National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 28, 2011 • Volume 8 / Number 13

BREAKING NEWS

Lung Screening Trial Results and Ovarian Cancer Analysis Published

Primary results from the National Lung Screening Trial show a 20 percent reduction in deaths from lung cancer among heavy smokers who were screened with low-dose helical computed tomography (CT) compared with those screened by chest X-ray. The findings, which appeared online in the New England Journal of Medicine, confirm initial findings from the study reported in November 2010 and include the rate of false-positive results. For more information, read the NCI press release.

In a study reported in Nature, The Cancer Genome Atlas (TCGA) Research Network has analyzed the genomic changes found in ovarian tumors from 500 patients, providing the most comprehensive and integrated look at any cancer type to date. TCGA is jointly funded and managed by NCI and the National Human Genome Research Institute. The NCI press release is available online.

NEWS

New Graphic Tobacco Warning Labels Backed by Research

Two of the nine new graphic warning labels for tobacco products For the first time in more than a quarter century, the look of a pack of cigarettes sold in the United States is changing, thanks to nine new graphic tobacco warning labels released last week by the Food and Drug Administration (FDA). 

By the fall of 2012, tobacco companies will be required to cover half of the front and back of cigarette packs and cartons with the warnings, which include images of cancer-ridden lungs, rotting teeth, and an infant surrounded by secondhand smoke. Read more > >


COMMENTARY

Dr. Martha Linet

A Conversation with Dr. Martha Linet on Cell Phone Use and Cancer Risk

Dr. Linet discusses the forthcoming IARC monograph that classifies exposure to mobile phones as "possibly carcinogenic to humans." Read more > >

  

IN DEPTH

UPDATES

  • FDA Update

    • Potential Cardiac Risks Associated with Smoking Cessation Drug
    • Diabetes Drug May Increase Risk of Bladder Cancer
  • Cancer.gov Update

    • NCI Launches International Clinical Trials Portal
  • Notes

    • In Memoriam: PDQ Board Member James Nachman
    • DCEG Training Program Receives Langmuir Award
    • NCAB Meeting Held This Week
    • NCI Hosts BSA Meeting June 20
    • Telephone Workshop for Cancer Survivors to Focus on Late Effects
    • Japanese Translators of the Bulletin Visit NCI

SCIENCE SNAPSHOTS

>A cross-section of a chest scan from The Cancer Imaging Archive What is this? Click on the image to find out.
A cross-section of a chest scan from The Cancer Imaging Archive (TCIA), a Web-accessible clinical imaging archive linked to The Cancer Genome Atlas (TCGA) tissue repository and the Lung Image Database Consortium data set. Learn more about the archive online.

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

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

New Graphic Tobacco Warning Labels Backed by Research

Two of the nine new graphic warning labels for tobacco products Two of the nine new graphic warning labels for tobacco products

For the first time in more than a quarter century, the look of a pack of cigarettes sold in the United States is changing, thanks to nine new graphic tobacco warning labels released last week by the Food and Drug Administration (FDA). By the fall of 2012, tobacco companies will be required to cover half of the front and back of cigarette packs and cartons with the warnings, which include images of cancer-ridden lungs, rotting teeth, and an infant surrounded by secondhand smoke.

The warnings will also be required to cover 20 percent of all forms of cigarette advertising, including magazine and newspaper ads, brochures, coupons, retail or point-of-sale displays, and Internet advertising. The new warnings are intended to encourage current smokers to quit and to deter nonsmokers, especially young people, from ever taking their first puff.

"The new graphic warning labels will be the toughest and most effective tobacco health warnings in this country's history, and they tell the truth," said Department of Health and Human Services Secretary Kathleen Sebelius at a White House news conference on June 21. "With these warnings, every person who picks up a pack of cigarettes is going to know exactly what risk they're taking."

The Family Smoking Prevention and Tobacco Control Act, signed into law on June 22, 2009, gave the FDA the authority to regulate tobacco products and required the implementation of new graphic health warnings. Last November, the FDA presented 36 proposed images, from which the nine final images were chosen.

"The final nine images were selected based on a number of important criteria," FDA Commissioner Dr. Margaret Hamburg noted at the White House press conference. "We took into account public comment from approximately 1,700 stakeholders, including experts and industry [representatives], some of whom submitted scientific research studies," she explained.

The FDA also conducted a national study to gauge people's response to graphic cigarette health warnings. It was the largest such study ever conducted, involving some 18,000 participants, Dr. Hamburg said.

"We examined how effective the proposed warnings were at communicating the health risks, as well as [their] ability to encourage smokers to quit and [whether] they discourage nonsmokers—particularly kids—from ever wanting to smoke," she added.

In addition to the large color images, every warning will include the number for the national network of smoking cessation quitlines, 1-800-QUIT-NOW, and educational text, such as "cigarettes cause cancer," "cigarettes are addictive," and "tobacco smoke can harm your children."

Evidence Supports New Warnings

More than 30 countries and jurisdictions already require graphic health warnings on tobacco packages. NCI's Tobacco Control Research Branch has funded a number of research projects studying the impact of graphic health warnings as they have been implemented in different countries.

A tobacco sales counter before the new rules take effect Click on this image to see how the new cigarette health warnings will look on packages and advertisements once the new rules take effect.

"Clearly one thing that stands out in our research is that the more gruesome the warning, the greater the effect in being noticed," said Dr. K. Michael Cummings of Roswell Park Cancer Institute, who led one of the research projects supported by NCI. "We also see that warnings that are pictorial and reflect truthfully the harm caused by cigarettes tend to affect knowledge and beliefs about the risk of smoking," he said. "The pictorial warnings certainly do a better job than what we've seen with text-based warnings."

Dr. David Hammond, of the University of Waterloo in Ontario, Canada, another NCI-supported researcher, agreed, saying, "The use of pictures ensures that [the warning labels] can be understood by low-literacy populations, including very young children. The warnings incorporate some of the best practices based on evidence: they are relatively large, they will appear on the front and back of [cigarette] packs, and at least some of the warnings include information that will engage on an emotional level."

