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Odds & Ends by Tom Swartz and Bruce Shriver
In this issue's column:
HopeLab is a non-profit organization that combines rigorous research with innovative solutions to improve the health and quality of life of young people with chronic illness. The HopeLab team includes individuals with expertise in a wide range of disciplines, including research, psychology, game development, nutrition, communications, health law and policy, and organizational development. They work closely with young people with chronic illness to incorporate their critical and ongoing input into product development. They are committed to the scientific study of interventions though formative research and outcome studies to ensure that these products and/or approaches are effective.
HopeLab’s first project was Re-Mission™ — a video game developed for adolescents and young adults with cancer. Early in her career, HopeLab’s founder, Pam Omidyar, had worked as a researcher in an immunology lab. As a video game enthusiast she had the idea that a video game for teenagers with cancer might play a positive role in helping them fight their disease. HopeLab researchers worked with leading video game developers and animators, cancer experts, cell biologists, psychologists, and young people with cancer themselves to create this groundbreaking game. Re-Mission is a challenging, 3D "shooter" with 20 levels that takes the player on a journey through the bodies of young patients with different kinds of cancer. Players control a nanobot named Roxxi who destroys cancer cells, battles bacterial infections, and manages realistic, life threatening side effects associated with cancer. HopeLab conducted a randomized, controlled trial to test the effect of Re-Mission on treatment adherence, cancer-related knowledge, self-efficacy, and quality of life among adolescents and young adults with cancer. Three hundred and seventy five male and female cancer patients aged 13 - 29 were enrolled at 34 medical centers in the US, Canada and Australia, and randomly assigned to receive PCs pre-loaded with a popular video game only or that same control video game plus Re-Mission. Study results, which were presented in March of 2006 at peer-reviewed scientific meetings, indicate that playing Re-Mission produced increases in quality of life, self-efficacy, and cancer-related knowledge for adolescents and young adults with cancer. In addition, young people who played Re-Mission maintained higher blood levels of chemotherapy and showed higher rates of antibiotic utilization than those in the control group, both results suggesting that Re-Mission helps patients adhere to cancer therapy regimens. In conjunction with the release of these positive study results, HopeLab is distributing a PC version of the game to young people with cancer, free of charge, through a website and online community at re-mission.net. Re-Mission is available in English, French and Spanish. The website also provides an interactive, online community where teens and young adults with cancer can share information and support one another.
The virtue of virtual reality — the ability to give users the sense that they are "somewhere else" — can be of great value in a medical setting. Researchers are finding that some of the best applications of the software focus on therapy rather than entertainment. In essence, virtual reality can ease pain, both physical and psychological. For the past several years, pain experts at the University of Washington School of Medicine, have been researching whether severely burned patients, who often face unbearable pain, can relieve their discomfort by engaging in a virtual-reality program during wound treatment. The results have been so promising that a few hospitals are now preparing to explore the use of virtual reality as a tool for pain control. Pain has a strong psychological component. The same incoming pain signal can be interpreted as more or less painful depending on what the patient is thinking. In addition to influencing the way patients interpret such signals, psychological factors can even influence the amount of pain signals allowed to enter the brain's cortex. Neurophysiologists Ronald Melzack and Patrick D. Wall developed this "gate control" theory of pain in the 1960s [see "The Tragedy of Needless Pain," by Ronald Melzack; Scientific American, February 1990]. Why is virtual reality so effective in alleviating pain? Human attention has been likened to a spotlight, allowing us to select some information to process and to ignore everything else, because there is a limit to how many sources of information we can handle at one time. While a patient is engaged in a virtual-reality program, the spotlight of his or her attention is no longer focused on the wound and the pain but drawn into the virtual world. Because less attention is available to process incoming pain signals, patients often experience dramatic drops in how much pain they feel and spend much less time thinking about their pain during wound care. More recent research has shown that the benefits of virtual-reality therapy are not limited to burn patients. What is more, improving the quality of the virtual-reality system increases the amount of pain reduction. Studies are continuing into the use of virtual realities and various types of pain, as well as phobias. As the technology continues to advance, we can probably expect even more remarkable applications in the years to come.
