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Chemotalk NewsletterChemotalk Newsletter, Vol. 29: September 1, 2010
September, the beginning of the school year. That means my neighbor's kids HAVE to get out of the pool! A line from last month's newsletter is worth repeating, and remembering: "In the real world, things happen at the edge of scientific proof." Something worth remembering ... Here's a concern patients rarely, if ever hear about: CANCER DOCTORS 'FRUSTRATED' BY LACK OF USEFUL INFORMATION IN JOURNAL ARTICLES Medical journals should include more clinical details in cancer research studies to help doctors better understand and utilize results, according to U.S. researchers. They analyzed 262 articles published from 2005 to 2008 in the Journal of Clinical Oncology, The New England Journal of Medicine, the Journal of the National Cancer Institute, and the journals Cancer and Blood. Only 11% of the articles offered all the information required by doctors in order to prescribe and monitor new cancer therapies, said the researchers at the University of Florida in Gainesville. The dose of the drug was almost always reported in the articles, but only 43% reported what premedication was necessary, and only 42% provided details about adjusting dosages if the therapy proved toxic to patients. The study was published in a recent issue of the Journal of the National Cancer Institute. The authors made several recommendations -- such as a change in the way journal editors edit and report on clinical trials -- that would lead to a major shift in the publication of clinical trials. "This study came out of our clinical frustration," said Dr. Thomas George Jr., a member of the UF Shands Cancer Center and director of UF's gastrointestinal oncology program in the college of medicine. "We were trying to teach our students and fellows how to care for patients with cancer and prescribe therapeutics safely. We had a really hard time finding the information we needed to provide care for these patients in the original scientific articles." "I think it just boils down to willpower on the part of the journal editors to agree that this is an important need," he added. "I think the scientific community -- the publishers, the editors and even the investigators who conduct the studies -- have been appropriately focused on justifying the scientific methods and merits of the study. We're just taking it to the next logical step, which is, how do we apply these results to the masses of patients who need to benefit from scientific progress?" * * * And of equal, if not greater concern ... RECESSION CAUSING CANCER PATIENTS TO QUIT LIFE-EXTENDING DRUGS In 2009 and 2010, as the economic collapse shuddered across the globe, oncologists in California noticed a troubling trend: Three patients who had had serious tumors under control for as long as eight years reappeared in the clinic with massive CANCER regrowth which, in one case, required emergency surgery. In retrospect, this downturn in fortunes should have been predictable: The economic recession had forced the patients to discontinue a life-extending medication. "In all three cases, the patients developed new symptoms and came in after having missed an appointment or two without us knowing that they had stopped the drug," said Dr. Katie Kelley, co-author of a letter-to-the-editor in a recent issue of the New England Journal of Medicine, which describes the cases. Kelley is also assistant clinical professor of medicine at the University of California, San Francisco (UCSF). And there have been other such cases, both at UCSF and around the nation, either of patients stopping medications altogether or rationing in the hopes of making precious supplies last longer. "Certainly we've seen an increase in affordability concerns," said Stephen Finan, senior policy director of the American Cancer Society Cancer Action Network in Washington, D.C. "Very definitely we've seen an upward trend in the last couple of years of people struggling with deductibles and cost sharing." "There has been some evidence to suggest that it is happening on a wider scale," added Robert Freeman, professor of pharmaceutical sciences at Texas A&M Health Science Center's Irma Lerma Rangel College of Pharmacy. "This not only happens when the economy turns down, but if Medicare programs run into budgetary problems and become restrictive or if private co-payments go up." All three patients described in the journal article had been taking Gleevec (imatinib) for gastrointestinal stromal tumors (GIST). Gleevec is considered by many to be a wonder drug, since it appears to be close to a cure for many people with a form of blood cancer known as chronic myelogenous leukemia (CML). The drug has also extended the average survival of GIST patients from just a few months to an average of five years, the UCSF team noted. However, Gleevec costs patients close to $5,000 per month. That's out of the reach of most Americans without health insurance, and it can make Gleevec tough to afford even when insurance is