Providing information on how to stop smoking directly on cigarette packaging and ads has also demonstrated positive outcomes. "We know from a number of studies that including information that allows smokers to immediately address the health threat posed in the warning messages, such as providing a quitline number or a Web site address where people can get help to stop smoking, will stimulate quit attempts and help [them find] evidence-based support to help them quit," Dr. Cummings said. (In addition to using 1-800-QUIT-NOW, smokers can get help to quit through www.smokefree.gov.)

Dr. Cummings indicated that more research will be needed to understand how often to rotate the warning messages and what new topics should be added to the labels so that consumers are adequately informed about the risks posed by tobacco products. For example, the lack of harm reduction from filtered and low-tar cigarettes and why nicotine addiction is so difficult to overcome are topics that could be considered for future warning labels.

Never Too Late to Quit

Surgeon General Dr. Regina Benjamin appeared at a second news conference to express her support for the new warnings and to provide perspective on the current state of tobacco use in the United States. "With a lot of effort, our nation has reduced tobacco use by half since [the] first Surgeon General's Report in 1964," she said. "However, since 2003, our progress has stalled. One in five adults in the United States continues to smoke. One in five adolescents smokes. Tobacco use remains the leading cause of preventable death in the United States and is responsible for more than 440,000 premature deaths every year."

In addition to loss of life, tobacco use has significant financial consequences. "Almost $200 billion is lost per year in the U.S. alone from increased health care costs and lost productivity costs," said Dr. Lawrence Deyton, director of the FDA Center for Tobacco Products. "We must work together to make tobacco-related death and disease part of America's past, not our future," he added.

"Despite enormous progress, tobacco use remains the leading cause of cancer deaths in the U.S. and is a leading cause of cancer health disparities," added Dr. Robert Croyle, director of NCI's Division of Cancer Control and Population Sciences. "We are very enthusiastic about the potential for the new graphic health warnings to contribute to reducing our nation's tobacco burden."

Quitting at any age and at any time is beneficial. It's never too late to quit, but the sooner you do the better.

—Dr. Regina Benjamin, U.S. Surgeon General

Dr. Benjamin encouraged smokers who want to quit to consult their doctors. Patients who are advised by their doctors have a 66 percent higher success rate, she explained. When smokers quit, the risk of heart disease drops sharply after just 1 year, and the risk of stroke falls to about the same as a nonsmoker's after 2 to 5 years. Risk of cancer of the mouth, throat, esophagus, and bladder are cut in half after 5 years, and risk of dying of lung cancer drops by half after 10 years.

"Quitting at any age and at any time is beneficial," said Dr. Benjamin. "It's never too late to quit, but the sooner you do the better."

A Long-Term Commitment

One concern about the new warning labels is the potential for consumers to become desensitized to the images and the associated health warnings. Dr. Hamburg stated that the FDA will regularly evaluate the success of the images and make changes as necessary. Any future changes will be proposed based on research and evaluation and through rulemaking that includes public notice and the opportunity for public comment.

In addition to updating the cigarette warning labels, regulators may want to consider a more comprehensive public education campaign on tobacco, suggested Dr. Hammond. He noted that increasing taxes and other policies that raise the price of cigarettes also reduce tobacco use.

When the time comes to improve the next generation of cigarette labels, the United States may want to look to countries like Canada or Australia, Dr. Hammond added. Graphic warnings have appeared on cigarette packs in Canada for almost a decade, and, beginning next year, the Australian government will require all cigarettes to be sold in "plain packages"—packages stripped of colors or symbols with the exception of the brand name written in a standard font.

"Given that tobacco use remains the leading cause of cancer deaths in the United States, NCI needs to maintain this commitment to tobacco cessation and control research over the long term if the country is to significantly reduce the cancer burden," said Dr. Hammond.

Jennifer Crawford

Cancer Research Highlights

Common Gene Mutation Found in Hairy Cell Leukemia

A gene mutation that occurs in melanoma and other cancers has now been detected in hairy cell leukemia (HCL), a rare cancer of the blood. The mutation, called V600E, occurs in the BRAF gene and appears to contribute to the disease, researchers reported in the June 16 New England Journal of Medicine

All 48 patients with HCL in the study had the mutation. Patients with HCL produce large numbers of abnormal B lymphocytes, a type of white blood cell. These abnormal cells appear “hairy” under a microscope and give the disease its name.

Dr. Enrico Tiacci of the University of Perugia, Italy, and his colleagues began by sequencing the complete exome (that is, all protein-coding regions of the genome) of both tumor and normal cells of a patient with HCL. This revealed five variants that were found specifically in tumor cells but not in normal cells, one of which was the V600E mutation in BRAF.

Little is known about the other four affected genes, but BRAF is often mutated in cancer, and the V600E mutation occurs frequently. The researchers then found this mutation in 47 other patients with HCL; it was, however, absent from 195 additional patients with other B-cell lymphomas or leukemias who were tested.

The presence of this mutation could serve as a diagnostic tool to help doctors distinguish HCL from cancers that have similar features, the study authors wrote. Further research, they noted, is needed to determine the frequency of the V600E mutation in a larger patient group and to clarify whether mutations in other genes may cooperate with BRAF mutations in the development of HCL.

Drugs that target the effects of BRAF mutations are in development, such as vemurafenib (PLX-4032). When the authors treated cells from HCL patients with the BRAF inhibitor PLX-4720, they observed biochemical changes that indicated a reduction in the activity of a growth-promoting pathway. These inhibitors could be tested in patients whose disease does not respond to initial treatment with other agents or who relapse, the authors said.

The study findings are both “unexpected” and “very interesting,” said Dr. Robert Kreitman of NCI’s Center for Cancer Research. “The [V600E] mutation is a potential target for treatment and diagnosis, and it may also play a role in why normal lymphocytes become hairy cells,” added Dr. Kreitman, who leads clinical trials in HCL. (See “Treating Multiply Relapsed or Refractory Hairy Cell Leukemia” and “Eliminating Hairy Cell Leukemia Minimal Residual Disease.”)