Cancer Research UK Secures Fenretinide Orphan Drug LicenceA previously shelved drug could prove effective for treating sarcomas, and Cancer Research UK announced in late February that it has been granted exclusive marketing rights for the drug by the European Commission and the Food and Drug Administration (FDA). The drug, called fenretinide, was first made in the 1970s by pharmaceutical giant Johnson & Johnson as a possible treatment for breast cancer, but the company didn't bring it to market. Now out of patent, fenretinide has been studied by research groups in relation to various types of cancer, including the Ewing's sarcoma family of tumors (ESFT). A number of laboratory studies of fenretinide in ESFT cells were carried out by Dr. Sue Burchill, based at Cancer Research UK's Clinical Centre in Leeds and supported by the local children's cancer charity, Candlelighter's. Her promising results convinced Cancer Research UK to apply for orphan designation for the use of fenretinide in the treatment of soft tissue sarcomas and malignant bone tumors.
Drugs for rare diseases are called 'orphans' because the small number of patients they would treat means they are often not developed by the pharmaceutical industry. The decision will make it easier for Cancer Research UK's development company, Cancer Research Technology Ltd (CRT), to attract biotech companies to partner with the charity to help develop fenretinide for clinical use. Fenretinide will be accelerated through the European Medicines Agency's (EMEA's) and FDA's approval processes, and CRT and its partners will have ten and seven years to exclusively market the drug in the EU and US respectively. The next step in the development of fenretinide is a phase II trial, which has been approved for funding by Cancer Research UK.
Dr. Ian Lewis, the pediatric oncologist who will be leading the trial at St James's University Hospital, Leeds, said: "Fenretinide has already been tested in adults and children in the first phase of clinical trials, so we know how it affects the body. We can safely move to phase II trials, and see if fenretinide lives up to the promise it has shown in the laboratory for Ewing's sarcoma and related cancers. A young person currently diagnosed with one of these forms of tumor will be treated with a cocktail of general chemotherapy drugs, surgery or radiotherapy. Despite improvement in treatment, many young people still succumb to ESFT. If we can confirm the effectiveness of fenretinide, it could significantly improve outcomes for this rare group of cancers." Harpal Kumar, chief operating officer of Cancer Research UK and chief executive of CRT, said: "This is the first time that Cancer Research UK has applied for orphan drug designation, and it represents our ongoing commitment to developing new treatments for all types of cancer, no matter how rare. Without this decision, it would be difficult, once we have completed our phase II trial, to attract biotech companies to form partnerships with us, which will be vital to successfully developing fenretinide as a treatment for ESFT."
More Gene Mutations Drive Cancer Than Previously Thought Scientists surveying the human genome have found that many more gene mutations drive the development of cancer than previously thought. The survey is reported in the journal Nature. In the largest survey of its kind, an international team comprising over 60 scientists from the UK, Hong Kong, the Netherlands, Belgium, USA and Australia, working for the Cancer Genome Project, examined more than 500 genes and 200 cancers and sequenced more than 250 million letters of DNA code. They found about 120 new genes that drive the development of cancer cells. All cancers are thought to be caused by gene mutations. Genes control the behavior of cells, for example they tell them when to divide and when to die; thus abnormal genes either issue faulty instructions or the correct instructions at the wrong time or both, which leads to abnormal cell development and cancer.
Michael Stratton from the Wellcome Trust's Sanger Institute in Cambridge, UK, and one of the survey team leaders said "This is a lot more cancer genes than we expected to find." The survey also discovered that two types of gene mutation are involved in cancer: driver and passenger. The driver mutations are thought to drive the rampant cell growth that causes cancer, while the passenger ones, which exist in much larger numbers, just go along for the ride.
