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Ovarian Cancer Markers Validated for Early Detection
A rigorous validation study of more than 50 potential markers for detecting early signs of ovarian cancer in blood has found that the most accurate marker is CA-125, a protein that is already routinely monitored in women with the disease. Panels of markers tested in the study offered, at best, only marginal improvements in the ability to detect the disease over CA-125 alone. Read more > >
Combination Therapy Targets Pancreatic Cancer Stem CellsIn mice, adding tigatuzumab to gemcitabine eliminated tumor-initiating cells
Potential Treatment for Brain Cancer IdentifiedDimethyl-celecoxib inhibits both tumors and supporting vasculature
Filter Captures Tumor Cells from BloodExperimental device uses a microfilter to detect circulating tumor cells
Markers for Chronic Lymphocytic Leukemia Found in BloodDisruptions to the immune system may be early signs of the disease
Survivors of Hereditary Retinoblastoma Face Second Cancers Later in LifePhysicians should be aware of the risk of another cancer among these long-term survivors
Director's Update: The Extraordinary Challenges and Opportunities Facing Cancer Research
The Director's Update for this issue is an abridged version of the remarks delivered by NCI Director Dr. John E. Niederhuber on Monday, April 20, at the 100th Annual Meeting of the American Association for Cancer Research in Denver. Read more > >
Guest Commentary by Dr. Margaret Foti: A Century of Progress, A Future of Promise
The chief executive officer of the American Association for Cancer Research shares her thoughts about past accomplishments and future efforts in cancer research Read more > >
Special Issue on Bioinformatics
Don't miss our May 5 special issue on bioinformatics, which will highlight recent meetings, progress on electronic health records, research advances, and resources for those who are looking to collaborate or secure project funding.
NCI Cancer Bulletin special issues are some of the most popular among our readers. Past special issues have focused on childhood cancers, personalized drug development, and cancer imaging.
Special Report: Simple Measures Can Encourage African Americans to Join Clinical TrialsClinical research staff from Meharry Medical College enrolled a majority of eligible patients at Nashville General Hospital
Spotlight: Studies Suggest Unintended Consequences of Angiogenesis InhibitionFindings from two recent animal model studies raise concerns about testing these agents in patients with early stage disease
Profiles in Cancer Research: Dr. Robert MotzerThe Memorial Sloan-Kettering oncologist has made integral contributions to kidney cancer treatment during his 20-year career
Featured Clinical Trial: Tomotherapy for Patients with Limited Metastatic CancerCan highly conformal radiotherapy stop or delay the spread of metastatic cancer?
NIH Update
- New Stem Cell Guidelines Proposed by NIH
FDA Update
- GSK Seeks Approval for HPV Vaccine
- Fraumeni Receives AACR Lifetime Achievement Award
- Barker Receives AACR Margaret Foti Award
- NCI Chief Operating Officer Lawrence Ray Retiring
- NCI Lecture Series Features Dr. Julie Overbaugh
Cancer.gov Update
- Cancer.gov Streamlines Clinical Trials Search Process
- New Resources on Cancer Health Disparities Research Available
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.
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Featured Article
Ovarian Cancer Markers Validated for Early Detection
A rigorous validation study of more than 50 potential markers for detecting early signs of ovarian cancer in blood has found that the most accurate marker is CA-125, a protein that is already routinely monitored in women with the disease. Panels of markers tested in the study offered, at best, only marginal improvements in the ability to detect the disease over CA-125 alone.
CA-125 remains the single best biomarker for the early detection of this cancer, but its performance was nearly matched by HE4, and several other candidates showed promise, Dr. Daniel W. Cramer of the Brigham and Women's Hospital said yesterday at the 100th Annual Meeting of the American Association for Cancer Research (AACR) in Denver.
"The validation study was an incredibly useful experiment," commented Dr. Michael Seiden, president of Fox Chase Cancer Center and a leader in NCI's SPORE program for ovarian cancer. He noted that whether screening women for ovarian cancer saves lives is a question that can only be answered through large prospective screening trials such as one underway in the United Kingdom.
The study—a joint project of NCI's Early Detection Research Network (EDRN) and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial—was closely watched because it included many of the field's experts and used high-quality PLCO blood samples, including prediagnostic samples from women who developed ovarian cancer during the trial.
"This was the first time a disparate group of investigators was brought together in an effort to systematically evaluate a panel of biomarkers," said Dr. Sudhir Srivastava, who heads the EDRN program. In general, the performance of markers on prediagnostic blood drawn within 6 months of a diagnosis of ovarian cancer was comparable to the performance of markers assessed at the time of diagnosis.
Following the presentation at AACR, Dr. David Sidransky of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and chair of the EDRN called the study a "tour de force" and said the results deserve close attention. He pointed out that the vast majority of cancer biomarker candidates that are discovered and reported in the scientific literature never make it through systematic validation. Now there are several for ovarian cancer.
Nonetheless, he added, "it's a little sobering at the end of all this to say that we're back to CA-125." Clearly, a high priority for the field is to find noninvasive markers for detecting the most deadly types of ovarian cancer in women before the disease is diagnosed. This is particularly challenging in ovarian cancer because many tumors may progress rapidly, he noted.
In women diagnosed with the cancer, blood levels of CA-125 are routinely measured to monitor how well a treatment is working or whether the cancer has come back. Only some women with ovarian cancer develop elevated levels, however, and levels can rise for reasons other than cancer.
The current guidelines of the U.S. Preventive Services Task Force do not recommend ovarian cancer screening with CA-125. Earlier this month another study using PLCO data concluded that screening women for ovarian cancer often led to unnecessary surgeries and failed to detect the disease in its early stages.
See also Ovarian Cancer Study Could Speed Early Detection (June 10, 2008).
—Edward R. Winstead
Cancer Research Highlights
Combination Therapy Targets Pancreatic Cancer Stem Cells
A new drug combination tested in mice may target the cells responsible for driving some pancreatic tumors. The combination of gemcitabine and the experimental drug tigatuzumab eliminated populations of cancer stem cells and reduced tumor growth in a mouse model of pancreatic cancer, researchers from the Johns Hopkins Sidney Kimmel Cancer Center reported at the AACR annual meeting.
The results provide a rationale for testing the promising combination in patients with this deadly disease, Dr. Rajesh Kumar NV and his colleagues concluded.
Cancer stem cells are thought to self renew while giving rise to tumors, and they may resist conventional treatments. The researchers found that human pancreatic cancer stem cells overexpress a protein called death receptor-5 (DR-5), which is involved in programmed cell death (apoptosis). The protein is also the target of tigatuzumab, a humanized monoclonal antibody also known as CS-1008.
To evaluate the drug's effects on these important cells, mice were given tigatuzumab alone, gemcitabine alone, or a combination. Although gemcitabine reduced tumor size, it increased levels of pancreatic cancer stem cells (as defined by the protein markers ALDH, CD24, and CD44), and all of the tumors recurred. The combination treatment, however, led to long-term remissions in half of the treated mice.
In addition, cancer stem cells were eliminated in mice that received tigatuzumab plus gemcitabine, which is the first-line treatment for patients with advanced pancreatic cancer. "It appears that tigatuzumab may be one of the first monoclonal antibodies to target cancer stem cells," said Dr. Kumar NV. The drug is being tested in a phase II clinical trial with patients who have inoperable, untreated pancreatic cancer.
Potential Treatment for Brain Cancer Identified
Researchers have identified a potential drug for treating brain cancer that appears to have effects on both tumors and the growth of blood vessels (angiogenesis) that provide essential nutrients and oxygen to the tumors. Growing evidence suggests this strategy may be important for treating glioma brain tumors, as it is for other cancers. In preclinical studies, the compound, 2.5-dimethyl-celecoxib, crossed the blood-brain barrier and inhibited both tumors and angiogenesis.
"Here you have a single drug that attacks both tumor cells and tumor blood vessels, and it can be used over the long term," said Dr. Florence Hofman of the University of Southern California Keck School of Medicine. The drug is not a COX-2 inhibitor, a family of drugs that has been associated with prohibitive side effects, and therefore it could potentially be used over several years rather than months.
While dimethyl-celecoxib is not expected to be a cure for brain cancers, the drug or a similar agent could extend survival for patients with this deadly disease by up to several years, the researchers said Sunday at the AACR annual meeting. They suggest that it may also have potential to treat tumors that spread to the brain and depend on the growth of blood vessels.
