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In a study published September 1 in Cancer Epidemiology, Biomarkers and Prevention, African Americans were significantly more likely than whites to die of pancreatic cancer, even after adjusting for all known risk factors for pancreatic cancer including smoking and obesity. These data suggest that unidentified genetic risk factors, environmental exposures, or gene-environment interactions may play a role in this health disparity. "Our data do not explain what is causing these disparities, but we hope it encourages researchers to continue looking for reasons why blacks develop and die from pancreatic cancer at higher rates than whites," stated lead author Dr. Lauren Arnold of Washington University in St. Louis in an accompanying press release.
Study Questions Value of Prostate Cancer Screening
Widespread screening for prostate cancer over the past 3 decades using the prostate-specific antigen (PSA) test has led to a flood of men being diagnosed with and treated for prostate cancer that never would have harmed them, according to a new study. The jump in diagnoses was most pronounced among younger men, with rates more than tripling for men aged 50 to 59 and increasing seven-fold for those aged 50 and younger. The study was published online August 31 in the Journal of the National Cancer Institute (JNCI). Read more > >
Genetic Study Points to Potential Treatment for MelanomaClinical trial is being planned to test lapatinib in selected patients
Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic CancerTrial testing the Gonzalez regimen was one of the first to compare survival following standard or alternative treatments
Denosumab Keeps Bones Strong during Prostate Cancer TreatmentThe monoclonal antibody prevented fractures in men receiving common therapy and is under consideration by FDA
Weight Lifting Reduces Lymphedema Symptoms after Breast CancerFinding contradicts past recommendations to avoid the activity
In West African Women, Majority of Breast Cancers Have a Poor PrognosisDisparate rates may be due to a combination of biological and non-biological factors
Guest Director's Update: Finding the Right Mix of Care Providers for Cancer Patients
Whether treatment is received at a comprehensive cancer center or, as is the case for the majority of patients, at a community hospital, it's unclear who is directing and coordinating the clinical care decisions for those undergoing active treatment. With the expected increase in cancer incidence (due in large part to an aging population), the health care community must begin to focus on this critically important issue. Read more > >
A Conversation about Personal Genomic Tests with Dr. Muin Khoury
The director of CDC's National Office of Public Health Genomics discusses the science behind personal genomic tests. These tests, which include "genetic risk profiles" for cancer and other common diseases, are sold directly to consumers. Read more > >
NCI Cancer Bulletin Articles
in Spanish
Beginning September 15, NCI will publish the Boletín del Instituto Nacional del Cáncer, a modified Spanish-language translation of selected articles previously published in the NCI Cancer Bulletin. This new resource offers Spanish-speaking readers up-to-date articles on the latest research advances in the prevention, treatment, and understanding of cancer. To receive the monthly selection, email email@example.com or view the articles at http://www.cancer.gov/espanol.
In Cancer, Hitting a Target Called HedgehogA new type of cancer drug shows promise in an early stage clinical trial
Growing Pains: Palliative Care Making GainsEvidence builds to make a case for palliative care's value, but challenges remain
Proton Therapy for Cancer: A New Technology BriefEnthusiasm for this promising therapy may be getting ahead of the research
Featured Clinical Trial: Testing a New Drug in Advanced BRCA-related CancerIs the combination of AZD2281 and carboplatin safe for women with BRCA-related breast or ovarian cancer?
FDA Update
- New FDA Center and Advisory Committee Launch Regulation of Tobacco
- Agency Issues New Rules for Obtaining Investigational Drugs
- Dr. William Dahut Named CCR Clinical Director
- NCI Tobacco Control Monograph Addresses Genetics of Nicotine Dependence
- CRCHD Hosted Professional Development and Diversity Training Conference
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 email@example.com.
Featured Article
Study Questions Value of Prostate Cancer Screening
Widespread screening for prostate cancer over the past 3 decades using the prostate-specific antigen (PSA) test has led to a flood of men being diagnosed with and treated for prostate cancer that never would have harmed them, according to a new study. The jump in diagnoses was most pronounced among younger men, with rates more than tripling for men aged 50 to 59 and increasing seven-fold for those aged 50 and younger. The study was published online August 31 in the Journal of the National Cancer Institute (JNCI).
That PSA screening has resulted in significant prostate cancer "overdiagnosis," as it is often called, is not new. Results from two clinical trials published earlier this year pointed to an identical conclusion. The new study, however, places the extent of the problem in stark context, estimating that in the 30 years since PSA testing was introduced, approximately 1.3 million more men have been diagnosed with prostate cancer than otherwise would have in the absence of such screening, and concluding that very few men's lives have been saved as a result.
The findings, said study co-author Dr. H. Gilbert Welch of Dartmouth Medical School, "show that there's been a pronounced population effect" associated with PSA testing; that it's "not just a theoretical problem seen in a clinical trial."
To conduct the study, Dr. Welch and his co-author, Dr. Peter C. Albertsen of the University of Connecticut School of Medicine, relied on NCI's Surveillance, Epidemiology, and End Results (SEER) program and the U.S. Census to get data on age-specific incidence of prostate cancer and patients' initial treatment following diagnosis from 1986 to 2005.
The base year, 1986, was chosen because it was the year before an influential study on PSA screening appeared in the New England Journal of Medicine. Prostate cancer incidence increased 10 percent the following year, "a magnitude of increase never before observed for prostate cancer in the SEER program and a magnitude that strongly suggests the onset of screening," the authors explained.
Among the estimated 1.3 million excess prostate cancer diagnoses, slightly more than 1 million men received definitive treatment, such as surgery, hormone therapy, or radiation therapy. "But even using the most optimistic assumption about benefit, the vast majority of these additional 1 million men did not benefit from early detection," the authors wrote.
That point, said Dr. Marc Garnick from Beth Israel Deaconess Medical Center in Boston, shows that the term "overdiagnosis" may incorrectly describe this problem. "I think it's perfectly reasonable to diagnose patients" based on PSA screening, he said. "The problem is that many men have been over treated."
Dr. Peter Carroll, chair of the University of California, San Francisco's (UCSF) Department of Urology, agreed. "When first diagnosed, patients view prostate cancer like lung and pancreatic cancer. They don't differentiate it from much more lethal forms of disease," he said. "We have to get that out there, in patients' and physicians' minds, that prostate cancer can be a manageable disease" without immediate treatment.
At Beth Israel and UCSF, a growing population of men who undergo PSA testing and are considered to be at low risk for progression of the disease—based on factors such as age, degree of cancer involvement on the biopsy, Gleason score (an indication of the tumor's potential aggressiveness), and other factors—are choosing active surveillance, where they carefully watch for symptoms and come in for periodic biopsies to monitor their disease.
But even active surveillance has significant implications, Dr. Welch countered, from the regular biopsies to the social impact of being considered a person with cancer. Education and communication are needed before the first PSA test is conducted, he said.
"Those who undergo PSA screening…should be informed patients who accept the harms and want to get the relatively small benefit, and accept all of the side effects that can occur along the way," he said.
At the same time, it should be noted that prostate cancer mortality has fallen 40 percent since 1993, most likely due in some part to PSA screening. An NCI-supported modeling study published last year suggested that PSA screening was responsible for as much as 70 percent of the decrease because testing shifted the stage at which the disease was diagnosed. And one of the two recently published prostate cancer screening trials, conducted in Europe, suggested that screening with PSA had a modest effect on prostate cancer mortality. The same trial, however, estimated that more than 1,400 men would have to be screened, and nearly 50 treated, to prevent 1 prostate cancer death.
In an editorial that accompanied the JNCI study by Drs. Welch and Albertsen, American Cancer Society Chief Medical Officer Dr. Otis Brawley took a grim view of widespread PSA screening. "Results from this article and recent results from prostate cancer screening and prevention trials demand reflection about what we as a society have done and are doing," he wrote.
—Carmen Phillips
A study released online August 31 in the Journal of Clinical Oncology confirms results from earlier studies showing that deferring treatment after prostate cancer diagnosis does not increase the risk of dying from prostate cancer. The study looked at more than 3,000 men diagnosed with prostate cancer between 1986 and 2007. Although only 10 percent of men chose to defer treatment after their initial diagnosis, approximately half still had no definitive treatment after 7 years of follow up. And the death rate from prostate cancer was nearly identical in men who deferred treatment compared with those who chose immediate treatment.