available. All three patients described in the journal had been part of the trial that led to Gleevec's approval for GIST and had been taking the drug since 2001. And all had suffered economic reversals, including job losses, that forced them to stop treatment. As a result, all experienced recurrences, often within a matter of months. "These were people who previously had had their drugs covered and all of a sudden the greater-than-$5,000-a-month cost became really prohibitive," said Kelley. "It's completely understandable." Fortunately, despite the massive regrowth of their cancers, none of the patients ended up with "major consequences" from their involuntary drug hiatus, said Kelley, though that isn't uncommon. "If a medication is controlling a chronic condition then the chronic condition is going to worsen over time. It may not be immediate but you're going to have the person's condition essentially return to the point it was before it started therapy," Freeman said. "You will see downstream costs go up as a result of that because the person will become sicker." Doctors did find a way to get the three UCSF patients back on their medications -- at least temporarily -- and some of these options are available to others as well. If a patient has a large co-pay, or no insurance at all, the "MAIN RESOURCE TO OFFER IS CONNECTION WITH PATIENT ASSISTANCE PROGRAMS RUN BY PHARMACEUTICAL COMPANIES" Kelley said. "THERE ARE SOME FOUNDATIONS AND CHARITIES THAT DO SPECIFICALLY HELP PEOPLE WHO ARE STRUGGLING WITH THEIR COST-SHARING ON PRESCRIPTION DRUGS, OR OTHER COST-SHARING PROBLEMS, AND SOME OF THE PHARMACEUTICAL COMPANIES HAVE ASSISTANCE PROGRAMS WHERE THEY WILL PROVIDE DRUGS AT LOWER OR NO COST FOR PATIENTS IN NEED," added Finan. "Those are the only real options at this point for people who are pressed to afford their prescription costs". Although "getting drugs for two months isn't ideal for patients who
still don't have insurance at the end of that time, it's a starting point,"
Kelley said. * * * A PLAN TO RECOVER MORE ORGANS FOR TRANSPLANT RUNS INTO DIFFICULTY By Anemona Hartocollis For years, even as the medical community persuaded more people to become organ donors, it faced a seemingly insurmountable problem: Most people do not die in hospitals, making saving their organs for transplant nearly impossible. Three years ago, an emergency doctor at Bellevue Hospital Center in Manhattan proposed a groundbreaking plan. The city would have an "organ preservation vehicle" monitor emergency radio frequencies and chase after ambulances, ready to swoop in as soon as a person was declared dead. But with a deadline to qualify for $1.5 million in federal grant money just a month away, the idea has run into what might be another insurmountable barrier: How to meet the needs of law enforcement officials who want to preserve the bodies -- with all the organs intact -- of people who die under circumstances that might need to be investigated? The objections come after exhaustive attempts by the plan's architects
to overcome things like ethical concerns about making sure no life-saving
treatment was withheld, and the more visceral reaction that having an
organ-harvesting crew shadow a medical crew sounds ghoulish. The police are required to report to the medical examiner deaths that result from apparent homicide, accident or suicide, or that occur in a correctional facility or in any suspicious or unusual manner, including people who are young and seemingly healthy. The medical examiner or a representative is then required, according to the city code, to go to the scene to "take charge" of the dead body and investigate the cause of death. But there is only a short window of time after death -- perhaps 20 to 30 minutes -- for the organs to be preserved. That leaves little time for the medical examiner to arrive at the scene and release the body. Mr. Browne said the concern was that responsibility for making the right call would be shirted to a police officer at the scene. Dr. Lewis R. Goldfrank, the leader of New York's project, and chairman of emergency medicine at Bellevue, the city's premier public hospital, said last week that he was working hard to overcome the concerns. He said the project had been configured to exclude "anyone who is conceivably involved in a crime -- a gunshot or stab wound, someone who might be strangled, you wouldn't touch." He said that the exclusions would be based on the examination of a physician at the scene, paramedics and police officers, an that the medical examiner could be consulted by phone. "We have already reached agreement with the office of the chief medical examiner that that's probably adequate," he said. An agreement had been made, he said, to take a blood sample to test for poisoning. Ellen Borakove, a spokeswoman for the medical examiner's office, said that the medical examiner wanted the project to work out but declined to comment further. Jennifer Scaperotti, a spokeswoman for Mayor Michael R. Bloomberg, said: "Because rapid organ recovery requires important decisions