"We're learning that the blood vessel target is critical in treating this cancer," said Dr. Hofman. "And we think that our way of getting at the target has advantages over other approaches."
Filter Captures Tumor Cells from Blood
A novel device employing a "membrane microfilter" can process blood and capture circulating tumor cells (CTCs), or cells that have escaped from a tumor into the circulatory system, researchers from the University of Southern California Keck School of Medicine and the California Institute of Technology said Sunday at the AACR annual meeting.
Circulating tumor cells have emerged as a potential "surrogate biopsy" for metastatic disease, and there is a growing need for noninvasive methods, such as capturing these cells, to diagnose and monitor cancer, noted Anthony Williams, a graduate student at the Keck School of Medicine who described the device in a press briefing. While the technology is not commercially available, the researchers said that it will be used in several upcoming clinical trials to monitor patients.
The device exploits differences in the sizes of normal and cancer cells. "Circulating tumor cells are larger than their normal counterparts," said Williams. "The pore sizes on the filter allow normal-sized blood cells to pass through, while it captures the larger tumor cells." Compared to other technologies, which can take hours to analyze a sample, the microfilter device is relatively fast, producing a result for certain samples in a matter of minutes.
Using Veridex's CellSearch system, the only FDA-cleared device for CTC detection and enumeration, researchers are already investigating whether cancer patients' CTC levels can be used to direct therapy. The microfilter device used in this study detected CTCs in approximately 93 percent of blood samples taken from nearly 60 advanced cancer patients, compared to only 46 percent when the CellSearch system was used on the same samples.
The research team plans more studies with the device to determine whether levels of CTCs can be used as early indicators of treatment efficacy, as well as to molecularly characterize captured CTCs for the identification of therapeutic targets.
Markers for Chronic Lymphocytic Leukemia Found in Blood
The blood of patients with chronic lymphocytic leukemia (CLL) may contain protein abnormalities that can be detected years before the disease is diagnosed, researchers said at the AACR annual meeting. An analysis of blood samples obtained up to a decade prior to a diagnosis of CLL revealed disruptions to the immune system in certain patients. In addition to providing clues to the biology of the disease, the findings provide a rationale for exploring whether prediagnostic changes in immune function have an effect on CLL prognosis, the researchers said.
To make the discovery, Dr. Huei-Ting Tsai of NCI's Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues obtained prediagnostic blood samples from 109 people who developed the disease over the course of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. This NCI-sponsored trial has serial blood samples from more than 77,000 people.
About 40 percent of patients who eventually developed CLL had evidence of immune disruption prior to diagnosis. In addition, 31 percent had a skewed free light chain (FLC) ratio, which is a measure of immune disruption. This change was evident in one patient 9.8 years prior to diagnosis.
The finding that CLL is often preceded by an altered FLC ratio points to infection or other immune changes as areas to investigate further, said coauthor Dr. Neil Caporaso of DCEG. "This is an important clue as we focus efforts on understanding the environmental, molecular, and genetic factors associated with that condition."
Little is know about the causes of CLL, though it is linked with family history and aging. With the prediagnostic samples, the researchers could distinguish between alterations that developed because of the disease and those that were present before the leukemia arose. "We were fortunate to have access to the PLCO samples so that we could look back in time to detect the protein abnormalities in this mysterious disease," noted Dr. Tsai.
In February, these researchers used PLCO blood samples to discover that a precursor state called monoclonal B-cell lymphocytosis was evident years before a diagnosis of CLL. Together, these findings illustrate the power of cohort studies to clarify precursor states for cancer, the researchers said.
Survivors of Hereditary Retinoblastoma Face Second Cancers Later in Life
Children who survive hereditary retinoblastoma, a rare cancer of the eye, have an increased risk of death from a second cancer later in life. The largest study to date of hereditary retinoblastoma survivors found that by 50 years after treatment, 1 in 4 survivors with the inherited form of the disease had died of a second cancer, whereas only 1 percent of survivors with nonhereditary retinoblastoma had died of second cancers. These included primarily bone and soft tissue sarcomas, melanomas, and cancers of the brain and central nervous system, as well as lung and uterine cancers.
Retinoblastoma, which involves mutations in the tumor-suppressor gene RB1, is diagnosed in about 300 children in the United States each year, most of them under the age of 5. In Western countries, the vast majority of children survive hereditary retinoblastoma, as well as the nonhereditary form of the disease.
Following up a previous report, Dr. Chu-Ling Yu of NCI's Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues identified the causes of death for 1,092 survivors of hereditary retinoblastoma and 762 survivors of nonhereditary retinoblastoma who were diagnosed between 1914 and 1996. The mortality rate due to second cancer was 35-fold higher in the hereditary retinoblastoma survivors and 2.5-fold higher in the survivors of nonhereditary retinoblastoma, compared with the general population.
Both the genetic predisposition of these patients to cancer as well as treatment with radiation likely contributed to the development of a second cancer in those with hereditary retinoblastoma, noted senior author Ruth Kleinerman of DCEG.
"It's important for physicians who care for survivors of this cancer to be aware that even with the excellent survival rates, patients with hereditary retinoblastoma are at greatly increased risk of developing a new malignancy later in life," said Ms. Kleinerman.
Director's Update
The Extraordinary Challenges and Opportunities Facing Cancer Research
The following is an abridged version of the remarks delivered by NCI Director Dr. John E. Niederhuber on Monday, April 20, at the 100th Annual Meeting of the American Association for Cancer Research in Denver.
We come together at a time that is truly like no other. The United States, and in fact the world, is struggling to right a financial system in turmoil, and far, far too many of our fellow citizens are unemployed or underemployed. The number of those around us who lack health insurance may now have reached 50 million. Even comparatively wealthy communities in the United States are struggling to support those in need. In Montgomery County, MD, for example, the home of NIH, food stamp requests have grown 16 percent since last year. All of the family shelter beds are full, and more than 50 additional families are currently housed in motels.
All of us gathered here are more than aware that science has not been immune to these economic hard times. Scientists everywhere have felt the strain of NCI budgets that, for 4 years, have received no increase. You have felt the strain of the upfront downward negotiation of your grants, on average 17 to 21 percent. As a result, I regularly hear from investigators who have had to decrease the scope of their studies, let a lab technician go, or were unable to add or replace a post-doctoral student. We have all worried that the pace of cancer research will suffer and that biomedical research will no longer attract the best and the brightest. These deep concerns have echoed from university laboratories to the offices of deans and university presidents to my office and to those of our elected officials, as well.
But, as surely as we live in an economically troubled time, we also come here today at a moment of extraordinary scientific opportunity.
On February 17, just over 2 months ago and right here in Denver, President Obama signed into law a sweeping economic recovery plan. The $787 billion bill is called the American Recovery and Reinvestment Act. This legislation is about employment; about creating and preserving jobs and righting the American economy. But it is about more than just that. When he signed the stimulus act into law, President Obama said: "I hope this investment will ignite our imagination once more, spurring new discoveries and breakthroughs in science, in medicine, in energy, to make our economy stronger and our nation more secure and our planet safer for our children." The President clearly recognizes that the future of our country and the stability of its economy will depend on the creation of new knowledge, of new technologies, of imaginations unleashed.
This is no small challenge. Yet, it strikes at the very heart of what we do as scientists. We are fortunate to work every day toward a collective goal that cancer will not be the feared diagnosis it is today. We are, I believe, on the threshold of altering the course of this disease for millions of patients, young and old alike. And I believe that in this hall, on this day, at this hour, we have the opportunity to tell President Obama that we are listening, and that we will wholeheartedly take up his call.
Yesterday, we heard from another stalwart supporter of cancer research, Senator Arlen Specter. Senator Specter believes deeply in the power of biomedical science, with a passion grounded in personal experience. His efforts helped make certain that the economic stimulus legislation included funds for research dedicated to curing human diseases. As a result, the stimulus package provides $10.4 billion to the National Institutes of Health, of which $1.3 billion goes to the National Cancer Institute during the 2-year span of 2009 and 2010.
During hearings and other meetings on Capitol Hill, Senator Specter and many of his colleagues often ask questions that begin with: "What will it take…" What will it take, they ask, to accelerate the downward curve of cancer death rates? What will it take to make certain that today's laboratory progress will become tomorrow's clinical successes?