New Cancer Vaccine Shows Promise against Tumors in Mice

A series of intravenous (IV) vaccinations with a virus carrying fragments of DNA coding for normal human prostate tissue surface antigens cured cancer in about 80 percent of mice with established prostate tumors, new study findings showed.

The study, published online June 19 in Nature Medicine, was led by Dr. Richard Vile of the Mayo Clinic in Rochester, MN, and Dr. Alan Melcher of the Cancer Research UK Clinical Centre in Leeds. If the new approach can be translated from mice to humans, such vaccines could “be readily constructed for off-the-shelf use and [could] be easily delivered” intravenously, the study authors wrote.

The researchers created the cancer vaccine by inserting an extensive “library” of DNA fragments from normal human prostate cells into a mutated form of a virus called vesicular stomatitis virus (VSV). Each VSV particle carries a different DNA fragment, and each fragment holds the code for making a particular human prostate antigen, a piece of protein capable of triggering an immune response.

When the researchers injected the virus particles intravenously into mice bearing prostate tumors, the DNA fragments, known as complementary DNAs (cDNAs) that coded for surface antigens, were translated in the mice into a wide range of human prostate antigens.

Bolstered by VSV itself, which produces a strong immune response, the antigens triggered an immune reaction that selectively targeted prostate tumor cells while sparing healthy prostate tissue and other normal mouse tissues. Injecting the vaccine directly into prostate tumors was not nearly as effective as intravenous injection and produced signs of an autoimmune response in the mice.

“By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system,” Dr. Vile said in a news release. “The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated.”

The researchers found that tumors in mice were cured more effectively with nine IV injections given every other day than with a series of three or six IV injections. Tumor cells that survived an initial round of three IV vaccinations “were readily treated by second-line virus-based immunotherapy” using DNA fragments that coded for antigens on the surfaces of resistant tumor cells, the study authors wrote.

Dr. James Gulley of NCI’s Center for Cancer Research, who studies human cancer vaccines but was not involved in the current work, said that a possible strength of the new approach “is the large number of potential antigens that can be targeted,” although he said that this might also make it harder to monitor the immune response to a similar vaccine in human studies. Dr. Gulley also noted the challenges inherent in taking promising vaccine approaches from mice into the clinic.

The method described by Dr. Vile and his colleagues is just one approach being explored in the search for effective cancer vaccines in humans, Dr. Gulley added. “I don’t think it really matters in the end what initiates an immunologically relevant killing of tumor cells,” he said. “The key is to get the immune system trained to kill the tumor cells, and it may be that multiple vaccine approaches will demonstrate similar effectiveness.”

Researchers Scrutinize Genetic Variants Linked to Melanoma

Researchers have identified five genetic variants that appear to be the most promising markers of susceptibility for melanoma from a set of 745 variants that have been linked to the disease in published studies. The results of this meta-analysis, which included 145 genetic association studies in melanoma, appeared online June 21 in the Journal of the National Cancer Institute.

Each of the five variants showed a statistically significant association with melanoma at the genome-wide level and had “strong epidemiological credibility,” Dr. Alexander Stratigos of the University of Athens Medical School in Greece and his colleagues found.

To conduct the analysis, the researchers collected and catalogued all genetic association studies published in the field of melanoma, including results from recent genome-wide association studies. Working with colleagues around the world, they then conducted a systematic meta-analysis for each genetic variant identified. For each variant that showed a statistically significant association with melanoma in the meta-analysis, the authors also assessed the epidemiologic evidence supporting such an association.

The strongest associations with melanoma included variants within genes that play an important role in determining the color of skin, hair, and eyes. This finding may reflect the fact that these variants had been tested in the original candidate gene studies precisely because of their effects on pigmentation, a well-known risk factor of melanoma, the study authors noted.

Nonetheless, the confirmation of some of these variants in genome-wide association studies
“strongly supports their contribution to melanoma susceptibility,” Dr. Stratigos wrote in an e-mail. “Whether their effect on melanoma risk is exclusively through their influence on pigmentation, or also partly independent of that, cannot be assessed with our systematic meta-analysis approach,” he added.

The results provide “an integrated perspective of the accumulated evidence of genetic associations” in melanoma, the authors concluded. Their evidence is available online at the MelGene Database, which provides “a regularly updated field synopsis of genetic association studies performed in melanoma,” according to the site.

Barrett Esophagus May Progress to Cancer Less Often than Thought

The risk of Barrett esophagus (BE) developing into esophageal cancer may be lower than previously thought, according to one of the largest studies of its kind. The study was conducted in Ireland, where the clinical parameters for diagnosing BE are different than they are in the United States. As a result, the implications of these results for care in the United States are unclear. The study was published online June 16 in the Journal of the National Cancer Institute.

Esophageal cancer incidence has been rising dramatically in the United States, with an increase of 300 to 400 percent in the last 30 years. BE is a strong risk factor for the development of esophageal cancer. Current clinical guidelines advise that people who have BE without evidence of significant cellular aberrations, known as dysplasia, undergo an endoscopy every 3 to 5 years, with more frequent endoscopies in people whose BE has more significant dysplasia.

In this study, researchers followed more than 8,500 BE patients who were listed in the Northern Ireland Barrett Esophagus Registry. After a mean follow-up of 7 years, 79 participants had been diagnosed with esophageal cancer, 16 with cancer of the gastric cardia (the junction between the esophagus and stomach), and 36 with high-grade dysplasia, meaning that the esophageal tissue had severe precancerous changes. The combined incidence of all three outcomes was 0.22 percent per year, lower than what has been seen in previous studies. Consistent with previous studies, cancer risk was higher among men and in patients over 50 years of age.