Cancer Research Highlights
Genetic Study Points to Potential Treatment for Melanoma
A survey of genetic changes in melanoma skin cancer has found that nearly one patient in five may have mutations in a gene called ERBB4. The investigators believe that these mutations contribute to cancer and may make tumors susceptible to therapies that target the mutations. One such drug, lapatinib (Tykerb), which is used to treat some breast cancers, slowed the growth of cells with ERBB4 mutations in the laboratory.
The study, in the September Nature Genetics, is part of ongoing efforts by researchers at the National Human Genome Research Institute (NHGRI) and NCI to investigate the biology of melanoma and to identify potential targets for new therapies. Dr. Steven Rosenberg, chief of surgery at NCI's Center for Cancer Research, co-led the study and provided tissue from patients with metastatic disease.
When Dr. Yardena Samuels of NHGRI and her colleagues sequenced the family of tyrosine kinase genes in 79 samples, they found ERBB4 mutations in 19 percent of them. Tyrosine kinases are proteins that help regulate the growth of cells, and mutations in these proteins can lead to cancer. Mutant kinases interest researchers because they have been the basis of successful drugs such as imatinib (Gleevec).
Lapatinib, which targets a related gene, eradicated cells with ERBB4 mutations. "The drug specifically kills cells with these mutations, and not cells without the mutations," noted Dr. Samuels. "This observation suggests that we have found what appears to be an Achilles' heel of a sizable share of melanomas."
No single tyrosine-kinase inhibitor is likely to have dramatic effects for patients, cautioned Dr. Rosenberg, who will lead a planned trial to test the strategy in patients. Nonetheless, he added, "this study is an elegant example of the translation of basic science to patient care. By pursuing basic research questions, we developed the information that could lead to an important treatment for patients."
Earlier this year, these investigators published a similar study of the family of matrix metalloproteinase (MMP) genes in melanoma. Knowledge gained from this study has informed efforts to develop therapies against tumors with MMP mutations, the researchers said.
Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic Cancer
In a clinical trial testing an experimental enzyme regimen against gemcitabine-based chemotherapy for advanced pancreatic cancer, patients receiving chemotherapy lived an average of 9.7 months longer. This trial was "among the first controlled, clinical studies to compare allopathic treatment to an alternative medicine program for a survival end point," wrote the authors from Columbia University. The results were published August 17 in the Journal of Clinical Oncology.
The trial was opened in 1998 as a randomized controlled study, but was altered in 2001 to a controlled, observational design due to slow patient accrual. Between 1998 and 2005, the researchers enrolled 23 patients into the chemotherapy group and 32 patients into the experimental group.
Patients in the chemotherapy group received treatment on a schedule chosen by their treating physician. Patients in the experimental group followed the Gonzalez regimen, in which they received pancreatic enzyme pills and nutritional supplements, ate a strict organic diet, and underwent a detoxification program. Patients in the experimental group survived for an average of 4.3 months after beginning treatment, compared to 14 months in the chemotherapy group.
The report was "a good attempt to bring as much rigor to the analysis as was feasible, given the inability to do a randomized controlled trial," said Dr. Jeffrey D. White, director of NCI's Office of Cancer Complementary and Alternative Medicine. "The study used a concurrent control with identical eligibility criteria and a statistical approach to check if significant bias was allowed in by the lack of randomization. That is a good strategy for other studies having similar difficulties with randomization."
Denosumab Keeps Bones Strong during Prostate Cancer Treatment
Treatment with the monoclonal antibody denosumab increased bone mineral density (BMD) and reduced the risk of fractures in men who received a common treatment for prostate cancer that had not spread to other parts of the body, according to the results of a large, placebo-controlled clinical trial. The findings appeared in the August 20 New England Journal of Medicine.
The Hormone Ablation Bone Loss (HALT) trial included nearly 1,500 men with nonmetastatic prostate cancer who were undergoing androgen deprivation therapy, a treatment that can increase the risk of bone fractures. The trial showed that two injections of denosumab, one every 6 months, increased BMD in the lumbar spine (the lower back) by 5.6 percent, whereas men who were randomized to receive a placebo experienced a 1 percent decrease in BMD in the same region. Denosumab also increased bone density in other areas, including the neck and hip.
"The beneficial effects in the denosumab group appeared robust, as they were found as early as 1 month after therapy was begun and were sustained for 3 years," wrote lead investigator Dr. Matthew R. Smith of Massachusetts General Hospital and his colleagues. The rates of adverse events were similar between the two treatment groups.
Denosumab is the first drug developed that targets a molecule called RANKL, which spurs the activity of cells called osteoclasts that break down bone. It works in a different way than several other classes of drugs, including bisphosphonates, that are currently used to treat osteoporosis and bone loss.
Publication of the trial results coincided with a meeting of an FDA advisory committee to consider whether denosumab should be approved by the agency for several indications. The committee voted in favor of an approval for denosumab for the treatment of bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer but against its use for bone loss prevention, due to the potential for the small, increased risk of certain infections, including skin and urinary tract infections, seen in some clinical trials involving denosumab.
"Some patients undergoing androgen deprivation therapy may not develop enough loss of BMD to cause an increased risk of bone fracture," explained Dr. James L. Gulley, of the Laboratory of Tumor Immunology and Biology in NCI's Center for Cancer Research, who was a voting member on the FDA advisory committee. "And the general feeling of the committee was, until we get more safety data, let's not recommend an indication for prevention of BMD loss," he said.
Weight Lifting Reduces Lymphedema Symptoms after Breast Cancer
Many breast cancer survivors develop lymphedema, an uncomfortable and sometimes painful swelling in the upper arm or hand that can be debilitating and disfiguring and for which there is no cure. Contradicting past recommendations to avoid heavy lifting and repetitive movement after breast surgery, the largest randomized controlled study conducted to date has shown that slowly progressive weight lifting does not increase arm swelling and appears to be safe. The women who lifted weights improved their strength, said the authors, and had far fewer lymphedema symptoms.
The study, which appeared August 13 in the New England Journal of Medicine, was led by Dr. Kathryn H. Schmitz, an exercise physiologist and assistant professor at the Abramson Cancer Center of the University of Pennsylvania. The researchers designed the intervention to be delivered by community fitness centers such as the YMCA with the hope that the program could be widely adopted.
Half of the 141 women were randomly assigned to the weight-lifting group. These women joined a local fitness center, where trainers taught them useful exercises, supervised their progress, and monitored them for lymphedema flare ups over the course of 1 year. The women assigned to the control group maintained their current level of exercise. Control patients received significantly more treatments for lymphedema flare ups than patients who lifted weights (195 times versus 77 times).
Dr. Wendy Demark-Wahnefried from the University of Texas M.D. Anderson Cancer Center in Houston called the study "a substantial contribution to the available evidence to support weight lifting intervention…[which] provides strong reassurance regarding the safety" of supervised weight training. She added that inclusion of "nonwhite women and women with a broad range of occupational and educational levels suggests that the study findings are highly generalizable…and may be particularly worthwhile in disadvantaged populations" that are affected the most by lymphedema.
"This study advances our understanding of lymphedema and adds a potentially important management strategy for this troubling cancer treatment effect," said Dr. Noreen Aziz, senior program director of NCI's Office of Cancer Survivorship. "The lymphedema measurement methodologies used by these investigators could be disseminated to practitioners involved in the care of women at risk for lymphedema so that this condition can be detected early and carefully monitored."
In West African Women, Majority of Breast Cancers Have a Poor Prognosis
An analysis of the distribution of breast cancer subtypes in West African women has found that the majority of tumors were triple-negative cancers, either basal-like (with gene signatures similar to normal basal cells in the breast) or unclassified subtypes. The study led by Dr. Olufunmilayo Olopade of the University of Chicago was published August 24 in the Journal of Clinical Oncology.
Different breast cancer subtypes are associated with different prognoses. Triple-negative breast cancer, which lacks both hormone receptors and HER2 proteins, has a poor prognosis and has been shown to disproportionately affect African American women.
Since West Africa "is the founder population of most African Americans," explained the researchers, they examined tissue samples taken from 507 women with breast cancer between 1996 and 2007 in six geographic districts in West Africa.
The proportion of breast cancers that were estrogen-receptor positive (which have a good prognosis) was only 25 percent among the West African women. A group of African American women with the same age distribution as the West African cohort would be expected to have 55 percent estrogen receptor-positive tumors.
The difference in subtype distribution observed "between whites, African Americans, and indigenous Africans suggests that both environmental exposures and genetic background determine breast cancer subtypes," concluded the authors.