The questions posed to us by Senator Specter and his colleagues are the same questions we see in the eyes of our patients. These are questions we at NCI have not taken lightly, and the answers are far from easy. The bottom line is that NCI is committed to the core belief that how we spend all of the resources we are granted, how we strive for comprehensive plans and strategies must, by their boldness and vision, provide answers that ultimately change the course of the diseases we call cancer; not one disease, but hundreds of diseases. The people rightfully expect us to do no less.
So today I want to share with you the ways the National Cancer Institute—your National Cancer Institute—is taking up the call: how we have more than just a vision; how we have developed a coordinated action plan to move cancer research forward in innovative ways.
When it became clear that economic stimulus funds would be coming to NCI, we began to carefully consider where $1.3 billion in new resources could do the most good; where the demand was greatest; where our knowledge of the biology of cancer and new technology were leading us. Given that the American Recovery and Reinvestment Act is a once-in-a-lifetime opportunity, we also thought long and hard about what Americans want from all of us. We came back repeatedly in these discussions to the conclusion that they want better ways to prevent cancer; they want the earliest diagnosis; and they want new therapies with fewer side effects that turn cancer into a condition you can live with and not die from.
Economic stimulus funds give us the chance to be visionary; to make strides today toward realizing the promise of personalized medicine; to enhance the process of drug development from target identification to translation into viable therapies; to move cancer research from the accumulation of scientifically exciting genomic data to a new way of approaching prevention, diagnosis, and therapy and to ensure access to our latest science for all.
My friends, this is not a time to be timid in our vision. By our vision and our creative actions, we must demonstrate that NCI is worthy of sustained, increased support for years to come. NCI needs to lead with a clear direction that will hasten the pace of cancer research.
The groundswell of interest in what we are doing with our Institute's share of economic stimulus funds comes in concert with an increase in our appropriated budget of about 3 percent. It is extremely important that I clarify how stimulus funds and appropriated funds must not be mixed. Each must be accounted for separately. NCI must maintain separate account numbers and accounting procedures, and there are different rules in many cases for what can be funded from which pot of money. We sometimes joke that some of these dollars are green and others purple, so that they cannot be comingled. We must optimally use the purple stimulus dollars to maximize the use of our green appropriated dollars. Above all, we must always strive to fund our best science.
President Obama also made it eminently clear that the economic stimulus plan "will be implemented with an unprecedented level of transparency and accountability." On the day he signed it, the president also said: "And we expect you, the American people, to hold us accountable for the results." That is an admonition all of us take most seriously. Indeed, recipients of the stimulus funds will also have some stringent requirements, particularly around reporting on your stewardship of these dollars.
A week ago, our first package of stimulus grant funding plans moved out of NCI, to go through a final administrative approval process. As the availability of funds nears, I am now able to offer you some broad highlights.
NCI's planning is grounded in the respect of the individual investigators who are at the very heart of scientific discovery and who embody a tradition that dates back many years, before there was an NCI or an AACR; of investigator-initiated scientific excellence and groundbreaking discovery. For you, NCI's support will not waver.
Because of that commitment, NCI is taking a series of steps to increase our support for Research Project Grants (RPG), particularly the investigator-initiated R01. I am well aware of the importance, both practically and symbolically, of the NCI payline—the line of demarcation between grants that are funded and not funded, based solely on peer review. For the 2009 fiscal year, I am proud to tell you the RPG payline will be rising considerably.
Using our increased fiscal 2009 appropriation, NCI has raised the payline from last year's 12th percentile to the 16th percentile. Funding grants that were meritoriously reviewed but fell outside of last year's payline is an important first step. As you well know, these are not simply science projects. They are laboratories that employ technicians and other highly skilled workers. They are places where experienced investigators work to develop doctoral students and fellows into the next generation of laboratory and clinical scientists.
In fact, a 2008 NIH study indicated that on average, every NIH grant supports six to seven full-time or part-time scientific jobs. And those jobs are estimated to be magnified threefold in their economic effect on local communities, thanks to the goods and services purchased by scientists and technicians.
But NCI's payline increases do not end at the 16th percentile. Through coordinated but separate administrations of stimulus and appropriated funds, NCI will, like many of its fellow NIH institutes and centers, raise the payline to the 25th percentile. We will utilize a combination of 2-year and 4-year grants, with concurrent increases in the grant payline for young, first-time investigators. While the numbers are not yet firm, it is clear that there will be a marked increase in the number of principal investigators studying cancer.
The economic stimulus package conveys 2 years of funding, which in laboratory science is a relatively short amount of time. For just that reason, it falls to NCI to carefully calculate and thoughtfully assume the risks of initially funding some 4-year grants with economic stimulus money, knowing that we will need to find additional resources for the out years. I believe it falls, as well, to our grantees to come forward with only their strongest science.
Within the hopeful and helpful news of greater funding of grants, we must also note the President's call to "ignite our imagination." We must not simply see the economic stimulus package as more dollars toward "business as usual." We must look to new ideas, new methods, new areas of cooperation and collaboration, none more important, I suggest to you, than fostering the next generation of cancer science and cancer scientists. NCI has a plan to fund early stage investigators who are physician scientists and Ph.D.s, who are committed to careers in translational cancer research. These start-up packages will assist young faculty members in establishing laboratories; in creating a foundation for a career of excellence. A parallel program will be available to investigators at the NCI-designated cancer centers and at institutions funded through the Minority Institution/Cancer Center Partnership program.
We are surrounded today by transforming technologies that are changing the nature of diagnosis, of prevention, of early detection. As Eric Lander so eloquently reminded us yesterday, the day of the $1,000 genome is no longer a futurist's provocative prediction. Dr. Lander predicted that complete cancer genome analysis could be routine in laboratory research in 5 years and in patient care in 10 years.
And that will necessitate some changes; a rebalancing, if you will, in the way we at our respective universities conduct the science of the future and translate that science to our patients.
NCI has outlined signature projects—areas of investigation that are uniquely positioned to accelerate discovery in a short number of years. Among NCI's signature projects, I am proud to announce here today three key initiatives that hold important promise to unlocking cancer's genetically driven pathways and move them forward to first-in-man-studies. The nature of much of this work will be focused, team science.
In 2006, NCI and the National Human Genome Research Institute initiated a pilot project designed to accelerate our understanding of the molecular basis of cancer through the application of high-throughput genome analysis technologies. Three years later, The Cancer Genome Atlas, or TCGA, as it is better known, has established characterization and sequencing centers, along with programs in data management, bioinformatics, and computational analysis. To date, TCGA has sequenced more than 200 tumors in glioblastoma, along with lung and ovarian cancers. Already in glioblastoma TCGA has identified three genes not previously associated with this deadly cancer and delineated as many as four subtypes of glioblastoma. With that foundation of success, we plan to move TCGA forward with a goal of identifying all of the relevant genomic alterations in 20 to 25 major tumor types.
In addition, during the past year, NCI has also begun a program in pediatric cancer genomics. TARGET, which stands for Therapeutically Applicable Research to Generate Effective Treatments, will apply next-generation sequencing to at least 100 tumor specimens per childhood cancer.
Programs like TCGA and TARGET, along with numerous other whole-genome association studies using large population cohorts to assess germline risk, are generating a mountain of data and revealing potential genetic defects that occur within cancer. While scientifically fascinating and intellectually groundbreaking, these data primarily remain raw information that must be developed into knowledge of causal pathways and functional biology. Based on an intimate understanding of these pathways through the development of new probes and new assays of biologic function, we will convert what is today considered "un-druggable" into functional pathways with clearly defined targets for manipulating those pathways.
Moving from data to function to target to therapy will not be simple, nor will it be easy or inexpensive. But NCI is firmly committed to using today's opportunities to design and construct a personalized cancer care drug development platform, which is the second of NCI's signature initiatives.
At the beginning of the platform will be functional biology centers: A virtual network of investigators who will take promising genetic alterations identified in TCGA and answer specific questions about biologic function and potential druggable targets. High-throughput screening will follow, using appropriate assays that compare vast libraries of compounds to newly defined targets.
Another network, the Chemical Biology Consortium, will provide the necessary chemistry and chemists to accelerate the discovery and development of new anticancer agents, which NCI will be able to have produced and moved into preclinical testing and toxicology.
In addition, NCI is taking steps to create the first of a small national network of patient characterization centers. Always employing the latest technologies, these facilities will serve wide geographic areas, bringing together genomics and genetics, proteins and proteomics, all in the interest of matching a genetically characterized patient and his or her characterized tumor to appropriate and optimal therapeutic solutions.