Of the 1,000 cancer-specific mutations found, the team believes that about 150 of them are driver genes. It is not easy to spot the difference between a driver and passenger gene, something this survey suggests will pose a great challenge for scientists. Dr. Andy Futreal, co-leader of the Cancer Genome Project explained "It turns out that most mutations in cancers are passengers." "However, buried amongst them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought," he added. The types of genes that Futreal and his colleagues investigated are known as kinase genes. They have been linked with cancer development before. These protein genes act like relays, switching different types of cell behavior on and off. One example of a kinase gene is the BRAF, which an earlier study showed to be mutated in 60 per cent of malignant melanomas. This led to the development of new drugs, now in clinical trials, to treat melanoma. This broader survey covered a wider range of the more common types of cancer, including breast, lung, colorectal and stomach cancers. The researchers also found that a particular group of kinase genes "involved in the Fibroblast Growth Factor Receptor signalling pathway was hit much more than we expected, particularly in colorectal cancers," said Dr. Futreal. The survey also showed that buried inside each mutation are important coded messages, and that the type of mutation varied widely between different cancer types. This suggests that in some cases the process of mutation begins decades before the cancer presents itself. It is as though gene mutations are "archeological sites" where written inside the DNA of each cell is a historical coded pattern that reveals the original cause of the cancer. In some cases the code can be deciphered, for instance damage from UV radiation or sunlight, or carcinogens in tobacco smoke, but in other cases the code is too hard to crack, which means more research effort is needed to unravel their mysteries. "This study vindicates all of the effort that went into the Human Genome Project," said Dr. Mark Walport, Director of the Wellcome Trust, the largest independent charity in the UK and the second largest medical research charity in the world, and the sponsors of the survey. "Understanding the mutations that cause cancer is crucial in order to develop accurately targeted treatments," added Dr. Walport.
Cancer Pain: Your Guide to Relief™ The American Pain Foundation provides information, coping strategies and tools to help cancer patients and their caregivers understand the basics of pain management and better communicate with their doctors. This site contains personal stories, medication fact sheets, reporting & management tools and tips on how to work with your medical team. Learn more about cancer pain and what you can do by reviewing this Spotlight on Cancer Pain section of the Foundation’s website.
Simple Two-Gene Test Sorts Out Similar Gastrointestinal Cancers A powerful two-gene test distinguishes between a pair of nearly identical gastrointestinal cancers that require radically different courses of treatment, researchers reported in February in the Proceedings of the National Academy of Sciences. "This simple and accurate test has the potential to be relatively quickly implemented in the clinic to benefit patients by guiding appropriate treatment," says senior author Wei Zhang, Ph.D., professor in the Department of Pathology at The University of Texas M. D. Anderson Cancer Center. The analytical technique employed to tell gastrointestinal stromal tumor (GIST) from leiomyosarcoma (LMS) with near perfect accuracy will have wider application in more individualized diagnosis and treatment of other types of cancer, study co-authors from M. D. Anderson and the Institute for Systems Biology in Seattle conclude. GIST was once thought to be a type of leiomyosarcoma because both originate in the smooth muscle cells of the gastrointestinal tract. However, GIST is treatable with the targeted medication known as Gleevec and is relatively unresponsive to chemotherapy. The opposite is true of LMS. An existing test distinguishes among the two cancers with about 87 percent accuracy, but intensive and time-consuming additional analyses are required for uncertain cases, Zhang says.
The researchers used common whole genome microarrays to measure gene expression in 68 GIST or LMS tumors, but then applied an analytical twist. Rather than identifying multiple genes that might distinguish each type of cancer, the researchers instead analyzed every possible pair of genes, says first author Nathan Price, Ph.D., research scientist at the Institute for Systems Biology, a process called Top Scoring Pair analysis. The result was a cancer classifier based on the expression ratio of two genes. If the gene OBSCN expresses more of its RNA than the gene C9orf65, then the tumor is GIST. If C9orf65 is more abundant, it's LMS. The test accurately identified 67 of the 68 microarrayed tumors, with the exception being one tumor with nearly a 50-50 split between the two expressed genes upon which no diagnosis could be made. An additional test using a more accurate measurement procedure on the two genes identified 20 of the original samples (including the sample with near equal gene expression) and 19 independent samples with 100 percent accuracy, the authors report.