In addition, the study found that not all triple-negative tumors can be classified as basal-like; there is a less aggressive unclassified subset of triple-negative tumors that lack molecular markers found in the basal-like subset. These unclassified tumors could be split into two subgroups based on whether they expressed a protein called VEGF, and these two subgroups also showed distinct patterns of tumor aggressiveness, which may have implications for treatment, the authors noted.
Guest Director's Update
Finding the Right Mix of Care Providers for Cancer Patients
Receiving a cancer diagnosis has never been more complex. Although surgery is still a mainstay of cancer treatment, the therapeutic options for many cancers include a growing array of targeted therapies, multiple choices for radiation therapy, and new chemotherapy drugs.
We also know more about the risks and benefits of different treatments, and how specific genetic mutations influence a patient's response to different therapies, meaning we can individualize care to a far greater extent than has ever been possible. And our understanding of the issues that affect cancer survivors, and how to best address them, is improving every day.
When it comes to effective models of cancer care, however, we know far less. Whether treatment is received at a comprehensive cancer center or, as is the case for the majority of patients, at a community hospital, it's unclear who is directing and coordinating the clinical care decisions for those undergoing active treatment. With the expected increase in cancer incidence (due in large part to an aging population), the health care community must begin to focus on this critically important issue.
A recent NCI-led study, conducted by the Cancer Care Outcomes Research and Surveillance (CanCORS) consortium, represents one of the largest efforts to date to address at least one aspect of this issue. The study, which involved a survey of nearly 1,700 primary care physicians (PCPs) and more than 1,600 oncologists, provides one of the first robust assessments of the role that PCPs play for those receiving active care for lung and colorectal cancer.
The findings might surprise some. Most PCPs reported at least some involvement in cancer-related care decisions, and approximately one in five reported heavy involvement in cancer-related care, including choices about surgery and management of co-morbid conditions, pain, and depression. Certain factors, such as age and barriers to referral for more specialized cancer care, influenced the extent of PCP involvement. Nevertheless, the study documented the active role these clinicians play in managing and influencing the treatment of patients with cancer.
There is a complicated and much broader societal context around these findings, including an anticipated shortage of as many as 4,000 oncologists over the next 15 years and indications that PCPs may already be in short supply. These concerning trends make it all the more vital to thoroughly assess existing cancer care models and, ideally, identify better options where they exist.
Along those lines, CanCORS investigators will also look at whether PCPs' active involvement makes a difference in the quality of care and patient outcomes. Such data can help to inform the extent to which PCPs can and should play a role in active cancer care and potentially generate leads for studying existing models of effective, coordinated care.
These studies can also provide the type of data needed for informed policymaking on issues such as training, measuring quality of care, and reimbursement.
With continuing progress in cancer prevention, early diagnosis, and personalized treatment, we will need parallel advances that ensure the appropriate and most effective delivery of care. They are intrinsically linked and essential to our goals of significantly reducing the cancer burden in the most effective and efficient manner possible.
Dr. Rachel Ballard-Barbash
Associate Director, Applied Research Program
NCI's Division of Cancer Control and Population Sciences
A Conversation With
A Conversation about Personal Genomic Tests with Dr. Muin Khoury
Last December, NIH and the CDC convened a workshop to discuss the science behind personal genomic tests. These tests, which include "genetic risk profiles" for cancer and other common diseases, are sold directly to consumers, who provide DNA through saliva or a cheek swab. At the workshop, representatives from academia, personal genomics companies, government, and policy groups discussed the scientific basis of the tests, what needs to happen before results can be used in the clinic, and recommendations for advancing the field.
Dr. Muin Khoury is the first author of a report on the workshop in the August Genetics in Medicine. He directs the National Office of Public Health Genomics at the CDC and is a senior consultant in public health genomics in NCI's Division of Cancer Control and Population Sciences.
What are some examples of personal genomic tests?
Over the last few years, more and more of these products have become available, and they come in a variety of flavors, such as tests for people interested in ancestry. Companies are also selling people genetic risk profiles to assess the risk of common diseases like cancer and diabetes. You can buy these services directly from the companies without interference from your health care provider. The business world seems to be trying to capitalize on recent advances in the science of gene discovery, and as the science continues to mature we are likely to see cheaper and cheaper products out there.
What are your concerns about some of these products?
I am most concerned about the tests that offer advice on health-related issues, such as screening and risk assessment that may lead to clinical interventions. These tests are not ready for prime time—that's the bottom line; I've said this many times and in many articles in the past few years. The currently available tests are not predictive enough to be useful for screening. By and large, they don't add much value to current risk factors used in risk assessment and targeted therapies.
The field of personal genomics is evolving, but it's still in its infancy. The promise of personalized medicine is not what's being offered today to consumers, and the reality is that we may have to wait a while longer before that promise gets fulfilled.
How are risk profiles for cancer determined?
For common cancers such as breast and prostate, researchers have used genome-wide association studies to identify anywhere from 5 to 30 robust genetic variants for each cancer that are associated with the risk of developing these diseases. These variants tend to contribute modestly to a person's overall risk of disease. But they can be assembled together to create some kind of a test to profile a person's risk. The problem with these tests is that, taken alone, they provide incomplete and potentially misleading information about a person's overall risk for these cancers. We do not yet know all of the genetic factors that contribute to risk or how these factors interact with environmental risk factors.
What is known about the usefulness of these tests in the clinic?
If you look at the clinical validity and utility of these tests, it's clear that we haven't crossed a certain threshold of evidence that would allow these tests to be used in the context of primary care. At present, these tests are not reimbursed or covered because of the lack of documented clinical utility.
What do you know about how these tests are being used?
In 2008, our office conducted national surveys of health care providers and consumers about their perceptions and use of personal genomic tests. We found that there was very little use of these direct-to-consumer tests in the community, but awareness of the tests was increasing. More people were asking questions about them. The survey looked at a cross-section of the population in 2008, and of course no one knows how these things will track over time.
Might personal genomic information lead people to change their behavior?
If you are not following the recommended health guidelines and practices, such as eating well and exercising, we do not know whether personal genomic information will cause you to change your behavior. Finding out, for instance, that you have a slightly increased or slightly decreased risk of developing disease "x" may or may not cause you to alter your behavior. At the end of the day, you should still follow the recommendations for screening and detection, and these recommendations currently do not make use of genetic risk information. This could change in a few years if we have additional information and interventions that are based on specific genetic profiles. But it's not the case now.
Do you think that talking about these tests may inadvertently draw people to them?
People need to be savvy consumers when it comes to their own health and health care. They should take a hard and a skeptical look at these products. I'm all for educating the public and the providers, and doing so can lead to teachable moments between providers and patients.
What would you like to see happen next in the field?
We need to discover more genes and understand what these genes do in relation to health outcomes, especially in the context of environmental and social factors. We need to figure out how people respond to genomic information and whether the public benefits from—or is hurt by—having incomplete information that may lead to unnecessary medical procedures, follow-up tests, or even surgical interventions.
In another area, there also needs to be more standardization within the industry. When you buy whole-genome tests that different companies put out, you should come up roughly with the same results. It is one genome after all. But there's been quite a bit of heterogeneity, or lack of consistency, in the laboratory processes and clinical interpretation. There are many kinds of questions, which are laid out in the workshop proceedings we just published in the August 2009 issue of Genetics in Medicine.
Are you curious about your own genomic profile?
If I had a few hundred dollars to spare, I probably wouldn't buy information about my own genome. Some people do find these tests interesting, amusing, and informative, perhaps from a recreational or some other perspective. But from the perspective of promoting health and preventing disease, I don't think we're there yet.
Is there a disease for which personal genomic information may be relevant soon?
Not yet. I don't want to be dogmatic because the science is moving so quickly that things could change in a hurry in this field. But as of today, we're not there.
Special Report
In Cancer, Hitting a Target Called Hedgehog
When new cancer drugs are first tested in people the main goal is to see whether an agent is safe and shows promise. Dramatic responses from patients are rare. So when a closely watched clinical trial published last week showed that patients with untreatable skin cancers had benefited from an experimental drug, it was good news for patients and researchers alike.
The trial was testing a drug designed to block the hedgehog signaling pathway, a cascade of interactions in cells that is essential as embryos develop. The pathway tends to be silent in most adult tissues, but it is switched on improperly in some cancers. A number of companies have experimental hedgehog inhibitors aimed at shutting down this important pathway when it is activated at the wrong time.