Creating an integrated, 21st-century translational science program will require data integration and a reinvigorated push for the cancer electronic health record, managed through NCI's cancer Biomedical Informatics Grid, better known as caBIG, and its companion BIG Health consortium. This will create, for translational research, a national cohort of highly defined cancer patients to match to experimental protocols.
To accomplish both the scale-up of TCGA and the genetic characterization of our patients, we will require state-of-the-art biospecimens collected using standardized protocols, tissue characterization, cataloging, and analysis, through NCI's caHUB program.
The NIH Clinical Center, NCI's SPORE program, the NCI Community Cancer Centers Program, Cooperative Groups, CCOPs, and NCI-designated Cancer Centers network will all be key players in establishing a highly characterized national cohort of patients who can be easily matched with potential new agents.
This wide-ranging plan will require the contributions of biologists, chemists, informaticians, and clinical scientists who are devoted to a clear path from discovery to patient. That is not only the nature of translation; I believe it will be a model for the study of many diseases and, ultimately, a model of 21st-century health care, when we are able to match pharmacogenomically characterized patients and molecularly profiled tumor types to highly-specific, molecularly-targeted therapies.
This platform is a vision for a new way of thinking. But it is not an unrealistic concept. It is an action plan, a blueprint for what we are beginning to assemble this year, making the optimal use of every new resource. It is a blueprint for 21st-century translation.
Hand in hand with the effort to develop a platform for personalized medicine, we need to develop an improved clinical trials system, to better accommodate the validation of highly targeted therapies and to accurately assess the targeting of those therapies in patients in real time. The challenge in translation is optimally matching the tumor and therapeutic recipe. As we move forward this will be the pattern of treatment for all malignancies.
NCI's third signature initiative is one that is personally extremely exciting and I daresay another bold answer to the President's challenge to expand the boundaries of science. Over a year ago now, NCI commenced a series of workshops that began to bring aspects of the physical sciences to the problem of cancer. We discussed how physical laws governing short-range and other forces, energy flows, gradients, mechanics, and thermodynamics affect cancer, and how the theories of Darwinian and somatic evolution can better help us understand and control cancer.
From those meetings has come an idea that is soon to become a network of NCI-supported physical sciences-oncology centers. Working closely with the cancer research community, these centers will foster a team science environment that incubates and tests novel cancer concepts by studying and sometimes challenging accepted scientific dogma. These centers will, I believe, be proof yet again that approaching a difficult scientific problem from a new perspective can advance all research. These new centers will interface exceptionally well with our very successful centers in nanobiology, proteomics, and systems biology.
Cancer is, after all, an old problem, and it is the nature of science to move judiciously and incrementally. Today's pace of discovery regarding the genetic basis of disease is unfolding at a rate never before envisioned. Even so, we must be mindful that our task is far from complete. Patients still need answers. Patients still need better treatments, better prevention, and better early detection. We must recommit ourselves to answering that call.
We have many challenges ahead, many discoveries still to be made. We would be wise to follow George Bernard Shaw's admonition that "science becomes dangerous only when it imagines that it has reached its goal." My friends, cancer will long be with us. We are undoubtedly moving toward the day when cancers will be diagnosed early and controlled. We will not rest until we have constructed molecular and genetic methods of cancer prevention. We will not rest until we have well and thoroughly prepared those who will take up the fight after we are done.
One of the great Americans to whom all of the National Institutes of Health owe many great debts is Mary Lasker.
Mrs. Lasker was a steadfast friend of cancer research and research funding; she was a prime advocate of the National Cancer Act of 1971. Several NIH institutes exist today because of her efforts. But consider, if you will, one of Mary Lasker's simplest yet stunning achievements: In the years after World War II, she convinced broadcasting pioneer David Sarnoff that his powerhouse company, the Radio Company of America, RCA, could allow the utterance of a single word: cancer.
Although now the word cancer is part of everyday conversation, can any of us say cancer causes less fear today than it did 50 or 100 years ago? Our collective foe remains a frightful one. I would venture that everyone in this room knows in some very personal way the heartache cancer brings. Losing my wife and best friend to breast cancer 7 years ago certainly brought it home to me, and it does so every day.
Because cancer remains such a feared condition, I believe the demand from the leaders of our country and the American people will intensify in the years ahead; a demand for there to be changes in the way we approach the conduct of science; changes in the way the outstanding science that springs from our laboratories is translated, rapidly and safely, into improved health for our patients.
The American Reinvestment and Recovery Act is a chance to enhance and to change cancer science. The world is watching, waiting to see what we make of it. I know that you will firmly grasp its every opportunity. Thank you for being here this morning and for listening to my thoughts on our exciting future.
Dr. John E. Niederhuber
Director, National Cancer Institute
Guest Commentary by Dr. Margaret Foti
A Century of Progress, A Future of Promise
The American Association for Cancer Research (AACR) held its 100th Annual Meeting in Denver this week, which drew almost 17,000 scientists, physicians, advocates, and survivors from nearly 90 countries.
I often reflect on what the 11 physicians and scientists who first met 102 years ago would think about what we have been able to accomplish. They knew so little about cancer or about the basic biology of cellular growth and division. Their tools were few, but they shared a belief that research would lead to an understanding and the cure of cancer.
This year, the AACR annual meeting presented about 6,000 proffered papers covering a broad spectrum of critical areas in basic, clinical, and translational research. Since our first annual meeting in 1907, science has grown more complex and global, yet we are bound together by a unifying goal to reduce the suffering and death caused by cancer.
Despite a worldwide economic crisis, the AACR continues to grow. This year under the leadership of our outgoing president Dr. Ray DuBois, we became a major cancer research funding organization as the scientific partner of Stand Up To Cancer. In its first year, Stand Up To Cancer raised over $100 million that will be distributed utilizing a unique funding model implemented by the AACR. The funding of translational research teams is contingent upon interdisciplinary and inter-institutional commitments and a measureable patient care benefit within 3 years. This approach has the potential to change the way cancer research is being done and to save the lives of cancer patients.
In addition, in this active year we launched several new meetings and workshops on topics that ranged from cancer biostatistics in clinical trials to translational research for the Ph.D. scientist. We recognize that for cancer research to move forward we must develop synergies between the basic biological laboratories and disciplines like mathematics, physics, computer science, and engineering. The efforts of our new president, Dr. Tyler Jacks, will play a key role in the goal of bringing these fields closer together in cancer research.
Because the federal government plays such a pivotal role in cancer funding, and shows signs of growth under President Obama's administration, we are expanding our efforts to educate people on Capitol Hill about the value of cancer research to public health. We applaud the courageous leadership of Senator Arlen Specter, who addressed our meeting this year, and we have put together a Council of Scientific Advisors to work on strategies to ensure that this country remains a leader in cancer and biomedical research.
As we look to the future horizons of promise in the cancer field, we recognize that the hope for future cures and preventive measures lies in the hands of our young investigators. The AACR will continue to provide support and encouragement for young investigators and for women and minorities who have a passion for cancer research. Many of these young men and women are making career decisions that will affect the field for generations to come, and we do not want to lose the best and brightest minds to other fields.
For over 100 years of cancer meetings, the AACR has had the privilege of being led by men and women who honor us with their time by serving as president of our organization. I have learned so much from Dr. DuBois over the past year, and I want to publicly extend a warm welcome to Dr. Jacks, who will lead us in the year to come. Like prior presidents, Dr. Jacks brings an energy and a recognition of the need for high-quality science that will accelerate our progress against cancer.
As we close out a century of progress and open another century of promise, we look forward to what the members and leadership of the AACR will be able to do to bring prevention, hope, and cures to patients living with cancer.
Dr. Margaret Foti
Chief Executive Officer, American Association for Cancer Research
Special Report
Simple Measures Can Encourage African Americans to Join Clinical Trials
African Americans participate in clinical trials far less frequently than do non-Hispanic whites. Mistrust and poor communication are among the barriers persistently identified by health disparities research. However, a program developed at Nashville General Hospital that targets some of these barriers provides 7 years of evidence that recruitment rates can be dramatically increased, according to results presented this week at the AACR annual meeting in Denver.