In addition to showing a lower risk of progression than previously seen, the study “makes it possible to more accurately determine risk in subgroups and to estimate changes in risk of progression over time,” wrote the study’s lead investigator, Dr. Shivaram Bhat of Queen’s University Belfast, and his colleagues.

However, only 46 percent of the BE patients in the registry had changes in the esophageal lining (identified during an endoscopy) known as specialized intestinal metaplasia (SIM), a condition which is used to diagnose BE in the United States. The remaining patients had been diagnosed with BE based on the presence of less severe changes to the esophageal lining, determined via a biopsy. The combined incidence of progression from BE to esophageal cancer, gastric cardia cancer, or high-grade dysplasia in patients with SIM was 0.38 percent per year. Patients without SIM at their first biopsy had a much lower incidence of progression, just 0.07 percent per year.

Diagnosing BE in patients without SIM “could meaningfully bias the results,” wrote Dr. Douglas Corley of the Kaiser Permanente Northern California Division of Research in an accompanying editorial. In the patients with SIM, he noted, the incidence of progression to cancer was only slightly lower than prior estimates. “The current study…provides general support for many paradigms underlying current thoughts about the management of Barrett esophagus,” explained Dr. Corley. Further studies will be necessary to determine “whether surveillance or treatment actually decrease cancer deaths and the development of better techniques for risk stratification.”

The conflicting diagnostic criteria for BE “makes it difficult to compare these results with other studies,” agreed Dr. Asad Umar of NCI’s Division of Cancer Prevention. The findings, he continued, “need to be analyzed with caution, as the practice of endoscopic and pathologic evaluations varies greatly among practices and research groups.”

A Conversation With

Dr. Martha Linet on Cell Phone Use and Cancer Risk

Dr. Martha Linet Dr. Martha Linet

The International Agency for Research on Cancer (IARC) published a synopsis of its forthcoming Monograph on the Evaluation of Carcinogenic Risks to Humans online June 22 in Lancet Oncology. The monograph classifies exposure to mobile phones as "possibly carcinogenic to humans." Dr. Martha Linet, chief of the Radiation Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics, discusses the IARC working group's decision and summarizes some of the ongoing research on mobile phones and cancer risk.

Is there evidence of an increased risk of cancer from mobile phone use?

Most studies to date have not found an association between cell phone use overall and the development of tumors. However, there are a handful of studies that have shown an association with increased risk for glioma among the small number of cell phone users who reported the highest level of call time. Among the positive studies, results are conflicting and don't show a dose-response. In addition, there is no biologically plausible mechanism or animal evidence for how cell phones might cause cancer. 

Why are there inconsistencies among the studies?

Most of the studies are based on data from interviews about cell phone use patterns from brain tumor patients and control subjects. We know that this kind of self-reported data is not necessarily accurate. Patients may be more likely to over-report use than controls, or they may mis-recall on which side of their head they held their phone. Cell phone technology has changed dramatically over time, and the studies cover different periods. The way people use cell phones has also changed over time, which makes accurate recall more difficult.

In addition, none of the epidemiologic studies measure actual radiofrequency exposure to the brain; the exposure is estimated from interview data.

How has the epidemiology community responded to IARC's decision to classify mobile phones as "possibly carcinogenic to humans?"

There's been a lot of lively debate among epidemiologists and interest at epidemiologic meetings. We have identified some gaps in the research, which ongoing studies are attempting to address. The three major gaps are: none of the studies—including Interphone, a large international study on cell phone use of more than 5,000 patients in 13 countries who had either glioma or meningioma—have a large number of long-duration, heavy-intensity cell phone users. So, risks associated with high exposures are based on fairly small numbers. 

Second, there are no published studies of cancer risk among people who began using phones as children or adolescents. 

Third, the animal studies have been limited to date, but the National Toxicology Program has a very large, well controlled study of rodents under way, involving thousands of rodents. Results are expected in 2014.

Would you describe some of these forthcoming studies? 

There is a large European study, involving mostly Nordic and northern European countries, called COSMOS, that is following 250,000 people 30 to 59 years of age with repeated interviews, comparisons with cell phone subscriber data, and periodic linkage with cancer registry data.

Studying Epidemiological Risk Factors of Meningioma

The Epidemiology and Genetics Research Program in NCI's Division of Cancer Control and Population Sciences is funding four population-based case-control studies of meningioma. Investigators are collecting information on potential risk factors, including cell phone use, from individuals diagnosed with intracranial meningioma and comparing them with control subjects matched by sex, ethnicity, geographic location, and age. These studies represent the first concentrated effort to examine environmental and genetic risk factors for meningioma.

There are several NCI-funded studies in the United States looking at cell phone and radiofrequency exposure and risk of meningioma and other brain tumors in different populations. (See the sidebar for more information.)

And there is another European-funded initiative called Mobi-Kids that is modeled after Interphone. Mobi-Kids is studying brain tumor risk associated with cell phone use among people 10 to 24 years of age.

What is the main takeaway from all this?

The IARC working group classified cell phone use as a possible carcinogen. If one keeps in mind that possible means "maybe," that fits with the positive reports but overall inconsistent data. The studies under way addressing key research gaps will provide important information that should clarify questions not addressed by the research to date, and it will be important to continue to monitor incidence trends in brain tumors.

The steps suggested by the Food and Drug Administration and the Federal Communications Commission to reduce exposure include reducing the length and number of calls made from cell phones, using landline phones instead of cell phones, and switching to a cell phone with a hands-free device.

Of course, one of the most important general safety recommendations is to not use cell phones while driving.

Spotlight

Technology
This is the seventh article in a series of stories related to new technology in cancer research. You can read more articles in the series here.