Mutations that turn on the pathway are common in basal cell skin cancer, and the trial included 33 patients with very rare cases of the disease, in which the cancer had spread or become so invasive that surgery was no longer an option. Among this group, however, half of the patients responded, some in dramatic fashion.
"This response was great to see, because in most phase I clinical trials you are simply trying to get the dose right and see how the drug behaves in the body," said lead investigator Dr. Daniel Von Hoff of the Translational Genomics Research Institute (TGen). "This was something really special, and we're hoping to see more of it."
Some tumors began to shrink just weeks after patients started taking the drug and side effects were manageable, the researchers reported last week in the New England Journal of Medicine (NEJM). Although the drug—a pill known as GDC-0449—stopped working in some patients, others took it for upwards of 20 months, said coauthor Dr. Charles M. Rudin of the Johns Hopkins Kimmel Cancer Center.
New Options
"What makes this study particularly exciting is that we really have had little to offer patients with advanced basal cell carcinomas," Dr. Rudin continued. "We now have a well-tolerated drug that can induce clinical responses in patients with a fairly high frequency."
In addition to Johns Hopkins and TGen, patients were treated at the Wayne State University Karmanos Cancer Institute in Detroit. The study was sponsored by Genentech, which makes the drug, and the company has opened a phase II trial for patients with this rare type of advanced skin cancer.
The drug is also being tested in children and in young adults with a brain tumor called medulloblastoma. A second report in NEJM describes the experience of a 26-year-old man with metastatic medulloblastoma who had a remarkable but transient clinical response to GDC-0449. Within weeks of starting the drug, he went from being bedridden and in considerable pain to being able to exercise and having no pain. Unfortunately, the disease eventually progressed, and the man died.
"The initial scans looked wonderful, with a really dramatic improvement in the extent of his disease, but his improvement was quite transient," said Dr. Rudin. "Certainly, most of the responses in the basal cell carcinoma appear to be more durable."
Dr. Andrzej Dlugosz of the University of Michigan Comprehensive Cancer Center, who coauthored an editorial accompanying the reports, called the results "quite exciting." He said that the two reports demonstrate the promise of this new class of cancer treatments.
The results need to be confirmed in larger studies, he cautioned, and said it will be important to try to understand why some patients develop resistance to the drug, as often happens with molecularly targeted cancer drugs. (An analysis of the mechanism of drug resistance in the man with medulloblastoma appeared online in Science last week.)
Three Strategies
Dr. Von Hoff presented results on a few patients in the trial at the American Society of Clinical Oncology annual meeting earlier this year, where he said that "the hedgehog pathway is one of the most exciting and promising targets in cancer research."
He then outlined three ways that hedgehog inhibitors could help treat cancer: by targeting tumors driven by the pathway, improving the delivery of conventional drugs, and providing a way to attack rare populations of cells that may give rise to tumors.
While it is critical in embryonic development, the hedgehog pathway also appears to be active in some types of self-renewing cells (also called cancer stem cells) that some researchers believe are critical for the development of some cancers. Many investigators are exploring the idea of disabling these cells by inhibiting the hedgehog pathway.
Hedgehog inhibitors may also boost conventional cancer drugs by altering the local environment around tumors. In May, British researchers said that a hedgehog inhibitor called IPI-926 helped a chemotherapy drug reach pancreatic tumors in mice when it was given along with chemotherapy. The animals that received the combination treatment fared better than those that did not, the team reported in Science.
"Among the pancreatic cancer research community, there is tremendous interest in hedgehog inhibition and the ability to improve the delivery of drugs to pancreatic tumors and ultimately prolong survival," said Dr. Margaret Read, who leads the team that developed IPI-926 at Infinity Pharmaceuticals.
"In the scientific community," she added, "hopes have been high that hedgehog inhibitors would work in basal cell carcinoma, and it's great to see that one has. The big question now is where else will they work?" Based on preclinical data suggesting the importance of this pathway in many cancers, her group and others are testing hedgehog inhibitors in a variety of tumors.
In addition to basal cell carcinoma and medulloblastoma, Genentech is testing its drug in cancers where the hedgehog pathway may be active but where mutations in the pathway do not appear to be present, such as colon and ovarian cancers, said Dr. Josina Reddy, medical director at the company and co-author of the basal cell carcinoma paper.
Genentech plans eventually to seek approval for GDC-0449 as a treatment for locally advanced and metastatic cases of basal cell skin cancer based on the results of the ongoing trials, she added.
In the meantime, the dramatic responses observed in the current study illustrate the promise of a relatively new approach to developing drugs for cancer, noted Dr. Rudin.
"We're linking the molecular biology that underlies a disease to the development of targeted therapies, and then testing them in patients who are likely to respond," he said.
—Edward R. Winstead
Growing Pains: Palliative Care Making Gains
At Virginia Commonwealth University (VCU) Medical Center, some third-year residents and nurses are taking part in something new: mindfulness training. Incorporating aspects of meditation, the 3-month pilot training program is meant to help them better deal with patients approaching the end of life.
"We are teaching these practices to increase clinicians' awareness of the emotional dimensions of end-of-life care," explained the program's leader, Dr. Amy Sullivan, from the school's Department of Social and Behavioral Health. "Our aim is to enhance clinicians' ability to respond to patient and family psychosocial needs at a very vulnerable time."
The goal, in part, added Dr. Thomas Smith, an oncologist and leader in the palliative care program at VCU's Massey Cancer Center, is to improve communication between doctor and patient. "On average, doctors give patients about 17 seconds before they interrupt them," Dr. Smith said.
Improving communication is important. Studies have linked poor doctor/patient communication with inferior outcomes and more aggressive care at the end of life.
The existence of such a training program is one small step in the evolution of palliative care. The growth and changes in palliative care are particularly significant for oncology, where an aging population and a corresponding increase in cancer incidence are expected to expand the need for palliative services. Now a recognized medical subspecialty whose value and importance have been endorsed by the Institute of Medicine and World Health Organization, palliative care has been shown to improve patient outcomes such as symptoms and quality of life, as well as patient and family satisfaction with care. The largest study of its kind, published last year, also demonstrated it can lead to significant cost savings by, among other things, decreasing intensive care unit visits.
Even with these data and recognition, the availability and role of palliative care varies tremendously from hospital to hospital, and funding for palliative care programs at institutions large and small is still limited, explained Dr. Diane Meier, director of the Center to Advance Palliative Care (CAPC) at Mt. Sinai Medical Center in New York. Even so, she continued, the field of palliative care has grown tremendously in the past decade. And with that growth come high hopes.
"Our goal is that all patients newly diagnosed with serious cancer will be seen simultaneously by the treating oncologist and a palliative care interdisciplinary team," Dr. Meier said. "Helping them get through diagnosis, the consequences of their disease, and the side effects of treatment with as good a quality of life as possible. That's the simultaneous-care concept that will be palliative care at its best and most appropriate form. But it will take time to get there."
Clearing Up Misconceptions
Although there are a number of barriers that have limited the penetration of palliative care into medical practice, perhaps the biggest, said Dr. Ann O'Mara, the head of palliative care research in NCI's Division of Cancer Prevention, is that palliative care is still often strictly equated with hospice and end-of-life care. A recent 5-year review of patients seen by the palliative care consult service at the Mayo Clinic, for example, found that although overall referrals for palliative care consultations had increased, the time between when patients with cancer were referred for their consultation and their death had shrunk two fold, from 33 days to 11.5 days. This left a little more than 2 days, the study authors noted, to develop a comprehensive palliative care plan.
Breaking through this misconception is plagued by numerous factors, those in the field report. Lack of training in medical schools is one, although studies suggest that is getting better. Others include the shrinking minutes oncologists have during patient appointments, as well as reimbursement issues.
Limited communication is another factor. "It can depend on how good the palliative care consult team is at educating the staff of oncologists and residents and fellows, letting them know that, 'We're here to help you manage the patients with difficult symptoms or difficult issues,'" Dr. O'Mara said. "Those patients may have a good prognosis but may also have an array of symptoms or psychological or spiritual issues, which the palliative care consult service is in a much better position to address."
Turning the Tide
Even here, Dr. Meier stressed, the ground is shifting in palliative care's favor. Acceptance among oncologists and other treating clinicians of palliative care's value has never been greater, she said. And despite the Mayo Clinic data, "the national trend is that palliative care consultations are occurring earlier and earlier in the course of illness."