The hospital is part of Meharry Medical College, the first medical school in the South for African Americans and part of the NCI-funded Minority-Based Community Clinical Oncology Program (MB-CCOP). Meharry participates with the Vanderbilt-Ingram Cancer Center in one of NCI's comprehensive partnerships, where minority-serving institutions that work primarily in the community setting forge an alliance with a major academic NCI-designated cancer center.
Since the Meharry-Vanderbilt partnership was established in 2000, researchers from the institutions have been developing a systematic model to increase enrollment by African Americans in appropriate cancer clinical trials. "The cornerstone of this approach is to identify eligible patients early, and to earn their trust with effective, honest communication, delivered by trained and permanent staff," said Dr. Debra Wujcik, director of Meharry's Cancer Clinical Trials Office.
The study involved 1,125 African American patients newly diagnosed with cancer and screened between 2001 and 2007. While the national average for African American participation in clinical trials is between 2 and 4 percent, the program at Meharry was able to enlist into trials up to 25 percent of all patients who were interviewed.
From 2001 to 2004, 569 patients were screened by the newly trained researchers, who were part of the permanent medical staff and fully integrated into the provision of clinical care. While only 164 were matched to a study, 95 agreed to enroll. This was 17 percent of those screened, but 58 percent of those who were eligible.
After an evaluation of these results, the researchers refined their techniques and began a new dataset in 2005. Through 2007, of 556 patients screened, 80 percent (138 of the 172 patients deemed eligible) agreed to participate in a trial. Combining the two datasets over 7 years, 68 percent of those eligible agreed to participate.
Navigating Cultural Roadblocks
"The program at Meharry proves once again that African Americans are just as willing to participate in trials if the persistent barriers that we know about can be overcome," said Dr. Harold Freeman, president of the Ralph Lauren Center for Cancer Care and Prevention in New York City and national leader on patient navigation.
"We have to explicitly invite minorities, make them feel welcome, communicate clearly what the research is about in a culturally sensitive manner, earn their trust, and ensure true access" by mitigating such factors as ability to pay and transportation, explained Dr. Freeman, a former director of NCI's Center to Reduce Cancer Health Disparities. When this happens, he continued, they are just as likely to participate as are non-Hispanic whites.
A Model of Old-fashioned Virtues
Over the course of 7 years, the researchers at Meharry have evolved and refined a culturally sensitive program that Dr. Wujcik believes can be replicated at other community hospitals. However, their success in this case owes much to the partnership with Vanderbilt-Ingram.
Dr. Wujcik explained one practical example. Meharry does not have the radiation facilities that many patients require, so often a patient will receive chemotherapy at Nashville General, and then go to Vanderbilt 4 miles away for radiotherapy. Even though Medicaid can reimburse the cost of transportation, patients who don't have someone to drive them or the money to take a cab could have their treatment seriously jeopardized.
Nurse navigators who can focus on such details have become an integral part of the clinical trials office system, Dr. Wujcik noted, and a private fund has been established to pay for cab fare when it is needed. It is the lack of "simple services like these that can often have patients falling through the cracks," she said.
"We also knew that often the clinical trial option is offered as an afterthought, which can lead to mistrust among African Americans if they perceive the research not to be to their benefit," explained Dr. Wujcik. "We monitor the clinic prospectively. When a patient first learns the results of their biopsy and receives a diagnosis, the list of treatment options already includes any clinical trials they are eligible for."
Meharry has an established patient navigation program and a patient's personal circumstances have been woven into this initial meeting. When patients first receive a cancer diagnosis and learn what their prospects might be, the discussion can be difficult, added Dr. Wujcik. Yet it can also provide a crucial opportunity to signal that they can expect trustworthy and personal care.
"The benefits of this partnership clearly run in both directions," noted Dr. Worta McCaskill-Stevens, who helped design and direct NCI's MB-CCOP program. "Not only does Meharry effectively expand their resources to include the major academic structure at Vanderbilt, but they also provide a real-world community context for young researchers in training––at both institutions––to appreciate the deeper human side of cancer research."
—Addison Greenwood
Studies Suggest Unintended Consequences of Angiogenesis Inhibition
Angiogenesis inhibitors, drugs thought to work by attacking a tumor's vasculature, are following a familiar pattern. Having proven that alone or in combination with chemotherapy they can modestly improve progression-free and/or overall survival in patients with several forms of advanced cancer, their investigational use is expanding. Several are now being tested as adjuvant (after surgery) and neoadjuvant (before surgery) therapy in clinical trials involving patients with earlier stage disease.
The first efficacy results from a phase III trial using adjuvant bevacizumab (Avastin), an angiogenesis inhibitor that targets the growth factor VEGF, are expected some time this year. The trial, the National Surgical Adjuvant Breast and Bowel Project's C-08 trial, enrolled patients with stage II and III colorectal cancer.
While the oncology community anxiously awaits the results, animal model studies published last month have further intensified interest in the trial. Angiogenesis inhibition did indeed shrink tumors in the animal models. But after the initial response, the tumors often returned with increased aggression, were far more likely to metastasize, and in some cases decreased survival.
The fact that tumors are developing resistance to treatment isn't unexpected, researchers agree. But the findings may require closer scrutiny of how anti-angiogenic agents are tested in patients, argued Dr. Robert Kerbel, a leading angiogenesis researcher at the University of Toronto whose lab conducted one of the animal model studies, because they suggest that rather than eliciting garden-variety resistance to treatment, these agents are radically altering the tumor's biology.
"If our mouse findings are relevant," he said, "you can see where one might predict that the outcome of [these] trials might not turn out as well as originally hoped or expected."
Like Water on an Oil Fire
Other lab and animal model studies have hinted that angiogenesis inhibition could have such untoward effects. But these recent studies appear to provide the most direct evidence.
In the study from Dr. Kerbel's group, led by Dr. John Ebos and published last month in Cancer Cell, several of the experiments were "crude representations" of neoadjuvant or adjuvant therapy, Dr. Kerbel explained. For example, when sunitinib (Sutent), which inhibits several proteins essential to angiogenesis, was given for a short time before or after the intravenous injection of metastatic breast cancer cells, it accelerated metastasis compared with untreated mice and decreased overall survival.
A second study published in the same issue of Cancer Cell tested several anti-angiogenic approaches in mouse models of glioblastoma and pancreatic cancer. In the pancreatic cancer model, treatment for 1 week with an investigational angiogenesis inhibitor initially shrank tumors. But as treatment continued, the tumors grew, developing "wide fronts of invasion," stretching out into the surrounding tissue, wrote Dr. Marta Pàez-Ribes, of the Catalan Institute of Oncology in Spain, and her colleagues. The untreated tumors, on the other hand, remained localized and were less invasive.
One intriguing aspect of these studies, explained Dr. Gabriele Bergers of the University of California, San Francisco and a co-author on the Pàez-Ribes paper, is that the tumors are adapting even as the endothelial cells on the vasculature that feeds the tumors are still sensitive to the agents being used to target them.
"The tumors find other ways to reinitiate neovascularization or to grow by becoming more invasive," she said. "This mechanism is very different and distinct from classical tumor cell resistance, in which tumor cells, for example, do not take up drugs anymore, or else expel them. The evasive adaptation allows the addition of other inhibitors that potentially block these evasive pathways. That is encouraging."
It's clear that angiogenesis inhibition elicits a strong response from the tumor and its microenvironment, Dr. Kerbel stressed. It actually increases, for example, levels of VEGF and PIGF-1, another growth factor important to angiogenesis.
"We've looked at G-CSF, SDF-1, SCF, and osteopontin, among others," Dr. Kerbel said. "We looked across the board and saw a lot of these other growth factors and cytokines and chemokines all increasing. But we don't know why it's happening." All of these factors are known, he added, to promote tumor growth.
Although he warns that it's difficult to extrapolate findings from animal models to humans, Dr. Axel Grothey of the Mayo Clinic, who specializes in gastrointestinal cancers, said these data offer some important lessons.
"It makes us realize how much we still don't know about tumor biology," he said.
Implications for Practice?
The ongoing clinical trials of adjuvant and neoadjuvant therapy using anti-angiogenic agents will hopefully shed some light on the issues raised by the animal model work, said Dr. Helen Chen of NCI's Cancer Therapy Evaluation Program. However, she stressed, it's important not to have tunnel vision with regard to this subject, noting that some preclinical studies of radiation therapy have showed similar effects on cytokine release and tumor cell behavior.