Genomic approaches to diagnosing, selecting treatment and determining a cancer patient's prospects of responding to care are beginning to work their way into the clinic, the researchers note. These approaches can rely on dozens of genes as biomarkers. Top scoring pair analysis allows the use of fewer genes to distinguish between similar cancers or between groups of patients who have one type of cancer yet respond differently based on genetic indicators, the authors note. For example, paired gene analysis may be used to determine which patients benefit from different types of chemotherapy and which patients are at risk of relapse. Zhang said the research group is using this analytical strategy to identify gene pairs that can predict which GIST patients respond to Gleevec and how other types of cancer respond to treatment as well.
NCCN Clinical Practice Guidelines — Soft Tissue Sarcoma 2007 The National Comprehensive Cancer Network (NCCN) is an alliance of leading cancer centers that, among other things, seeks to “advance the state of the art in cancer prevention, screening, diagnosis and treatment through excellence in basic and clinical research.” One of the programs sponsored by NCCN include The NCCN Practice Guidelines in Oncology which are “the recognized standard reference for appropriate practice in the field of oncology.” The NCCN has released its Practice Guidelines for Soft Tissue Sarcoma 2007 (v.1.2007), which are available in this PDF. For 2007, changes were made in the practice of management of gastrointestinal stromal tumors and desmoids tumors. It should be noted that the Sarcoma Guidelines do not include the management of rhabdomyosarcoma, Ewing's sarcoma, or desmoplastic small round cell tumors.
Grind For Life, Inc. was founded in 2003, by life-long skateboarder Mike Rogers, after his second battle with sarcoma. Mike's tumor was located behind his right eye and nasal cavity. He endured a 17 hour surgery a cranial-facial resection with a brain-lift, removal of his eye, cheekbone, and half of the roof of his mouth and some of his teeth. He beat cancer once as a pre-teen, and again 25 years later. Mike beat the odds and is skateboarding competitively again. The mission of the Grind For Life organization is to provide financial assistance to cancer patients and their families when traveling long distances to doctors and hospitals. In addition, they educate and inspire these patients and families concerning cancer survival and recovery. Those who qualify may request assistance for travel and lodging expenses, meal, and personal needs. Funds for this organization are raised by, but not limited to, the hosting skateboarding events and festivals. The organization’s ultimate goal is to have a couple of apartments near Memorial Sloan-Kettering Hospital in New York, so people who are receiving treatment at the hospital can have their family near them. They want to be able to provide a comfortable place to stay, charge fees based on a sliding scale, provide support for those who are not accustomed to the city, and make a rough situation a little easier for those who travel long distances for treatment. Check out their website for their latest skateboarding events, or to make a donation.
How Many List Members Does It Take to Change a Light Bulb? For those who frequent one or more online support groups to help them on their journey with sarcoma. you may find a little comic relief in the answer.
Radiation-Induced Fractures a Significant Challenge After Sarcoma Surgery: Presented at AAOSRadiation-induced pathologic fractures continue to be a difficult problem in patients who have previously undergone treatment for soft tissue sarcoma of the extremities, investigators reported at the 2007 Annual Meeting of the American Academy of Orthopaedic Surgeons (AAOS). Kevan Saidi, MD, resident, orthopaedic surgery, London Health Science Center, Toronto, Canada, presented outcome data in 32 patients who developed 34 fractures after receiving radiation and soft tissue sarcoma resection. All subjects were treated at Mount Sinai Hospital between, 1986 and 2005. While earlier trials identified risk factors for pathologic fractures in patients undergoing treatment for soft tissue sarcomas, the outcomes in these patients once they developed such fractures has not been studied, Dr. Saidi noted in his presentation on February 15th. In the present study, the researchers defined a radiation-induced pathologic fracture as a fracture that developed in the radiation field of a patient who had previously undergone combined management using radiotherapy and surgery for an extremity soft tissue sarcoma. Of the 34 fractures, 32.3% healed and 67.7% either had a persistent non-union at the most recent follow-up, amputation for non-union, or required arthroplasty.