At centers like VCU and Mt. Sinai, which have been at the forefront of palliative care for more than a decade, inroads with medical staff have been well laid and are paying off.
Four oncologists at VCU, including Dr. Smith, are board certified in hospice or palliative care. Palliative consultations are "pretty much integrated into much of our [oncology care]," he said. "When we first started, we were only called near the end of life, often as a pre-hospice referral. …Now we often care for those who are made very ill by their treatment or disease and for the actively dying while in the hospital."
Nevertheless, said Dr. Meier, there is a learning curve among oncologists that influences the extent to which palliative care is offered to patients. Part of that is related to the fact that palliative care programs are operated as a consulting service.
"Our goals as consultants are framed by what the referring oncologist asks us to get involved in," she said. If they are called for a consultation, the palliative care team—an interdisciplinary group that can include nurse practitioners, psychologists, social workers, massage therapists, and others—will meet with the patient and make recommendations to their treating oncologists.
Ensuring that palliative care staff don't overstep their role as consultants is critical, stressed Dr. John Cowan, an oncologist who directs the palliative care program at Blount Memorial Hospital, a community hospital approximately 20 miles from Knoxville, TN.
"We want the [treating] physicians involved" in the discussions about patients needs for palliative care and the options open to them, Dr. Cowan said. "If they're not interested, they're probably not going to follow through on our recommendations."
As has been the case at the larger academic medical centers, the palliative care program at Blount Memorial has grown considerably since its inception in 2000. The palliative care team is now more involved in care delivery, but has still struggled to become an ingrained part of the care process "further upstream," Dr. Cowan acknowledged.
Part of that struggle—and something that available evidence suggests is a somewhat universal issue—can be traced back to the patients, who often can be resistant to discussions that veer from those about eliminating their disease. "The patients are staying focused on getting their disease treated and they tend to minimize their symptoms or other problems," Dr. Cowan said.
Patients may also avoid discussing issues like pain and other symptoms, Dr. O'Mara added, out of fear that any changes might represent worsening disease or result in changes to their therapy.
In addition to ongoing research aimed at further delineating the value and improving the conduct of palliative care, CAPC and other groups are also addressing key impediments to the growth of the field, such as securing more training slots and palliative care faculty at medical schools.
There is both a quality of care and business case to be made for palliative care, Dr. Meier believes, and changes could be made to help bring the field along. "I'm hoping to see more cancer centers and hospitals and oncology treatment groups bring palliative care professionals on to their own staff," she said. This way "they don't have to go to a phone to get a consult. Palliative care will just be part of the core services they offer."
—Carmen Phillips
A Closer Look
This is the second article in a series of stories related to cancer technology. Look for the symbol on the left in an upcoming issue for the next article in the series.
Proton Therapy for Cancer: A New Technology Brief
Of the estimated 1.47 million Americans who will be diagnosed with cancer in 2009, 60 to 75 percent will undergo radiation therapy for their disease. In select cities around the country, some of these patients who are hoping to improve their odds for a cure and minimize the long-term adverse effects of radiation therapy will be treated with a relatively new form of it called proton therapy.
Public interest in proton therapy has grown substantially since the FDA approved it in 2001. However, there is concern among members of the medical and research communities that enthusiasm for this promising therapy may be getting ahead of the research.
"Proton therapy has wonderful potential as a treatment for some cancers," said Dr. Kevin Camphausen, chief of NCI's Radiation Oncology Branch, who has referred patients to be evaluated for the treatment when he felt it might work well for their tumor type. "But I don't think its use should become widespread until we can validate where it's needed, and where it has the greatest potential benefit for patients."
The first proton accelerator dedicated to medicine opened at Loma Linda University in California in 1990. Today, a total of seven proton therapy centers in the United States are treating patients and numerous others are under construction or in the planning phase. The treatment is being used most often in children with many cancer types, as well as in adults who have small, well-defined tumors in organs such as the prostate, brain, head, neck, bladder, lungs, or the spine. Proton therapy centers are continuing to test its use for additional cancers.
Better Precision, but What about Accuracy?
When x-rays are fired at a tumor, because they have no charge, they transfer their energy at an evenly decreasing rate to the healthy tissues between the surface of the body and the target, as well as to the tissues beyond the tumor, until they exit the body.
Proton beams, on the other hand, have a positive charge and deliver most of their energy at a defined depth, within a region called the Bragg Peak, like a depth charge delivered to its calculated destination. When the target is hit, healthy tissues are largely spared side effects from treatment and there is greater damage to the tumor. This may diminish the chance of it coming back or of new tumors in the surrounding tissue arising later on.
"Theoretically, proton beams are much more exact than x-rays," said Dr. Norman Coleman, associate director of the Radiation Research Program (RRP) at NCI. "On the computer screen, the calculations look great, and the enthusiasm is understandable. But is that what's really happening in the patient?"
There is no published evidence to indicate that proton therapy is detrimental to patients, Dr. Coleman said, but "when you have something that is so precise with such sharp edges, you need to make sure that it's also accurate. This requires being certain that the target is hit as planned on the computer, including accounting for the uncertainties in diagnostic imaging, reproducibility in patient setup, and internal organ motion."
Dr. Bhadrasain Vikram, who is chief of the Clinical Radiation Oncology Branch in RRP, noted that those who administer proton beams to patients are fairly confident of the width of the beam, but as for the final stopping point, "there is some nervousness that what they're seeing on the computer screen may not be happening in the patient." So for tumors in front of the spinal cord, for example, they will align the proton beam sideways during treatment to minimize the risk of the beam going too far and damaging the neural tissue, he explained.
Assessing the Value for Patients
Experts at NCI and around the country also point out that there is a lack of published randomized controlled trials (RCT) to show that proton therapy works better than standard radiation therapy at increasing survival or improving quality of life for patients.
Dr. Nancy Mendenhall, medical director at the University of Florida Proton Therapy Institute in Jacksonville, explained that while her institution is committed to learning more about the best uses of proton therapy through clinical research—since the facility opened in 2006, approximately 1,500 patients have been treated there, she said, and 95 percent were enrolled in an observational study—there are numerous practical and ethical barriers to conducting an RCT with proton therapy.
"Proton therapy is a rare resource; less than 1 percent of patients in this country have access to it," Dr. Mendenhall said. This is because there are so few centers that provide it, and they can only treat a limited number of patients in a day, she explained. The University of Florida Proton Therapy Institute has three proton therapy rooms where between 110 and 120 patients are treated per day.
"It would likely take 800 or more patients to complete enrollment for one arm of an RCT, but with the same number of patients and time interval, 4 pilot studies could be completed that would advance our understanding of the potential of proton therapy for dose escalation, dose intensification, and hypofractionation, which are our basic radiation therapy methods of increasing disease control," she said. "We believe we have approached these limits with x-ray therapy, but not with proton therapy. We have already completed three pilot studies and feel it is important to continue such studies to learn how to maximize the potential of proton therapy."
Furthermore, she explained, most of the people who come to Florida for proton therapy would not accept being randomized to the control group in a clinical trial. "These are a very special group of patients who are extraordinarily well informed. They've researched the treatment, they understand the technology, and they've decided that it's best for them," she said, adding that in many cases they have also traveled thousands of miles to get it.
Dr. Mendenhall believes that for now, comparing the outcomes of proton therapy with previously published studies of x-ray therapy should be sufficient, until the treatment capabilities of proton therapy have been explored more, there are more treatment slots available, and there is more confidence in the technology and tools that are used to assess outcomes for the comparison group.
The Ultimate Test: Head-to-Head Comparison
The position of those at NCI is that, while this technology is very promising, the gold standard for research is still an RCT. "We would encourage patients who are looking into proton therapy for their particular disease to seek out an NCI-sponsored clinical trial at one of the facilities that provides the treatment," said Dr. Vikram.
At the University of Texas M.D. Anderson Cancer Center and Massachusetts General Hospital, more of these trials will soon be available due to a major P01 "Research Project Program" grant from NCI to fund their collaborative RCT studies of proton therapy for lung cancer and pediatric cancers, as well as technology development.
Studies are also under way through the Children's Oncology Group, noted Dr. James Deye, program director of medical physics in RRP. To ensure that data can be compared across institutions, he added, RRP recently published guidelines for the clinical trials that it sponsors.
In the midst of the national discussion of health care reform, proton therapy may soon start to gather attention for another reason: its suitability for comparative effectiveness research.