Imaging Boot Camp for Cancer Researchers

Students at NCI's Cancer Research Imaging Camp get a lesson in using contrast to improve the visibility of a tumor on an MRI scan. (Photo by Sharon Reynolds) Students at NCI's Cancer Research Imaging Camp get a lesson in using contrast to improve the visibility of a tumor on an MRI scan. (Photo by Sharon Reynolds)

In a basement lab, a group of students gently place a tumor-bearing mouse into the bore of a small-animal MRI machine to test several methods for distinguishing cancer from surrounding fat cells. Upstairs, another group of scientists rotates through three optical imaging stations, observing the different ways that visible and infrared light can be harnessed to visualize cancer cells in a mouse. At the ultrasound table, a young researcher uses a receiver to deliver a burst of energy to a small tumor in vivo, lighting up a contrast agent designed to bind to and highlight tumor blood vessels.

NCI's annual Cancer Research Imaging Camp, sponsored by the Cancer Imaging Program (CIP) and held June 19–24 this year at Washington University in St. Louis, provides a one-of-a-kind immersive experience for junior scientists eager to incorporate modern imaging methods into their research. Trainees can't possibly gain a comprehensive understanding of imaging technology in 6 days, but that's not the goal of the program, explained Dr. Kenneth Krohn, professor of radiology, radiation oncology, and chemistry at the University of Washington in Seattle and an instructor at Imaging Camp since its inception.

"What we want them to take away is that there are lots of evolving technologies, and that the most important thing is for them to formulate their research questions first and then find the best technology to answer those questions." What researchers should avoid, said Dr. Krohn, is using an imaging method in their research simply because they are familiar with it, or because it has been the only thing available to them.

Although some Imaging Camp participants have experience with one or more of the methods taught during the week, many are learning these methods for the first time.

By the third day of this year's program, Dr. Ashley Snider, an assistant professor of medicine and lipid researcher at the Medical University of South Carolina and the Ralph H Johnson VA Medical Center, and novice imager, had already picked up some ideas. She is working on a collaborative project with two senior cancer researchers, looking at how colon cancer forms in patients with ulcerative colitis. Dr. Snider plans to test some of the techniques she learned at Imaging Camp to monitor the overproduction of blood vessels and track drug delivery in the colon.

"I had never done in vivo imaging before camp," she said. "We'd seen in cells and in animals that an inflammation-associated lipid…contributes to carcinogenesis, but we want to take that work to the next level and monitor the response of tumors to inhibitors we're developing with in vivo imaging. That's why I'm here."

Setting Up Camp

The idea for Imaging Camp sprang from NCI's Imaging Integration and Implementation (I2) group, which was set up in 2004 to encourage greater use of imaging in cancer research. Early on, the group recruited Dr. Bonnie Sloane, distinguished professor and chair of pharmacology at Wayne State University, as a liaison to the CIP to help cancer biologists gain a better understanding of imaging techniques. She identified a basic lack of training as the main barrier to greater use of imaging in cancer biology.

Two Imaging Camp students watch a demonstration of a fluorescent probe used to highlight a tumor for optical imaging. (Photo by Sharon Reynolds) Two Imaging Camp students watch a demonstration of a fluorescent probe used to highlight a tumor for optical imaging. (Photo by Sharon Reynolds)

"If you're trained, it's easy to use a technology. But if you don't understand the modalities and the pluses and minuses of each, you don't know how they could help answer your research questions," she explained. Conceived in 2005 and launched in 2007, Imaging Camp draws junior researchers from diverse disciplines that intersect with cancer biology and treatment.

"It's amazing how imaging has infiltrated this field completely," commented Dr. Suresh Mohla, associate director of NCI's Division of Cancer Biology, who co-chaired the Imaging I2 group. "More and more people are using whole-animal imaging to monitor tumor progression, to understand the behavior of tumors and surrounding cells. It's opened up a whole new perspective on how cancer develops in vivo that wasn't available before, and this program is contributing to training the next generation of cancer researchers in these innovative techniques," he continued.

"We hope that the Imaging Camp students will become the experts of the future, and train their own students. Since we can't train hundreds each year, we're trying to sow the seeds," Dr. Mohla explained.

Labor of Love

For its first 2 years, the camp was hosted by Duke University before the mantle was passed to Washington University in St. Louis in 2009. Beginning next year, the camp will be held at Vanderbilt University. Each year, the all-volunteer faculty members come from these and a dozen other institutions around the country to teach, and many have been instructors since the program began.

The planning—including logistics, recruiting new instructors, and managing the animal models required for the program—takes a good part of the preceding year, explained Drs. Joseph Ackerman and Joel Garbow of Washington University, who have served as the program hosts for the past 3 years.

"But it's such a labor of love for these faculty," said Dr. Anne Menkens, program director of the CIP's Molecular Imaging Branch and NCI coordinator of Imaging Camp. "We don't have to spend any time cajoling people into participating. Training the next generation is what drives them."

The student-to-faculty ratio is kept almost one-to-one; having only 25 students attend each year allows for nearly constant interaction between the imaging experts and the trainees. The faculty often learns new facts about cancer biology from the students, recounted Dr. Cristian Badea, a physicist and associate professor of radiology at Duke who has served as an instructor since Imaging Camp's first year.

"Every camp is a new experience. People bring all kinds of expertise, and I learn new things every year from the participants," he said. "I think the future of imaging is multidisciplinary, and while we're here we can start to break down the barriers of communication between the disciplines."

Through these conversations, "the students learn to talk to the imagers, the lingo, what to ask about their research," Dr. Sloane elaborated. "This is critically important because a lot of [imaging technology] is so sophisticated, a lot of junior people who haven't been exposed to it can be intimidated."

Creating Collaborations and Professional Relationships

Imaging Camp emphasizes collaboration and cooperation. The process begins on the first night, when participants present their current research and solicit ideas from the audience—both faculty and fellow students. Sharing continues in the halls as students are encouraged to swap papers and suggestions, many of which have led to collaborative projects among the trainees, said Dr. Menkens. The collaboration and cooperation continues in formal question-and-answer sessions designed to make sure that every question reaches the most appropriate experts.

The faculty also helps point the new imaging researchers toward potential mentors, bringing the trainees into their own extensive networks. "We encourage them to use the expertise of the camp to help them find a laboratory to work with that has that technology they need," said Dr. Krohn.