Fractures that did not heal occurred at a mean of 58.5 months after resection of the sarcoma. Fractures that healed occurred at an average of 19.2 months after sarcoma surgery. The difference between the two groups was not statistically significant. Sixteen fractures (47.1%) developed after periosteal stripping at the time of sarcoma resection, while the remaining 18 fractures (52.9%) developed without periosteal stripping. Most of the non-healed fractures were displaced fractures that were managed operatively. The study also documented a high non-union rate of 80% in the femur. "This is worrisome and is apparently associated with a significant worsening in the patient's functional outcome," Dr. Saidi said. "While intramedullary nailing and repeated attempts at bone grafting of femoral fractures may occasionally produce union, it may be prudent to consider alternate treatments such as vascularized fibular grafting or endoprosthetic replacement in the femur in order to avoid prolonged disability," he added. This series is, to his knowledge, the largest case series of patients with radiation-induced fractures after surgery for soft tissue sarcoma ever reported, Dr. Saidi said.
ARIAD Provides Update Regarding AP23573 Phase 3 Trial in Metastatic Sarcoma ARIAD Pharmaceuticals, Inc. announced on April 5th that the Company has received feedback from the U.S. Food and Drug Administration (FDA) regarding its Special Protocol Assessment on the design and endpoints for its Phase 3 pivotal trial of oral AP23573, its novel mTOR inhibitor, in metastatic sarcoma. Based on the FDA's response, the Company intends to pursue its Phase 3 trial in the same treatment setting as originally proposed (patients with metastatic sarcoma following a favorable response to chemotherapy), with overall survival as the primary endpoint and progression-free survival as a key secondary endpoint. As a result, the Company anticipates that initiation of patient enrollment may be delayed from the second to the third quarter of 2007. The Company expects to provide further details concerning the registration trial based on receipt of follow-up Protocol Assistance from the European Medicines Agency (EMEA) and ongoing interactions with the FDA. "We are working to ensure that our pivotal trial for AP23573 conforms to the guidance and requirements put forth by both the U.S. and European regulatory agencies and will initiate patient enrollment as soon as possible," said Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD.
Monies Will Be Used to Investigate the Neural Crest Origin of Ewing's Sarcoma Researchers from the University of Southern California (USC) recently received approximately $3.4 million from the California Institute for Regenerative Medicine (CIRM) for stem cell research. One of the proposals that was selected to receive funding from these monies was a proposal by Elizabeth Lawlor, MD, PhD. to investigate the neural crest origin of Ewing's sarcoma. Dr. Lawlor, an assistant professor at the Keck School of Medicine at USC is developing the tools to identify and study the elusive Ewing’s sarcoma stem cell. Click here for her website.
Oncolytics Biotech Inc. announced on April 11th that subsequent to the regulatory review period for this submission, it is proceeding with a Phase II trial to evaluate the intravenous administration of REOLYSIN® in patients with various sarcomas that have metastasized to the lung. "This multi-centre, Phase II trial follows the successful completion of systemic administration trials with REOLYSIN® in the U.K. and the U.S.," said Dr. Karl Mettinger, Chief Medical Officer of Oncolytics. "This trial is the second in a series of Phase II trials the Company has planned for this year, and represents yet another step forward in the Company's clinical development strategy for REOLYSIN®. We are excited to expand our clinical program to specifically include patients with sarcomas." The trial (REO 014) is a Phase II, open-label, single agent study whose primary objective is to measure tumor responses and duration of response, and to describe any evidence of anti-tumor activity of intravenous, multiple dose REOLYSIN® in patients with bone and soft tissue sarcomas metastatic to the lung. REOLYSIN® will be given intravenously to patients at a dose of 3x1010 TCID50 for five consecutive days. Patients may receive additional five-day cycles of therapy every four weeks for a maximum of eight cycles. Up to 52 patients will be enrolled in the study. Eligible patients must have a bone or soft tissue sarcoma metastatic to the lung deemed by their physician to be unresponsive to, or untreatable by standard therapies. These include patients with osteosarcoma, Ewing sarcoma family tumors, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma and leiomyosarcoma.
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