re astonished,” said Dr. Pandolfi. “It’s a new, largely unexplored dimension of cell biology, and it never occurred to me that I would live through such a transformative phase in biology and cancer research.”

—Addison Greenwood

Community Update

Physician Assistants Valued for Patient Care and Research Support at NCI

In this highly competitive world, those whose work contributes to success are far too often unsung and anonymous. The medical and research community is no exception. But from October 6–12, one key element of the health care team hopes to shine the light on their many contributions. At NIH and across the country, the vital role that physician assistants (P.A.s) play in patient care and education is being celebrated during National Physician Assistant Week.

P.A.s have been providing patient care at NIH since 1990 in a wide range of medical disciplines and for a variety of diseases, including cancer, HIV/AIDS, other infectious diseases, and autoimmune diseases. But how P.A.s fit into the wider cancer care continuum is something most people aren’t as familiar with as, say, the roles of doctors and registered nurses.

Physician Assistant Jeri Akins attends to a patient at the University of Texas M. D. Anderson Cancer Center. Physician Assistant Jeri Akins attends to a patient at the University of Texas M. D. Anderson Cancer Center.

“The P.A.’s role in cancer research is evolving,” noted Dr. Ramaprasad Srinivasan, staff clinician and principal investigator in NCI’s Urologic Oncology Branch (UOB). “I view the P.A. role largely as one of clinical support. They spend the majority of their time focusing on patient care.

“However,” he added, “there are going to be certain branches at NCI and certain P.A.s who want greater involvement in research. Fortunately, NIH is a place where that is possible.”

The P.A. profession started in the mid-1960s at Duke University in response to a growing shortage of primary care physicians. Today, more than 78,000 P.A.s practice in the United States in a variety of health care settings, according to the American Academy of Physician Assistants. P.A.s are able to diagnose and treat patients, prescribe medications, and perform a variety of clinical procedures under the supervision of a physician.

Increasingly, the contribution that P.A.s can make to clinical research is also being recognized.

“The nice thing about being a P.A. is that you can switch from one medical specialty field to another, because you have a background in general internal medicine, which suits a P.A. for a broad variety of patient care needs,” explained Julia Friend, a P.A. who works with Dr. Srinivasan in the UOB.

She previously worked for the National Institute of Allergy and Infectious Diseases but said she was drawn to the UOB, and particularly to Dr. Srinivasan’s work, because of what she heard about his research with novel therapies for familial kidney cancers.

“I thought that the combination of clinical trials for kidney cancer in an outpatient setting was interesting,” she said. “The job involved a lot of general internal medicine, a lot of genetics, and a lot of patient teaching and patient care.”

Dr. Srinivasan says that regular contact with patients is what makes Friend such a valuable member of his research team.  In this role, she is able to approach him with interesting research questions related to her patient care in the course of the study, such as a finding of high parathyroid hormone blood levels among kidney cancer patients receiving an experimental therapy. “That is the type of research question that needs to be tracked down; questions that require a fair amount of clinical knowledge to try to understand exactly what is happening,” he said.

P.A.s can also help manage clinical research protocols, including screening patients for study participation. That is a job that P.A. Kerry Ryan, of NCI’s Medical Oncology Branch, has performed. “I’ve been involved in a clinical trial where my role was to screen all of the patients, both inpatients and outpatients; record their histories; perform physicals; and provide their medical care while they were at the NIH Clinical Center,” she said.

Although Friend relishes her contributions to cancer research, “Patient care comes first for a P.A.,” she said. “I’m at UOB because patients come in, and they have other medical problems besides their cancer. I help to manage and coordinate care for many of their other medical problems. Perhaps more importantly, I help manage the side effects caused by chemotherapy. It’s part of taking care of the whole person.”

Bill Robinson

Learn more about the role P.A.s play in health care and the research community from the American Academy of Physician Assistants. Update

NCI Launches Redesigned Science Serving People Web Site

Science Service People home page

NCI’s Science Serving People Web site has been updated with a fresh new design, expanded content, and improved navigation. This resource, published by the Office of Advocacy Relations, features NCI budget information, the latest policy news, and state-specific cancer information all in one place. The site also provides information on the cancer research process and the cost of cancer in the United States.