Sometimes those mentors are Imaging Camp faculty. Dr. Sloane has hosted a former Imaging Camp student who wanted more optical imaging experience. Dr. Samuel Achilefu, a professor of radiology at Washington University, who has run the optical imaging program at Imaging Camp for the past 4 years, is proud that several former students from Imaging Camp have collaborated with his group.

Some of these collaborations have turned into major projects. Dr. Garbow is participating in the first year of research on a grant won by Dr. Cheryl Jorcyk, an associate professor at Boise State University who attended Imaging Camp in 2009. "By chance we sat down next to each other at dinner, and when we stood up we had a research plan," remembered Dr. Garbow.

Their research project, funded by the Susan G. Komen for the Cure foundation, combines Dr. Jorcyk's expertise in the biology of breast cancer metastasis with Dr. Garbow's experience in imaging small-animal models of cancer. "I think our project is a model for the way collaborations might develop through this kind of training program," concluded Dr. Garbow.

Sharon Reynolds

Cancer Research Imaging Camp Students

Every year, 25 students are selected for the Cancer Research Imaging Camp. They come from diverse backgrounds, including chemistry, molecular biology, pharmacology, and even comparative oncology. Read profiles of three students and their interest in imaging training below.

Dr. Monique Spillman Dr. Monique Spillman

Dr. Monique Spillman
Assistant Professor of Gynecologic Oncology
University of Colorado, Denver

For her research on the effects of estrogen and progesterone on ovarian cancer, Dr. Spillman had previously developed a mouse xenograft model and used fluorescence to detect cancer cells within the abdomen, but that technique "lacks sensitivity for deep lymph node metastases," which is an area of translational research she and her colleagues hope to explore, she explained. Lymph-node staging for women with early-stage ovarian cancer, which is vital for determining appropriate treatment, currently requires extensive surgical sampling. An in vivo imaging probe that recognizes deep metastases "would be less invasive and more informative," and could also be used in her laboratory to better understand the biology driving the spread of ovarian cancer to lymph nodes.

Dr. Vijay Ramakrishnan Dr. Vijay Ramakrishnan

Dr. Vijay Ramakrishnan
Postdoctoral Researcher in Hematology
Mayo Clinic

Dr. Ramakrishnan has been testing novel drugs and drug combinations on human multiple myeloma cell lines and in cells taken from patients, examining the role of bone marrow stromal cells and endothelial cells in disease progression. "We know that the bone marrow stromal cells and endothelial cells interact, but we don't understand how that interaction affects disease progression and response to chemotherapy," Dr. Ramakrishnan explained. He hopes to develop an animal model to monitor these interactions noninvasively in vivo. But before he attended Imaging Camp, Dr. Ramakrishnan had no experience with imaging. "[My colleagues and I] think both in vivo and live-cell imaging are going to be very informative as to how these cell-cell interactions are altered after treatment with particular chemotherapy agents," he said.

Dr. Jackie Wypij Dr. Jackie Wypij

Dr. Jackie Wypij
Assistant Professor of Veterinary Clinical Medicine
University of Illinois, Urbana-Champaign

As a member of the Comparative Oncology Trials Consortium, Dr. Wypij not only works on clinical trials of novel therapies for pets with cancer, she also looks for ways to translate her knowledge to human cancers. "There's a big black box between mouse and human research, and maybe our patients can fill this in. The genetics in some canine and feline cancers are quite close to some human cancers," she explained. "People are interested in having their pets participate in trials. They want to do it for their pets, but they also feel good about giving something back, that they might be helping people in the future as well." Her group does a lot of clinical imaging for dogs and cats, but "we don't yet incorporate the advanced research imaging methods into our research and trials, and that's what I'd like to do, particularly to look for biomarkers we can use for testing new treatments," she elaborated.

Featured Clinical Trial

Adding Targeted Therapy to Treatment for Esophageal Cancer

Name of the Trial
Phase III Randomized Study of Radiotherapy, Paclitaxel, and Carboplatin with versus without Trastuzumab in Patients with HER2-Overexpressing Esophageal Adenocarcinoma (RTOG-1010). See the protocol summary.

Dr. Howard Safran Dr. Howard Safran

Principal Investigator
Dr. Howard Safran, Radiation Therapy Oncology Group

Why This Trial Is Important  
Esophageal cancer that is confined to the esophagus and nearby lymph nodes (locally advanced disease) is often treated with a combination of chemotherapy, radiation therapy, and surgery (called trimodality therapy). Although trimodality therapy sometimes cures the disease, relapses are common, and many patients ultimately die from their disease. New strategies are needed to help prevent recurrences in patients with locally advanced esophageal cancer.

Samples of tumor tissue removed during biopsy or surgery indicate that about 20 percent to 30 percent of esophageal cancers express a growth factor receptor protein called HER2 (that is, the tumors are HER2 positive). Treatment with trastuzumab (Herceptin), a drug that targets HER2, improves the survival of women with HER2-positive metastatic breast cancer, and the drug markedly decreases cancer recurrence and improves the survival of women with earlier-stage HER2-expressing breast tumors. Doctors hope that trastuzumab may likewise reduce disease recurrence and improve the survival of people with HER2-positive esophageal cancer.

A recent phase III trial involving patients with advanced gastroesophageal and gastric cancers has bolstered the case for using trastuzumab in esophageal cancer. In that trial, patients with HER2-expressing tumors that could not be removed surgically (unresectable disease) were treated with chemotherapy and trastuzumab or with chemotherapy alone. Patients who received trastuzumab were more likely to respond to treatment and lived about 2.4 months longer. 

In another trial, researchers at Brown University, led by Dr. Safran, conducted a pilot study of trastuzumab combined with chemotherapy and radiation therapy followed by surgery in 19 patients with locally advanced HER2-positive esophageal cancer and showed that the combined therapy was safe. They now want to see if adding trastuzumab to potentially curative therapy will help patients avoid disease recurrence and death.