"Radiologists and radiation oncologists accumulate electronic data easily; it's just part of the way that we go about our daily business," said Dr. Coleman, who explained how the field is particularly ripe for doing comparative effectiveness research with proton therapy, as well as other emerging radiation therapies, such as carbon ion therapy.
"We have the images and the data right in front of us," he said. "If we add outcomes to that, then we have a lot of good information about whether something new actually works better in the long run than what we were already using."
Featured Clinical Trial
Testing a New Drug in Advanced BRCA-related Cancer
Name of the Trial
Phase I Study of AZD2281 and Carboplatin in Patients with BRCA1/BRCA2-associated or Familial Metastatic or Unresectable Breast and/or Ovarian Epithelial Cancer (NCI-08-C-0092). See the protocol summary.
Principal Investigator
Dr. Elise Kohn, NCI Center for Cancer Research
Why This Trial Is Important
The genes BRCA1 and BRCA2 are human tumor suppressor genes. People who inherit a mutated form of either of these genes are at much higher risk of developing certain types of cancer, including breast and ovarian cancer, than people in the general population. Previous research has indicated that cancers associated with BRCA gene mutations may be particularly sensitive to drugs that target a protein called PARP1.
PARP1 is required for one of several processes that cells use to repair damaged DNA. The proteins produced by normally functioning BRCA genes participate in a different DNA repair process. When either process is blocked, the other appears to pick up the slack. Scientists speculated, therefore, that cells with defective BRCA proteins might be especially vulnerable to drugs that inhibit PARP1. Indeed, laboratory and animal studies have shown that PARP1 inhibitors are much more toxic to cells with BRCA gene mutations than to cells with normal BRCA genes. Early clinical studies of this therapeutic approach have yielded promising results.
In this clinical trial, women with advanced breast or ovarian cancer who carry a known BRCA gene mutation or who have a strong family history of these diseases (and are, therefore, likely to carry such a mutation) will be treated with a new drug called AZD2281 (olaparib) together with the chemotherapy drug carboplatin. AZD2281 inhibits PARP1, and preclinical studies suggest that combining it with a platinum-based drug, such as carboplatin, may lead to better outcomes.
"The idea is to stress the cancer cells with carboplatin, which is known to be effective in ovarian cancer and possibly some breast cancers, while blocking DNA repair pathways," said Dr. Kohn. "Mutation carriers have increased susceptibility to platinum drugs, and we hypothesize that they will be even more susceptible with PARP1 inhibition.
"Since this is a phase I trial, we are looking primarily at safety, but we hope to see responses as well," she added.
The researchers are also planning to expand the trial to include women with triple-negative breast cancer or high-grade serous ovarian cancer who do not have BRCA-related or familial breast or ovarian cancer. Some studies have suggested that these women may also benefit from treatment with PARP1 inhibitors.
For More Information
See the lists of entry criteria and trial contact information, or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll-free and confidential.
FDA Update
New FDA Center and Advisory Committee Launch Regulation of Tobacco Products
The historic Family Smoking Prevention and Tobacco Control Act was signed into law June 22 and gave the FDA authority to regulate tobacco products. On August 19, the FDA established the Center for Tobacco Products to oversee the law's implementation and named Dr. Lawrence Deyton, clinical professor of medicine and health policy at George Washington University in Washington, DC, the center's first director. The center and its regulatory activities will be funded by fees levied on manufacturers and importers of tobacco products.
Dr. Deyton said he is eager for the challenge to lead the tobacco products team at the FDA and "make progress in combating tobacco use—the leading cause of preventable death in the United States." He previously served in leadership positions at the National Institute of Allergy and Infectious Diseases at NIH for 11 years.
Another activity mandated by the tobacco control bill began on August 25, with the creation of the Tobacco Products Scientific Advisory Committee; the chair will be appointed by FDA Commissioner Dr. Margaret A. Hamburg, and nominations are open for the other eight voting members, as well as three non-voting members from the tobacco industry.
Agency Issues New Rules for Obtaining Investigational Drugs
On August 12, the FDA published two new rules to clarify how seriously ill patients can access investigational drugs outside of the clinical trials system, once all standard treatment options have been exhausted. Since clinical trials have strict entry criteria, not all interested patients qualify to participate.
The first new rule expands access to investigational drugs for individual patients, intermediate-sized patient groups, and larger patient populations under a treatment protocol or an investigational new drug application (IND). Both patients' physicians and the companies developing the investigational drugs will still need to work with the FDA to authorize any use outside of a clinical trial.
The second new rule clarifies how a company may charge patients for an investigational drug, both on and off clinical trials. The new rules do not guarantee that a manufacturer will be willing or able to provide access to a drug outside of a clinical trial.
The FDA defines investigational drugs as "new drugs that have not yet been approved by the FDA or approved drugs that have not yet been approved for a new use, and are in the process of being tested for safety and effectiveness."
"For patients seeking expanded access to investigational drugs and biologics, the new rules make the process easier to understand," said FDA Commissioner Dr. Margaret Hamburg in a press announcement.
The new rules will go into effect 60 days after their publication in the Federal Register.
Dr. William Dahut Named CCR Clinical Director
Dr. William Dahut has been named the new clinical director of NCI's Center for Cancer Research. Dr. Dahut will be the primary interface between NCI and the NIH Clinical Research Center for patient care and clinical operations. He will oversee areas critical to the Clinical Research Program, the quality of patient care, and the ability of principal investigators to develop and carry out clinical research protocols. These areas include data management, regulatory compliance, patient recruitment, credentialing, contract medical services, outpatient/inpatient census, training and continuing education, protocol development, information technology, patient travel and lodging, and space management.
Dr. Dahut received his M.D. from Georgetown University and completed his clinical training in internal medicine at the National Naval Medical Center (NNMC) in Bethesda, MD, followed by further training in hematology and medical oncology at the NNMC and what was NCI's Medicine Branch. Dr. Dahut worked as an attending physician in the NCI-Navy Medical Oncology Branch until 1995. He then joined the faculty of the Lombardi Cancer Center at Georgetown University before returning to NCI's Medicine Branch in 1998 as head of the prostate cancer clinic. In 2002, Dr. Dahut became chief of the Genitourinary/Gynecological Clinical Research Section in what is now the Medical Oncology Branch. Dr. Dahut's primary research interest has been in the development of novel therapeutic strategies for the treatment of adenocarcinoma of the prostate.
NCI Tobacco Control Monograph Addresses Genetics of Nicotine Dependence
NCI recently released Tobacco Control Monograph 20, Phenotypes and Endophenotypes: Foundations for Genetic Studies of Nicotine Use and Dependence, which reviews the growing body of research findings in tobacco genetics to develop a scientific plan for incorporating genetic research into cross-disciplinary studies of nicotine dependence.
Tobacco-use behavior is dependent on complex genetic and environmental influences and interactions that are currently not well understood. Identifying different patterns of smoking behavior may help guide future research, tailor treatments for individual smokers more effectively, and enhance existing public health policy in tobacco prevention and control.
Monograph 20 presents new and innovative concepts and methodologies for the field of behavioral genetics and makes a strong case for continued and expanded research of genetic influences on tobacco use. A better understanding of the role of genetic susceptibility within the context of known environmental influences on tobacco use may advance the goals of the public health community to prevent and control tobacco use.
Past tobacco control monographs are available online.
CRCHD Hosted Professional Development and Diversity Training Conference
On August 5–6, NCI's Center to Reduce Cancer Health Disparities (CRCHD) hosted a conference titled, The Path Forward: Training Fundamentals and Research Advancement. More than 80 grantees from CRCHD's Continuing Umbrella of Research Experiences (CURE) program met in Rockville, MD, to share accomplishments, network, and learn professional development strategies that will drive career success. A number of the attendees received awards for their podium and poster presentation at the professional development workshop.
The workshop "provides grantees with the opportunity to craft sound research career trajectories and enhance fundamentals like grantsmanship and publication," said CURE Program Director Dr. LeeAnn Bailey.

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Street Style: Bragging Rights
The Black Retail Action Group, a not-for-profit organization celebrating African Americans in the fashion industry, held its 42nd annual gala and the turnout was a who's who of stylish sisters. Check out the chicest girls gone glam in evening wear at this fine affair.
Photo Credit: Hannan Saleh


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Anticipating more volatile weather, more extreme temperatures and violent storms in the future, scientists are busy analyzing the potential effects on agriculture.To help prepare for these potential changes, USDA recently completed a study and released a detailed report titled "Climate change and agriculture in the United States: Effects and adaptation."