"This is a phenomenon of the body or the tumor responding to any stress," she explained. "The nature and magnitude of response as well as the net outcome, however, may vary depending on the specific agents and tumors under study."
Based on the body of data on anti-angiogenic agents, said NSABP C-08's lead investigator, Dr. Carmen J. Allegra, of the University of Florida Shands Cancer Center, the new studies don't have immediate clinical relevance. But, he continued, "they certainly give me reason to rethink how we apply these agents," particularly "in a potentially curative setting, where it's possible that the only disease [patients] have is what we see."
While differences in how the drugs were used complicates the comparison, evidence that the animal model results may not have clinical relevance, at least in the advanced-disease setting, come from the BRiTE study, led by Dr. Grothey. This observational, nonrandomized study of 1,900 patients demonstrated a more than 2-year overall survival associated with the use of bevacizumab. However, in the more than 1,400 patients whose disease progressed while taking bevacizumab as part of first-line therapy, those who remained on bevacizumab even after disease progression had a 52 percent improvement in overall survival compared with patients taken off bevacizumab after their disease progressed. The median survival difference between the groups was nearly 1 year.
Although patients develop resistance to angiogenesis inhibitors, Dr. Grothey said, in patients he has treated he has not seen the type of hyper 'adaptive response' reported in the Cancer Cell papers. Even so, he stressed, those studies highlight the importance of not using these drugs off-label outside the confines of a clinical trial.
In the meantime, Dr. Chen added, lab and animal model studies can help investigators choose and prioritize the most potentially efficacious—and safe—therapies to test in combination with anti-angiogenic agents.
"The real challenge," she said, "is to understand what additional, compensatory pathways are involved and how to hit them in a rational way."
—Carmen Phillips
Update: On April 21, Genentech, which manufactures bevacizumab, announced that the NSABP C-08 trial had failed to meet its preliminary endpoint of improved disease-free survival. The announcement was based on a planned final analysis of the study data, according to a company news release. The complete results of the final analysis have been submitted for presentation at the upcoming American Society of Clinical Oncology annual meeting, which begins on May 29.
Profiles in Cancer Research
Dr. Robert Motzer
Attending Physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Medical College, Cornell University
In the 20 years since he became the first oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC) to focus on advanced kidney cancer, Dr. Robert Motzer has led more than 50 clinical trials in patients with the disease and in men who have testicular cancer. He has published more than 300 papers in the medical literature, and his research has contributed to the development of three of the four targeted drugs (sorafenib, sunitinib, temsirolimus, and everolimus) that within the past 5 years have begun to transform metastatic kidney cancer from a lethal malignancy to a chronic disease.
The decision to pursue a career as an oncologist and clinical researcher came to Dr. Motzer on his first day of oncology rounds as a medical student at the University of Michigan in the late 1970s.
"I was struck by the extent of the unmet need cancer patients had for effective treatment," he recalled. Nowhere was the inadequacy of treatment more evident to him than in kidney cancer. "Kidney cancer was considered to be about the worst from the standpoint of treatment futility," he said. Kidney tumors were notoriously resistant to both chemotherapy and radiation therapy. Although early stage renal cancer could sometimes be cured by surgery, a diagnosis of advanced kidney cancer generally meant a life expectancy of a year or 2 at most.
From the mid-1980s until 2005, standard therapy for metastatic kidney cancer consisted of the biologic agents interferon alpha and interleukin-2 (IL-2). Results from trials of these agents were inconsistent, however, and the absence of reliable criteria for evaluating patients' prognosis made it difficult to compare trial findings. "I thought a standard prognostic system would help us to compare outcomes across different centers, so that when an effective drug came along, we would have a baseline for assessing its effect," Dr. Motzer explained.
He established a database of 670 patients with newly diagnosed metastatic kidney cancer who had been treated with interferon in MSKCC clinical trials. Working with MSKCC biostatisticians, he then identified five risk factors that correlated with overall survival in this patient population. Patients with none of these risk factors survived the longest and were thus considered a favorable-risk group. Patients with one or two risk factors survived a shorter time and constituted an intermediate-risk group, whereas those with three or more risk factors had the poorest survival and represented a poor-risk group.
Subsequent analyses have shown that these risk classifications accurately predict survival in other subgroups of patients with advanced kidney cancer. Known as the MSKCC risk system, or informally as the "Motzer criteria," these factors have been independently validated and are now widely used as standard criteria both in selecting patients for participation in clinical trials and in recommending treatment options to patients not enrolled in trials.
"The Motzer criteria have provided clinical investigators with an extremely useful quantitative measure both for identifying patients who are most appropriate for clinical trials in metastatic kidney cancer and for evaluating the effectiveness of the targeted agents being studied in those trials," said Dr. W. Marston Linehan, chief of the Urologic Oncology Branch in NCI's Center for Cancer Research.
In his latest project, Dr. Motzer is trying to determine the optimal way of sequencing therapy for advanced kidney cancer with the multiple drugs that are available. "The limitations of these agents have been that complete remissions are uncommon and most patients' disease does progress at some point," he said. "However, we are in a situation similar to that of colon and breast cancer, where patients can be treated sequentially with different agents."
He is a principal investigator for two international phase III trials of promising second-generation targeted agents, axitinib and pazopanib, as well as for a study to identify the molecular characteristics of tumors that respond to treatment with sunitinib. "If we understand the underlying biology of the pattern of response, we can begin to individualize treatment," he said. "The goal is to identify which agent is the right one for each patient."
In addition to his work on advanced kidney cancer, Dr. Motzer participates in trials aimed at improving therapy for difficult-to-treat germ cell tumors. These trials have helped to establish the value of adding paclitaxel to multi-drug chemotherapy for this disease and have also shown that high-dose chemotherapy followed by stem-cell rescue did not improve treatment outcomes compared with conventional-dose chemotherapy in patients with poor-risk metastatic germ-cell tumors.
After toiling for 2 decades in a relative backwater of cancer research, Dr. Motzer said that he is gratified to see kidney cancer finally getting some attention as a result of recent treatment breakthroughs.
"When I entered this field, kidney cancer was not considered a rewarding area in which to work. But the success of these new agents has brought a lot of attention to kidney cancer," he said. "That's bringing more researchers into the field and has resulted in more patients being referred to medical oncologists for clinical trials. I am hopeful that these developments will help to bring further advances in kidney cancer treatment to the clinic in the near future."
—Eleanor Mayfield
Featured Clinical Trial
Tomotherapy for Patients with Limited Metastatic Cancer
Name of the Trial
Phase II Study of Hypofractionated Highly Conformal Radiotherapy with Helical Tomotherapy in Patients with Extracranial Oligometastases (NCI-07-C-0230). See the protocol summary.
Principal Investigator
Dr. Deborah Citrin, NCI Center for Cancer Research
Why This Trial Is Important
Most people who die from cancer succumb to metastatic disease, cancer that has spread to other parts of the body. Treatment for metastatic cancer is usually undertaken to help relieve pain and other symptoms because the cancer is often considered too widespread to be cured.
Sometimes, though, metastatic cancer can be detected and treated before it becomes widespread. Moreover, certain types of cancer may spread to only one or a few other locations. Such limited metastatic tumors are called oligometastases (the Greek word "oligos" means few or little). Previous studies have shown that removing these tumors surgically can result in long-term survival for some patients, effectively curing them of their cancer.
Doctors want to find ways to extend treatment with curative intent to patients whose oligometastases cannot be surgically removed or who are unwilling to risk the complications of major surgery. One approach being investigated is the use of high-dose radiotherapy delivered over a short period of time (hypofractionated) to destroy tumors without surgery.
In this trial, patients with oligometastases outside the brain will be treated with a type of radiation therapy called helical tomotherapy. Helical tomotherapy uses a machine that is similar to a CT scanner but also contains a source for therapeutic levels of radiation. The tomotherapy machine delivers high-dose radiation from any angle, allowing the precise targeting of small or irregularly shaped tumors (that is, the radiation pattern is "highly conformal"), which minimizes the radiation exposure of surrounding normal tissue. In contrast, traditional external-beam radiotherapy targets the tumor from only one or a few angles, exposing surrounding normal tissue to substantial doses of radiation and limiting the amount of radiation that can be delivered.
"The idea of this study is to look at patients with limited metastatic disease as potentially curable, even if their tumors can't be removed surgically," said Dr. Citrin. "If we can destroy the patient's tumors with another local therapy, in this case highly conformal radiotherapy, we may be able to extend survival and possibly cure some people."