In this phase III clinical trial, people with confirmed HER2-positive locally advanced adenocarcinoma of the esophagus will be randomly assigned to receive preoperative radiation therapy and chemotherapy, with or without trastuzumab. Following surgery, patients assigned to the trastuzumab arm of the study will receive maintenance therapy with trastuzumab for 1 year. The study is designed to determine whether the addition of trastuzumab improves disease-free survival and overall survival.

"The recurrence rate in locally advanced esophageal adenocarcinoma is very high, and we can only cure about 25 percent of the patients we treat with trimodality therapy," said Dr. Safran. "In [HER2-positive] breast cancer, trastuzumab reduces recurrence by about 50 percent. So one would hope that, in patients with esophageal cancer, it will have that same reduction in recurrence."

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

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/featured.

FDA Update

Potential Cardiac Risks Associated with Smoking Cessation Drug

The Food and Drug Administration (FDA) has updated the prescribing information label on the smoking-cessation drug varenicline (Chantix) to warn that the drug may increase the risk of certain cardiac events in people with underlying cardiovascular disease.

The change is based on findings from a clinical trial of 700 smokers who have cardiovascular disease, according to a safety announcement issued by the FDA on June 16. Trial participants were randomly assigned to receive varenicline or a placebo for 12 weeks and were then followed for an additional 40 weeks without treatment. Although cardiac events “were infrequent overall,” the agency noted that “certain events, including heart attack, were reported more frequently in patients treated with Chantix than in patients treated with placebo.”

Other cardiac events included small increased risks of chest pain, the need for coronary revascularization procedures, and peripheral vascular disease. The two most common events in patients taking varenicline were nonfatal heart attacks (7 versus 3 among those taking the placebo) and coronary revascularization procedures (8 versus 3). Five of the seven patients who required a revascularization procedure were from the same group of participants who had had a nonfatal heart attack.

Physicians should be aware of these risks and discuss the benefits and potential risks of varenicline with their patients who have heart disease, the agency stated in the announcement. In July 2009, the FDA added a “black box” warning about the increased risks of neuropsychiatric symptoms associated with their use to the labels of varenicline and another smoking cessation drug, bupropion (Zyban).

Diabetes Drug May Increase Risk of Bladder Cancer

Use of the diabetes drug pioglitazone (Actos) for more than 1 year may increase the risk of developing bladder cancer, according to a June 15 safety announcement from the FDA.

The announcement is based on a 5-year interim analysis of a 10-year prospective cohort study of safety data being conducted by the drug’s manufacturer, Takeda Pharmaceuticals. The study includes more than 193,000 patients who are part of the Kaiser Permanente Northern California health plan. All patients in the study are 40 years of age or older and have been diagnosed with diabetes.

No overall increase in bladder cancer risk was seen in those using pioglitazone compared with those who had never taken the drug. Patients who had been taking the drug for 12 to 24 months, however, had a 40 percent higher risk of developing bladder cancer than people who had never taken it. 

“Although there was no overall increased risk of bladder cancer with pioglitazone use, an increased risk of bladder cancer was noted among patients with the longest exposure to pioglitazone, and in those exposed to the highest cumulative dose of pioglitazone,” the FDA reported.

French health officials recently announced similar findings from a much larger retrospective study of 1.2 million patients taking pioglitazone. Based on the finding, health officials in France halted the use of pioglitazone. In addition, German health officials have ordered clinicians not to prescribe the drug to new patients.

The FDA has advised U.S. physicians not to prescribe pioglitazone for patients with bladder cancer and to use it “with caution” in those who have been treated previously for bladder cancer. “The benefits of blood sugar control with pioglitazone should be weighed against the unknown risks for cancer recurrence,” the agency stated.

Cancer.gov Update

NCI Launches International Clinical Trials Portal

Screenshot of the International Collaboration in Clinical Trials portal

NCI has launched the International Collaboration in Clinical Trials portal, a site designed to strengthen international alliances in cancer clinical trials. The portal provides a central location for online resources that will help investigators outside the United States navigate the legal and regulatory issues that come with collaborating on clinical trials with U.S.-based research groups.   

Legal, regulatory, logistical, and financial hurdles often delay international clinical trials, and clinical investigators from other countries sometimes need step-by-step guidance on launching a study protocol or joining a U.S. cooperative research group. Moreover, international cancer researchers typically have questions about NCI's role in clinical trials and how the U.S. clinical trials process works in general.

NCI conducted in-depth interviews with clinical cancer investigators from more than 11 countries to determine what should be included in the new portal. Based on those interviews, the portal provides background information on NCI-designated cancer centers, U.S.-based clinical trials cooperative groups, and NCI's international programs.

A section of the site is dedicated to answering common questions about biospecimen collection, clinical trial ethics, insurance, drug labeling and distribution, and quality assurance. As international investigators navigate through the portal, they will find links to registration forms and laws that regulate U.S. clinical trials.

"This new portal on Cancer.gov will help NCI's existing partners—and prospective new partners—navigate hurdles to keep up momentum of our clinical trial alliances," said Dr. Ted Trimble, acting director of NCI's Center for Global Health. "Collaborating internationally on cancer clinical trials enables progress in cancer treatment and screening. Completing larger trials across multiple countries can ensure that new methods have a global reach."

Notes

In Memoriam: PDQ Board Member James Nachman

Dr. James Nachman Dr. James Nachman (Image courtesy of University of Chicago)

Dr. James B. Nachman, 62, who served for 13 years as a member of NCI's Physician Data Query (PDQ) Pediatric Treatment Editorial Board, died June 10 while on a rafting trip with friends in the Grand Canyon.

Dr. Nachman was an internationally renowned authority on the medical management of hematologic cancers in adolescents and young adults and an acknowledged expert in bone cancer and soft tissue sarcomas. He was a professor of Pediatrics and director of the Leukemia/Lymphoma Program at the University of Chicago Comer Children's Hospital.