Based on their analysis, the authors say the effects will be variable but mostly detrimental to crop and livestock production, which contribute about $300 billion per year to the U.S. economy. Direct effects such as rising temperatures and altered precipitation will reduce crop productivity more than any potential benefit from higher carbon dioxide levels, according to the report, and indirect effects such as changes in the competitive ability of weeds, diseases, insect pests and beneficial insects also will challenge productivity.
For livestock specifically, the report lists four ways in which climate change could affect productivity.
- Feed-grain production, availability and price: Each crop species has a given set of temperature thresholds that define the upper and lower boundaries for growth and reproduction, along with optimum temperatures for each developmental phase. Pollination, the authors note, is one of the most sensitive stages to temperatures, and exposure to high temperatures during this period can greatly reduce crop yields and increase the risk of total crop failure.
- Pastures and forage crop production and quality: Many perennial crops have a winter chilling requirement and yields will decline if the chilling requirement is not completely satisfied. Also, mid-winter warming can lead to early bud-burst or bloom of some perennial plants, resulting in frost damage when cold winter temperatures return.
- Animal health, growth and reproduction: For many species, deviations of core body temperature in excess of 2°C to 3°C cause disruptions of performance, production, and fertility, the report notes. For cattle that breed during spring and summer, exposure to high temperatures decreases conception rates. Livestock and dairy production may be more affected by changes in the number of days of extreme heat than by adjustments of average temperature.
- Disease and pest distributions: Warmer, more humid conditions will also have indirect effects on animal health and productivity through promotion of insect growth and spread of diseases. These effects are not well understood, but earlier springs and warmer winters could enable greater proliferation and survivability of pathogens and parasites. Regional warming and changes of rainfall distribution may lead to changes in distributions of diseases sensitive to temperature and moisture, such as anthrax, blackleg and hemorrhagic septicemia.


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We want our loved ones sacrifices to be honored by bringing our nation's sons and daughters home from the travesty that is Iraq IMMEDIATELY, since this war is based on horrendous lies and deceptions. Just because our children are dead, why would we want any more families to suffer the same pain and devastation that we are.
Cindy SheehanMother of Casey Sheehan, Killed in Action, Iraq, April 4, 2004.
The up-to-the-second total cost of the war now is $178, 136, 219, 056 (that actually was thirty minutes ago).
That's one billion dollars per week.
These same funds could have purchased:-nationally, health insurance for 46.4 million people,or Head Start enrollments for 27 million kids,or 8.6 million four-year college scholarships,or 3.5 million new elementary teachers, or seven years of fully-funded global anti-hunger efforts;
Carry these facts to your friends, congressional district offices, PTA meetings and recruitment centers, and there will be effects.Dr. Martin Luther King once said that peace is not the absence of tension, but the presence of justice. Our job is to continue to fight for peace and justice.
Tim CarpenterExecutive Director ofProgressive Democrats of America.
We must end this war because it was built on lies. Everything built on lies, fails. Life can be beautiful - but not while living a lie. Lies destroy beauty and life. Ending this war and leaving Iraq without building permanent military bases is the way to reveal, admit and end the lie.This is a NIMBY war - Not In My Back Yard -- as expressed in "Better to fight to them over there than have them here." The moral repugnance of that argument, which demands that others give their lives, homes, family and country for Americans' safety and principles, should be obvious. But Americans do not see it because of the lie.We cannot undo the damage the lie has done. But we can make reparation. The fact that the Administration insists the occupation's "job" is repair is one reason Americans are confused about withdrawing. "The job" of the occupation is also to establish a secure flow of oil. Until that is admitted, until Americans are allowed to discuss whether or not that "job" is do-able or wise, its completion is dubious. Meanwhile, repair of Iraq's civilian infrastructure is obscured and impeded.This is the lie: George Bush said on television,early in the war, "We did not choose this war; it was thrust upon us." The exact opposite is true.After 9-11, it was clear that Saudi Arabia, whose citizens launched the attacks, might not be a future reliable source of oil. At the same time, it was clear that the attacks required an American response. Our nation was thrust into a new situation. But the response of the Bush Administration was war, and that was chosen - not just in Afghanistan, but in Iraq. The lie said to Americans: We invade Iraq to protect you. The lie said to Iraqis: We invade Iraq to liberate you -- from, among other things, torture and violence.The blood on our hands is deep and red. We must end this war because it is the moral thing to do, to admit and end the lie and the killing. The moral argument underpins all others: the health of our democracy and our people, our national security, the problem of violence in the world, the future of the world and its children.Without admission, there can't be forgiveness. And to quote from the title of Bishop Desmond Tutu's book: No Future Without Forgiveness. End the lie and make reparation.
Mimi KennedyActivist, Author and Actress
They didn't attack us. We are not their liberators. We are their jailors, we have turned them into targets. Children are dying. We have no right or reason to be there. They don't like us being there.
Carrie FisherWriter and Actor
Funding [for cancer] is tough to come by these days. The biggest downside to a war in Iraq is what you could do with that money. What does a war in Iraq cost a week? A billion? Maybe a billion a day? The budget for the National Cancer Institute is four billion. That has to change. It needs to become a priority again.
Polls say people are much more afraid of cancer than of a plane flying into their house or a bomb or any other form of terrorism. It is a priority for the American public.
Lance ArmstrongTour de France 7-time winner
The threat posed by terrorism is real. If we are going to be successful in overcoming it, we have to acknowledge the fact that the war in Iraq has made the U.S. and the world LESS safe. After more than $200 billion and thousands of U.S. and Iraqi casualties, we have created a terrorist recruitment camp and fanned the flames of anti-Americanism around the world.
We need to bring our troops home, ensure that there will be no permanent US military presence in Iraq, and make sure that national security includes economic security through cleaner air, healthy kids, thriving schools and safer communities.
Dr. Martin Luther King once said that peace is not the absence of tension, but the presence of justice. Our job is to continue to fight for peace and justice.
Barbara LeeU.S. Congresswoman
Ever since 9/11, I have been arguing that the 'war against terror' is immoral and counterproductive. It sanctions the use of state terror----bombing raids, tortures, countless civilian deaths in Afghanistan and Iraq----against Islamo-anarchists whose numbers are small, but whose reach is deadly.
The principal cause of this violence is the violence that is being inflicted on the people of the Muslim world. The bombing of innocent people is equally barbaric in Baghdad, Jenin, Kabul as it is in New York, Madrid or London. And unless this is recognized the horrors will continue.
The real solution lies in immediately ending the occupation of Iraq, Afghanistan and Palestine. These three wars are reported sporadically and mean little to the everyday life of most people in the West, but they arouse much anger and bitterness in the Muslim world and its diasporas. As long as Western politicians wage their wars and their colleagues in the Muslim world watch in silence, young people will be attracted to the groups who carry out random acts of revenge. I've always argued that when you have ugly occupations, you cannot have a pretty resistance.
I foresee a continued struggle until there is a large antiwar movement in the U.S. that puts sufficient pressure on senators and congressional representatives to pull out of Iraq, like what happened in Vietnam. And the notion that the Iraqi people are incapable of determining their own future is a total joke. They are perfectly capable of doing deals with each other - they've done so in the past, and they'll do so again.
Tariq AliWriter, journalist and film-maker
Until we leave Iraq; the violence will continue to escalate, our reputation around the world continue to plummet, lives will continue to be stolen from their loved ones, and monies that should go to programs desperately needed in the United States will continue to be used to kill innocent people. Iraqi's cannot begin the long road of rebuilding their country and their lives until we have left and given them the financial support we owe them to help in their rebuilding.
Jodie EvansCODEPINK cofounder
Many of our policymakers seem resigned to an open-ended occupation. Calls to maintain the status quo echo the same rationale used to keep us in Vietnam. To those who contend that we would weaken our credibility if we withdraw, the nation's standing would greatly improve if we demonstrate the judgment to terminate an unwise course.
Our continuing presence in Iraq feeds the insurgency and gives the insurgents a certain legitimacy in the eyes of much of the world. We know from our own history that armies of occupation are seldom welcome.
The United States should begin the discussions now as to how we can bring our troops home. We should accelerate and pay for the training of Iraqi security forces with the help of Egypt, Jordan, and other Arab allies. We should consult with the current Iraqi government and other Arab nations about the necessity for an Arab-led security force to complement the Iraqis in the short term. We should also work with the United Nations to solicit ideas and assistance from the international community on how we can best disengage.