For More Information
See the list 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.
NIH Update
New Stem Cell Guidelines Proposed by NIH
Last Friday, NIH released draft guidelines for embryonic stem cell research funding that will establish policy and procedures and "will help ensure that NIH-funded research in this area is ethically responsible, scientifically worthy, and conducted in accordance with applicable law," NIH Acting Director Dr. Raynard Kington wrote in a statement.
President Barack Obama signed Executive Order 13505 on March 9, lifting restrictions on federal funding for research on embryonic stem cells. The draft guidelines would allow funding for research using human embryonic stem cells that were derived from embryos created by in vitro fertilization for reproductive purposes and no longer needed for that purpose.
The public is welcome to comment on the guidelines within 30 days following their publication in the Federal Register, slated for April 24. Instructions for submitting comments can be found online. Specific questions about grant funding should be directed to NIH.
FDA Update
GSK Seeks Approval for HPV Vaccine
Last month, GlaxoSmithKline (GSK) submitted final data from a phase III study of its cervical cancer vaccine Cervarix to the FDA in a Biologics License Application (BLA).
The study, HPV-008, involved 18,600 women aged 15 to 25 years from 14 countries in Europe, Asia, and Latin and North America. According to a news release issued by the company, GSK will submit the data included in the BLA "to a peer-reviewed journal in the coming months."
BLA reviews are typically conducted within 6 months, GSK noted in the news release. If approved, Cervarix would be the second HPV vaccine available in the United States. Gardasil, manufactured by Merck, was approved in 2006.
Fraumeni Receives AACR Lifetime Achievement Award
Dr. Joseph F. Fraumeni, Jr., director of NCI's Division of Cancer Epidemiology and Genetics, received the American Association for Cancer Research Award for Lifetime Achievement in Cancer Research at the AACR annual meeting on April 19. The award recognizes his seminal research contributions in understanding the causes and prevention of human cancer. Among his many accomplishments are the discovery of a familial cancer syndrome that bears his name along with his colleague Dr. Frederick P. Li, and the development of the U.S. Cancer Mortality Atlas project that identified high-risk areas where Dr. Fraumeni and his colleagues conducted epidemiologic studies to uncover several environmental hazards that inspired cancer control measures. For more than 30 years, Dr. Fraumeni has been the architect of NCI's intramural research program in epidemiology and related areas, while developing fellowship programs designed to train and mentor the next generation of interdisciplinary scientists.
Dr. Margaret A. Foti, chief executive officer of AACR, said, "Dr. Fraumeni's contributions throughout his auspicious career, especially with regard to the detection of environmental and genetic risk factors, have helped lay the foundation for epidemiologic research around the world. His outstanding leadership continues to spur new lines of basic and translational research, while promoting the career development of junior scientists."
Barker Receives AACR Margaret Foti Award
Dr. Anna D. Barker, NCI's deputy director for Strategic Scientific Initiatives, received the AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research at the AACR annual meeting on April 19. The award recognizes Dr. Barker's commitment to cancer research, specifically for promoting advanced technologies and new scientific disciplines such as cancer genomics, nanotechnology, bioinformatics, and the physical sciences.
NCI Chief Operating Officer Lawrence Ray Retiring
Lawrence Ray, NCI's chief operating officer, will retire on May 1. Since August 2007, he has overseen administrative management of NCI's programs and played a key role in executing the budget and work force management.
Prior to rejoining NCI 2 years ago, Mr. Ray spent 26 years in federal service, principally at NIH. Fourteen of those years were with NCI as chief administrative officer of the Division of Extramural Activities, coordinator of patent licensing and collaborative research and development agreements for the Institute, chief administrative officer of the Division of Cancer Treatment, and deputy associate NCI director, responsible for all aspects of administrative management.
NCI Lecture Series Features Dr. Julie Overbaugh
NCI's Center for Cancer Research continues its Eminent Lecture Series with presentations by nationally recognized scientists who conduct cutting-edge research designed to stimulate a scientific exchange of ideas.
Dr. Julie Overbaugh, associate program head of the Human Biology Division at Fred Hutchinson Cancer Research Center, will present the next lecture on April 27 at 3:00 p.m. in Lipsett Amphitheater on the NIH campus in Bethesda. The title of Dr. Overhaugh's talk is "HIV Transmission Challenges for Vaccines and Presentation." She will share her lab's insights from their long-standing interest in understanding the mechanisms of HIV transmission and pathogenesis.
Cancer.gov Update
NCI Streamlines Clinical Trials Search Process
Last Friday, NCI launched a redesigned clinical trials search form (www.cancer.gov/
clinicaltrials/search) on Cancer.gov. The new form is based on extensive user research with patients, caregivers, health professionals, and information specialists from NCI's Cancer Information Service. It uses a "progressive discovery" design model to help users explore the available search options. Users begin with a condensed form and can expand search choices as needed instead of being presented at the start with a long form. Enhancements include:
- A single search form (combines features from previous basic and advanced search tools)
- Better user interface for long selection lists
- Expanded search choices for interventions/treatment modalities
- Keyword search that can be used to focus searches
- Intuitive layout for display of search results
The clinical trials search feature is one of the most visited areas of NCI's Web site. The redesigned form streamlines the search process to help visitors find trials of interest with precision and ease.
New Resources on Cancer Health Disparities Research Available
NCI's Center to Reduce Cancer Health Disparities (CRCHD) recently redesigned their Web site, http://crchd.cancer.gov. New features include a new diversity training section, an introduction and overview of the Minority Institution/Cancer Center Partnership (MI/CCP) program and its grantees, and useful information about the Continuing Umbrella of Research Experiences (CURE) program that supports a continuum of diversity training and career development opportunities. The site also provides practical and up-to-date information about funding and training opportunities for junior investigators from diverse backgrounds; a new resources page with information about cancer health disparities research priorities; and an overview and history of CRCHD and health disparities research across NCI and NIH. A complete CRCHD staff listing with photos and biographies is also featured on the site.


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One of the most recognizable landmarks of downtown Minden is Main Street with its bricks.
We often like to mention Minden's brick streets, but as was recently pointed out to me by a relative newcomer, we now only have a single brick street.
The bricks were, of course, removed from Broadway (or Back Street) during the 1970s so the plural usage is now incorrect.


text:
Narrow your search
With slim 13-inch SSD laptops now well under $1,000, Sony's expensive, high-end Z series laptop is a tough sell, although the long-life slice battery and unique GPU/optical dock help make its case.
This phablet packs the Xperia Z's beautiful design in a supersized 6.44-inch frame and looks set to give the Samsung Galaxy Note range a run for its money.
Pricing not available
Though awash in features, the Xperia Tablet Z's $500 price is a decidedly bitter pill to swallow when a better, cheaper alternative exists for $100 less.
The Sony Z Ultra Google Play Edition's insanely large size and stratospheric price make the Nexus 5 and Note 3 better options for pure Android power.
Sony's unique attempt at a big-screen hybrid looks great and is reasonably priced, but it works better as a laptop than a tablet.
Pricing not available
Sony's thin, powerful Tap 11 tablet shows up the competition in terms of design. It's not ideal for everyone, but only a few tweaks away from being the runaway leader in this smallish category.
The Sony Xperia Z makes sense if a water-resistant design and excellent photos are a priority, but skip it if you demand blazingly fast performance and long battery life.
This latest effort from Sony, unveiled at IFA, is an 8-inch tablet that lets you play PS4 games in the bath.
Pricing not available
There may be a lot of touch-screen tabletop Windows 8 tablet PCs, but the Vaio Tap 21 has the looks to compete.
This hybrid can shift between laptop, tablet, or kiosk modes, and includes a copy of Photoshop Elements 12.


text:
Search for
additional physicians or researchers:
- The Johns Hopkins Hospital
- Johns Hopkins Bayview Medical Center
- Johns Hopkins Community Physicians
Or find a doctor at another Johns Hopkins Medicine member:
John Krakauer, MD
Professor of Neurology
Main Location
The Johns Hopkins HospitalView All Locations
- Director, the Center for the Study of Motor Learning and Brain Repair
- Professor of Neurology
Neurology, Stroke
Research Interests
Dr. Krakauer's research focus is in the general area of experimental and computational motor control with a particular focus on how motor learning occurs in the brain, and how such learning is affected by lesions.