Dr. Nachman was also a leader of the acute lymphoblastic leukemia (ALL) and lymphoma study committees of the Children's Oncology Group, which is part of NCI's Clinical Trials Cooperative Group Program. He was a member of the American Society of Hematology and the American Society of Pediatric Hematology/Oncology, as well as a co-founder of the International Ponte di Legno ALL Study Committee.

After graduating from the University of Illinois in 1970, Dr. Nachman went on to earn his medical degree from the Johns Hopkins University Medical School in 1974. He completed his residency in pediatrics and a fellowship in hematology/oncology at Children's Memorial Hospital in Chicago before joining the faculty of the University of Chicago as an assistant professor in 1980. He was promoted to associate professor of Clinical Pediatrics in 1985 and professor in 1999.

Survivors include his father, Dr. Adolph Nachman; his brother, Robert; and his sister, Cathy.

DCEG Training Program Receives Langmuir Award

Dr. Jackie Lavigne accepts the Alexander D. Langmuir Award for Training Program Excellence and Innovation on behalf of DCEG. Dr. Jackie Lavigne accepts the Alexander D. Langmuir Award for Training Program Excellence and Innovation on behalf of DCEG.

NCI's Division of Cancer Epidemiology and Genetics (DCEG) last week won the inaugural Alexander D. Langmuir Award for Training Program Excellence and Innovation. Dr. Jackie Lavigne, chief of DCEG's Office of Education (OE), accepted the award during a ceremony at the 3rd North American Congress of Epidemiology in Montreal, Quebec, Canada.

The award highlights epidemiology training programs that emphasize research experience and skills development, the application of epidemiology principles and advanced methods, and the importance of collaborative and integrative epidemiologic approaches.

"This award acknowledges NCI's training program for having developed and implemented creative educational offerings that effectively train future leaders in epidemiology," said Dr. John Vena, the award committee chair.

Under the guidance of experienced mentors, DCEG fellows design and execute research studies, analyze data, and interpret and publish the results. DCEG also offers fellows practical opportunities to develop professional skills, including giving research presentations, planning scientific events, mentoring, and grant writing. Current and recent DCEG fellows are lead authors in most of the top journals in the field—evidence of the program's success.

The award honors the memory of Dr. Alexander D. Langmuir, who created the Epidemic Intelligence Service, a combined training and service program for epidemiologists at the Centers for Disease Control and Prevention.

NCAB Meeting Held This Week

The 158th meeting of the National Cancer Advisory Board (NCAB) was held yesterday and today on the NIH Campus in Bethesda, MD.

Dr. Harold Varmus opened the meeting with the NCI Director's Report. The board then heard presentations on a number of topics, including the Pharmacodynamics and Therapeutics Functional Working Group, the 12th Report on Carcinogens, and the results from NCI's National Lung Screening Trial.

The agenda is available online, and an archived videocast of the meeting will be posted in a few days.

NCI Hosts BSA Meeting June 20

NCI's Board of Scientific Advisors (BSA) met June 20 on the NIH campus in Bethesda, MD. In addition to a report from NCI Director Dr. Harold Varmus, the meeting included presentations on the cancer Bioinformatics Grid (caBIG) and NCI's Provocative Questions project. NCI Deputy Director for Clinical and Translational Research Dr. James Doroshow provided an update on the current shortage of drugs for cancer and other diseases.

In response to a request from the NCI director, BSA chair Dr. Richard Schilsky of the University of Chicago Pritzker School of Medicine reflected on his experience serving on the board for more than a decade. Among other remarks, Dr. Schilsky noted that there is "enormous talent" on the board and offered some thoughts about how NCI might best use this talent moving forward. A group discussion followed.

Dr. Schilsky and other board members who have completed their terms were recognized. These included Dr. Paul M. Allen of the Washington University School of Medicine in St. Louis; Dr. Christopher J. Logothetis of the University of Texas M. D. Anderson Cancer Center; Dr. Todd R. Golub of the Broad Institute; Dr. James K. Willson of the University of Texas Southwestern Medical Center; Dr. Jean Y. J. Wang of the University of California, San Diego, School of Medicine; and Dr. Edith A. Perez of the Mayo Clinic in Jacksonville, FL.

A PDF of the agenda is online, and a videocast of the full meeting is available here.

Telephone Workshop for Cancer Survivors to Focus on Late Effects

The final telephone workshop in the annual "Living With, Through, and Beyond Cancer" series will be held July 12 from 1:30 to 2:30 p.m. ET. Part IV of the series is titled "Fear of Recurrence and Late Effects: Living with Uncertainty."

The free series offers cancer survivors, their families, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends. The workshops are presented by CancerCare in collaboration with NCI, LIVESTRONG, the American Cancer Society, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Speakers for the July 12 workshop are Richard Dickens of CancerCare, Dr. Merle Mishel of the University of North Carolina at Chapel Hill, and Dr. David Spiegel of the Stanford University School of Medicine.

These workshops are free; no phone charges apply. To register, visit the CancerCare registration page.

If you missed any of the earlier workshops in the series, you can listen to Part I: Chemobrain, Part II: Weight Changes After Cancer Treatments, and Part III: Stress Management for Caregivers online.

Japanese Translators of the Bulletin Visit NCI

Japanese translators and Bulletin staff Takako Tadokoro (left) and Dr. Takefumi Komiya met some of the Bulletin staff on June 10. (Photo by Sarah Curry)

The staff of the NCI Cancer Bulletin met with Takako Tadokoro, vice president of the Japan Association of Medical Translation for Cancer, on June 10. The association translates NCI Cancer Bulletin articles and other NCI materials into Japanese. These translations, Tadokoro explained, provide information about cancer to ordinary people in Japan, where, she said, very little cancer information is available for a nonscientific audience.

Dr. Takefumi Komiya, a clinical fellow in NCI's Medical Oncology Branch and a volunteer translator, arranged the meeting.

Japanese readers may find the translations online.