There are no guarantees that militarily withdrawing from Iraq would contribute to stability or would not result in chaos. On the other hand, we do know that under our occupation the violence will continue. We also know that our occupation is one of the chief reasons for hatred of the United States, not only in the Arab world but elsewhere.
Wars are easy to get into, but hard as hell to get out of. It is time for lawmakers in Washington -- and for concerned citizens across the nation -- to demand that this sad chapter in our history come to an end. The path of endless war will bankrupt our treasury, devour our soldiers, and degrade the moral and spiritual values of the nation. It is past time to change course.
George McGovern, the 1972 Democratic nominee for president, represented South Dakota in the US Senate
The US should end the occupation of Iraq because both Iraqis and Americans want them to. During my visits to Iraq, I constantly heard Iraqis blame the United States for fomenting the violence that plagues their country, subjecting them to daily humiliations at checkpoints, in prisons and during house raids, and using Iraqi oil money to line the pockets of U.S. companies like Halliburton instead of rebuilding Iraq. They often refer to the U.S. occupation of their country as ``the new Saddam.''
A Zogby poll taken a week before the Jan. 30 Iraqi election showed that 69 percent of Shiites and 82 percent of Sunnis want U.S. forces to withdraw ``either immediately or after an elected government is in place.''
The United Iraqi Alliance, the Shiite party that won the most seats in the new constitutional assembly, had a campaign platform that called for the US troops to leave. And in July 2005, 126 members of Iraq's 275-member National Assembly called for the "departure of the occupation forces."
Here in the United States, the war is increasingly unpopular, with a majority of Americans now saying it's time for the troops to come home. Six in ten Americans say that the United States is bogged down in Iraq, the war is not worth fighting, it has not made us safer, and the troops should begin to come home.
Democracies are supposed to listen to their people. It high time for the US government to start listening to the American people-and the Iraqis.
Medea BenjaminCODEPINK cofounder
In less than three months after the April 28 formation of the new Iraqi government, car bombings alone killed close to 1700 Iraqis. The United States has a population at least 11 times that of Iraq, so this is proportionately something like six 9/11's that Iraqis have gone through in just the past few months - without even counting deaths, injuries, and torture inflicted by U.S. and Iraqi government forces.
It's harder and harder for anyone to justify any aspect of the Iraq war. You simply can't argue that Iraqis are better off - the violence far exceeds that of Saddam's later years, unofficial militias intimidate everyone and restrict basic political freedoms almost as much as Saddam did, and, indeed many basic rights that Saddam guaranteed, especially women's rights, are gone now.
It's time to recognize that the anti-war movement was right all along-we should have never gotten into this war and we should end it immediately.
Rahul Mahajan, author of Full Spectrum Dominance: U.S. Power in Iraq and Beyond
Throughout the 1960s and into the 1970s, a prevailing argument was that removing U.S. troops from Vietnam would be a betrayal of U.S. responsibility to the people of South Vietnam. Today, likewise, opposition to a swift U.S. pullout from Iraq is often based on the idea that the American military must stay because of a responsibility to the people of Iraq.
But most Iraqis want the U.S. military out of their country - pronto. As Newsweek reported in its January 31 edition: "Now every major poll shows an ever-larger majority of Iraqis want the Americans to leave." It's time we started listening to the Iraqis.
Norman Solomon, author of War Made Easy: How Presidents and Pundits Keep Spinning Us to Death.
A majority of Iraqis voted in the election for a political party, the United Iraqi Alliance. The second plank of their platform was calling for a timetable for withdrawal. Then you have all the people who boycotted the elections because they believed that a clear statement about withdrawal was the prerequisite for having elections, that you couldn't have elections before you had that commitment. Iraqis have expressed this through opinion polls, through protests, through their votes.
And the anti-imperialist sentiment in Iraq is so strong that it actually makes it harder for Iraqis to take on the actual fascist forces in their countries, because there is this feeling that anything that is hurting the occupation has to be in some way supported. So there isn't a clear ability to go after the people who are targeting other Iraqi civilians.
The presence of US troops is abandoning Iraq to violence, to daily humiliation, and checkpoint killings. That is abandoning Iraq.
Naomi KleinAuthor
Observing Iraq up close, as I did (that is, without a massive security detail and living with Iraqis and without the filter of an obsequious news media), the overwhelmingly negative consequences of the occupation become impossible to ignore: the 100,000 dead (the majority of them civilians); wide-scale violations of human, political and civil rights; the destruction of the country's health, education and other crucial social systems; the massive unemployment; a violent and destabilizing insurgency that is likely to last a generation or more; the rending of a delicate social fabric that managed to survive a bloody British occupation, several wars, and the even bloodier rule of Saddam Hussein (which we should never forget was made possible in good measure by decades of support from administrations as far back as President John F Kennedy).
In Alcoholics Anonymous, apologizing and making amends for the hurt one has done to others are among the most important steps in the long path toward sobriety. Clearly, Bush, who believes Iraqis should "put the past behind them", isn't about to engage in soul searching about the mission and consequences of our Iraq adventure. But if Americans can admit to - and in doing so, comprehend - the damage our government has wrought in Iraq in our name and with our consent, we will take an important first step in ending our addiction to an unsustainable corporate-led, consumer-driven culture, and the wars and systematic violence it requires world-wide. In doing so we will begin the long but necessary task of building a sustainable and peaceful future, for Iraq, for ourselves, and for the world at large.
Mark LeVine, professor of modern Middle Eastern history and author of Why They Don't Hate Us: Lifting the Veil on the Axis of Evil.


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You've been known to go all out to impress your special lady friend. Take the easy route with this Classed belt from O'Neill! Its canvas construction with leather accents and a pattern-detailed metal buckle will easily make an impression on your gal. Pair this sick belt with a fun date night for the perfect combo!
- 100% Cotton fabric
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Remember what happened when your buddy introduced you to his girl and bragged about your awesome sense of style? She was overcome with admiration and left your nice, yet dowdy friend by the wayside. Don't make the same mistake and always look fresh in this Backfire long sleeve hooded tee from Rip Curl. It's got yarn-dyed stripes, contrast-colored sleeves, a henley button placket, a drawstring hood and woven Rip Curl labels.
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World Badminton
Badminton involves the use of a 5 foot net, lightweight rackets, and a shuttlecock. It can be played by individuals or paired teams either indoors or outdoors.
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If the serving side doesn't return the shuttlecock it loses its serve. If the receiving side doesn't return the shuttlecock the serving side gets a point and serves again. The game ends when one side gets 15 points except for women's singles which ends when one side gets 11 points.
History of Badminton
Badminton came be traced back over 2000 years ago to games the ancient Greeks played. The modern game of badminton began in 1870 when guests at Duke of Beaufort's Badminton House in Gloucestershire played it at a lawn party. Badminton developed from a children's game known as battledore and shuttlecock in which players batted a cork filled with feathers back and forth in the air using paddles, the idea being to keep it in the air the longest period of time possible.
The first official set of rules for the game of Badminton was published in 1893 by the Badminton Association of England. By 1934 there was a league of nine countries belonging to what was known as the International Badminton Federation (IBF). Badminton started in the US in 1878 with the American Badminton Association being formed in 1936 and the US joining the IBF in 1938. In 1978 the official changed its name to the U.S. Badminton Association.
The first men's Thomas Cup matches were held in 1948-1949. The first women's tournament, the Uber Cup, followed in1956-1957. Since then other competitions have been added including tournaments for mixed teams and juniors and The World Cup. Badminton became an official Olympic sport in 1992. More about the history of Badminton.
Badminton Today
What started as a lawn party game has become a fiercely competitive sport for professionals playing for money. The sport is getting more popular and the IBF which started with only nine members has over 150 members. Asian and Scandanavian countries dominate competitions with badminton being second in popularity only to soccer in these countries. With increasing coverage badminton can look forward to a bright future!


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Understanding the Truth, Issue 1, January 1, 1918
Têgeyştinî Rastî (Understanding the truth) was a semiweekly newspaper published by the command of the British army in Iraq in 1918–19. At the time, Britain was at war with the Ottoman Empire, which had ruled Iraq since the 16th century. When British forces began advancing north toward the Iraqi Kurdistan region in the spring of 1918, the paper became the mouthpiece of the British Empire, propagandizing in support of British positions when dealing with political, social, and cultural issues. The paper sold for one ana, or four fils, a ...


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