Dr. John Krakauer is a Professor of Neurology and Neuroscience, and Director of the Center for the Study of Motor Learning and Brain Repair at Johns Hopkins.
Dr. Krakauer's clinical interest is stroke, including ischemic cerebrovascular disease, subarachnoid and intracerebral hemorrhage, arteriovenous malformation, cerebral vasculitis, cerebral aneurysm, and venous and sinus thrombosis.
He received his bachelor's and master's degree from Cambridge University, and his medical degree from Columbia University College of Physicians and Surgeons where he was elected to Alpha Omega Alpha Medical Honor Society. After completing an internship in Internal Medicine at The Johns Hopkins Hospital, he returned to Columbia University for his residency in Neurology at the Neurological Institute of New York. He subsequently completed a research fellowship in motor control in the Center of Neurobiology and Behavior at Columbia and a clinical fellowship in stroke at the Neurological Institute at Columbia University Medical Center.
- English
- Spanish
- Portuguese
Additional Resources
Education +
- Columbia University College of Physicians and Surg (New York NY) (1992)
- New York Presbyterian Hospital / Neurology (New York NY) (1996)
- Columbia University College of Physicians and Surgeons (New York NY) (1998)
- Columbia University College of Physicians and Surgeons / Neuroscience (New York NY) (1997)
- General, American Board of Psychiatry & Neurology / Neurology (2013)
Research & Publications +
Research Summary
Areas of research interest:
- Experimental and computational studies of motor control and motor learning in humans
- Tracking long-term motor skill learning and its relation to higher cognitive processes such as decision making.
- Prediction of motor recovery after stroke
- Mechanisms of spontaneous motor recovery after stroke in humans and in mouse models
- New neuro-rehabilitation approaches for patients in the first 3 months after stroke.
The work of the Brain, Learning, Animation and Movement Laboratory can be broken down into four main areas.
- Tracking recovery after stroke using functional and structural imaging, non-invasive brain stimulation, psychophysics and clinical scales.
- A mouse model of stroke to examine the interaction between spontaneous biological recovery, training protocols, and drugs such as SSRIs.
- The development of interventions early after stroke that combine immersive gaming environments with 3D exoskeletal robotics and non-invasive brain stimulation.
- Tracking recovery of multi-tasking using video-games in patients who recover and return home after TBI-induced coma.
Academic Affiliations & Courses +
Activities & Honors +
Videos & Media +
Recent News Articles & Media Coverage
Could a video game be the key to stroke recovery? National Geographic (9/30/2014)
I Am Dolphin Physics Game May Help Stroke Victims, The Escapist (08/08/2014)
Virtual Dolphin on a Mission: Can a cyber-dolphin influence neuroscience, game design, and wildlife conservation? National Geographic (06/15/2014)
Research On Video Games And Mental Health, NPR's Diane Rehm Show (11/27/2013)
Events +
Contact & Locations +
LocationsThe Johns Hopkins Hospital600 N. Wolfe StreetHospital Main Entrance - Sheikh Zayed TowerBaltimore, MD 21287Phone: 410-955-9441Location MapJohns Hopkins Outpatient Center601 N. Caroline StreetBaltimore, MD 21287Phone: 410-955-9441Location Map
- Neurology - Cerebrovascular


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By PAUL NEWBERRYAP Sports Writer
ATLANTA (AP) - For most of the season, the Atlanta Braves were overachievers.
They lost seven players to season-ending injuries. Two key players batted under .200. Even with all that, Atlanta managed to win 96 games and capture its first division since 2005.
But once October arrived, it was the same ol' story.
Another postseason disappointment.
The Braves haven't won a postseason series since 2001, their streak of eight straight losses now the second-longest in baseball history to the Chicago Cubs, who dropped 10 series in a row between 1910 and 1998, according to STATS LLC.
Brian McCann is a free agent and may have played his final game with the Braves. Also, the team must figure out what to do with B.J. Upton and Dan Uggla, who both struggled through miserable seasons.
Copyright 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
WTTG FOX 5 & myfoxdc5151 Wisconsin Ave. NWWashington, DC 20016Main Number: (202) 244-5151Newsroom: (202) email@example.com


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Love Bird Box
(1 review)
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Choose between 36 Nibblers® bite-sized cookies or a combo including 18 Nibblers® bite-sized cookies, 12 Brownie Bites and 2 hand-frosted heart cookies.
Dimensions: 8" x 9" x 2.5"**Due to our dough mixing process, all of our products may have come in contact with nut oils.
- Nibblers® bite-sized cookies come in an assortment of our most popular flavors.
- Nibblers® bite-sized cookies come packaged in half dozens in a special wrapper designed to preserve out-of-the-oven freshness since no preservatives are used.
- Cookies taste best when eaten the same day they are received.
- Brownies are best when refrigerated or frozen.
- Some tips if you have to save some cookies for later: never refrigerate - they dry out, store in an airtight container with a piece of white bread, may be frozen in an airtight bag.
- Thawed cookies can be warmed in the microwave for up to 10 seconds or a 375 degree oven for 1-2 minutes.
- Frozen cookies can be warmed in the microwave for 20-30 seconds or a 375 degree oven for 1-3 minutes.
1 customer review has been submitted for the Love Bird Box.
Overall Rating:(5.0 of 5)
Cute anniversary gift!(03/09/2013)I ordered this box for my husband for our 2-year wedding anniversary. Super cute! It only took 8 days to ship to his military APO address (I was expecting 2 weeks). The nibblers in the box were wrapped and labeled separately by flavor. My husband said they were delicious!
IMPORTANT NOTICE: We apologize for the inconvenience but this gift is not currently active.
May we suggest another product you may like:
Love Nibblers® Box
Love Letter Box
72 Nibblers® Basket
Frosted Hearts Basket
($39.99 - $54.99)


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Single Eye Shadow
Shipping 3-6 working daysOver 850 brandsScandinavia's No 1 Fashion Site
Single Eye Shadow from MIYO. An eye shadow with silicone and mineral formula that provides plenty of color and a lasting result. Dermatologically tested.
Item no.: 101356-2438
Colour: Bubble Gum
Size reviewsSmall in size
More about the brandMIYO is a new line of make up that offers great prices on colourful make up. MIYO offers a complete make up line that includes 40 shades of eye shadow, four different mascaras and 33 shades of nail polish. Products are made of bright colours, given fun names and are great quality. And all can be shopped from Nelly.com at great value prices.
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User Tip: If you're unsure of your vehicle type, you may skip the machine type selection box.
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"Customer service is priority #1 at Rocky Mountain ATV/MC. We value our customers and strive to be the best shopping experience- when you buy from us, you are buying lifetime service."
-Dan Thomas, CEO and Founder
We take pride in offering no hassle returns. In the event of a return, please call, email or chat with us to receive a solution to the problem. For apparel that doesn't fit quite right, Click here to see our Fit Guaranteed Program.
We will stand behind all products we sell with regards to manufacturing defects in workmanship and material. Most products are limited to the manufacturer's warranty. However, we will do everything in our power to take care of the problem.
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Comments On May 12, 2014:great product replaced my chain and both sprockets and the renthal sprocket is holding up just fine as long as you adjust your chain tension as needed. good product and looks awsome
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Comments On May 07, 2014:Great sprocket, very happy with it and would purchase again.
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Comments On Apr 12, 2014:GNCC / Enduro racing... 25 hrs of racing, needed replaced
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Comments On Apr 08, 2014:this sporket looks good on my bike and it looks more like a race bike than a trail bike. The sproket fits on th ebike but by a new set of bolts because the one's come standad don't fit the sproket
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Comments On Mar 23, 2014:lightweight, good quality
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Comments On Mar 18, 2014:I've owned black, red and silver sprocket they all have performed well and lasted longer then cheaper sprockets. I especially like the look over the renthal sprockets best.
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Comments On Feb 18, 2014:I changed from the 48 tooth to 50 tooth and love how the bike feels it really is a lightweight sprocket that looks great with the DID 520 Chain! Must Have!
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Comments On Feb 12, 2014:Looks great, light weight , good buy
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Comments On Feb 09, 2014:Strong. Held up for 2 seasons. Would recommend.
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Comments On Feb 06, 2014:I was surprised how well the color and the teeth have held up since its made of aluminum. Great sprocket really makes a noticeable impact looks wise,
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