Send questions or comments about the redesigned site to


NCI to Host Science Writers’ Seminar on Human Papillomavirus

On October 19, NCI will host a science writers’ seminar to discuss new research findings and future directions in human papillomavirus (HPV)-related cancer research. NCI experts Drs. Mark Schiffman, Diane Solomon, Allan Hildesheim, and John Schiller will discuss the natural history of HPV and HPV-related cancers, advances in screening techniques and tools, the role of vaccines and microbicides in prevention, and future research directions.

The seminar will run from 9:00 a.m. to 11:30 a.m. and include ample time for questions and answers and interaction during the talks.

Take part in the seminar online and dial-in toll-free for audio at 866-502-8312 (the passcode is 836302).

NCI Launches Next Phase of Nanotechnology Program

NCI has approved a second phase of its Alliance for Nanotechnology in Cancer initiative, which aims to leverage nanotechnology to improve the diagnosis, treatment, and prevention of cancer. The Institute has awarded multi-institution grants totaling approximately $30 million per year for the next 5 years.

In the last 5 years, Alliance researchers have discovered and developed a host of novel nanotechnologies for use in diagnosis, imaging, and therapeutics. Several of these innovations are being tested in clinical trials and some are undergoing commercialization.

The next phase of the Alliance initiative consists of newly selected Centers of Cancer Nanotechnology Excellence and Cancer Nanotechnology Platform Partnerships. The centers and platforms are focused on advancing new nanotechnology discoveries into clinical applications that are relevant to cancer. Two new components, the Pathway to Independence Awards in Cancer Nanotechnology Research and the Cancer Nanotechnology Training Centers, will train the next generation of multidisciplinary cancer researchers in cancer biology, oncology, and principles of physics and engineering.

The Alliance also continues to support the Nanotechnology Characterization Laboratory, the hub for preclinical characterization of nanomaterials, and to foster the development of nanotechnologies that are ready to be submitted as investigational new drugs or devices to the FDA.

NCI Awards Grants to Increase Public Awareness of Pediatric Cancers

NCI recently awarded five administrative supplements totaling over $1 million to programs that increase public awareness of pediatric cancer and available treatments and research. The U.S. Department of Health and Human Services was authorized to provide the funds under the Caroline Pryce Walker Conquer Childhood Cancer Act of 2008.

The five funded programs will inform the public about the best available therapies and clinical trials, ensure access to information about the late effects of pediatric cancer treatment, and increase awareness of support services for parents and loved ones. Each grantee will partner with an advocacy organization to develop, review, and disseminate the final product.

Funding will go to:

  • Dr. James W. Dearing of the Kaiser Permanente Institute for Health Research, who is partnering with the Cancer Research Network
  • Dr. Judith Gasson of the Jonsson Comprehensive Cancer Center, who is partnering with the UCLA Department of Computer Science and Community Advisory Board
  • Dr. Charles Keller of the Oregon Health and Science University, who is partnering with the Northwest Sarcoma Foundation
  • Dr. Ana Navarro of the Comprehensive SDSU-UCSD Cancer Center Partnership
  • Dr. Gregory Reaman of the Cure Search for Children’s Cancer, who is partnering with the National Childhood Cancer Foundation

President’s Cancer Panel Discusses Future of the National Cancer Program

The President’s Cancer Panel held the first meeting of its 2010–2011 series, “The Future of Cancer Research: Accelerating Scientific Innovation,” on September 22, in Boston, MA.

The Panel brought together leaders in the research, health care, and advocacy communities, as well as government agency representatives and members of the public, to discuss the vision for the National Cancer Program over the next 15 years and how it can be enhanced. Speakers also identified principles that the stakeholders of the National Cancer Program should embrace in this new and exciting era of science.

Meeting participants agreed that continued investment in research will be critical to identify new ways to prevent and treat cancer and to improve the quality of life of those diagnosed with the disease. Speakers urged that the focus of cancer research should shift from treatment of the disease to prevention, and that radical changes to the clinical trials system are urgently needed to adapt to a swiftly evolving field of research, as well as to increase the speed and efficiency with which trials are initiated, conducted, and completed.

Speakers called for greater collaboration and enhanced communication across all sectors of the research community—among academic and industry settings, as well as government agencies—and stressed the need to more quickly translate research findings into beneficial treatments. Participants also highlighted the importance of continuing to involve advocates so that the interests of patients and the public remain at the forefront.

The next meeting in the series will be held on October 26, 2010, in Philadelphia. The agenda can be found on the Panel’s Web site. The Panel will summarize findings and recommendations from meetings of the 2010–2011 series in an annual report to the President of the United States.