to be made in new ways under tight deadlines, we have to think through the procedures for releasing a boy in the hospital to prevent the policy from having unintended consequences. "The city is very interested in promoting organ donation and continues to discuss the possibility of a rapid organ-recovery ambulance to expedite the process and save lives." Dr. Goldfrank said the protocol had also been adjusted to address uneasiness about the approach. The organ-recovery vehicles would be parked out of sight of the ambulances, an the emergency medical crews would not be made aware of their presence, to avoid influencing their efforts to save the person. Also, a person's consent for organ donation would no longer be presumed, even if, for example, it said so on the person's driver's license. A family member would have to be at the scene to assent to the donation, he said. Dr. Goldfrank said the pilot (study) was meant to last six months in the area around Bellevue and would involve KIDNEY DONATION. He hoped it could then be expanded citywide. "Ninety-five percent of people die outside a hospital," he said. "They die when walking on the street or in their homes in bed." He estimated that nationwide every year, recovering organs outside the hospital could result in about 20,000 additional people becoming donors. While that would help, it would make only a dent in the demand: Nearly 6,000 people are waiting for kidneys in the New York area alone, according to the New York Organ Donor Network. Another barrier the project may encounter is the relatively small number of New Yorkers who have registered as organ donors. In New York City, about 580,000 residents are registered as potential donors, according to the New York Organ Donor Network. New York's proposed organ recovery project would be the only one of its kind presently operating in the United States, officials said, although it is based on models in Europe. * * * SURVIVAL RATES BETTER FOR CERTAIN HEART TRANSPLANT PATIENTS Patients who have a HEART TRANSPLANT to correct the most common type of genetic heart disease -- hypertrophic cardiomyopathy -- have better long-term survival rates than those who have transplants for other heart diseases, a new study finds. In patients with hypertrophic cardiomyopathy (HCM), the pumping chamber of the heart, known as the left ventricle, thickens over time. This makes it stiff and less able to relax in order for blood to fill the heart chambers. This serious, potentially fatal condition affects about 500,000 people in the United States. In the new study, published in the journal Circulation: Heart Failure, U.S. researchers analyzed data from 26,706 adult heart transplant patients included in the United Network of Organ Sharing Registry. HCM patients account for about 1% of all heart transplants performed nationwide. One year after transplant, the survival rate was 85% for patients in the hypertrophic cardiomyopathy group and 82% for those with other heart diseases. The survival rates were 75% and 70%, respectively, after five years, and 61% and 49%, respectively, after 10 years. "Patients with this disease who are undergoing transplant can expect reasonable long-term survival rates -- that's a crucial clinical message for this small but important subgroup of patients," said lead author Dr. Martin S. Maron, an assistant professor of medicine, director of the Hypertrophic Cardiomyopathy Center and co-director of Advanced Cardiac Imaging at Tufts Medical Center in Boston. * * * Not only does virtual colonoscopy identify COLORECTAL CANCER, it also boosts the likelihood of detecting cancers outside of the colon, a new study shows. Virtual colonoscopy is less invasive than regular colonoscopy. In addition to offering doctors a look at the inside of the colon, virtual colonoscopy examines the entire abdomen and pelvis. The ability of virtual colonoscopy to identify significant lesions outside the colon at an early, treatable stage "may increase the yield" of colorectal cancer screening, thus underscoring its potential as a major screening technique, said study author Dr. Ganesh R. Veerappan, from the American College of Radiology. The study included 2,277 people who underwent a virtual colonoscopy. Findings of cancers and lesions outside the colon were identified in 1,037 of the patients, including 787 insignificant and 240 significant findings. Regarding findings outside the colon, a virtual colonoscopy "increased the odds of identifying high-risk lesions by 78%. [It] should be considered as an alternative to optical colonoscopy for colorectal cancer screening or as a onetime procedure to identify significant treatable intracolonic and extracolonic lesions," Veerappan said. The study appears in the American Journal of Roentgenology. * * * For the first time, scientists have succeeded in isolating the lengthy protein encoded by the BRCA2 gene. Dysfunction of this gene can up the risk for both BREAST and OVARIAN CANCER. By separating the protein from the rest of the components of human cells, researchers were able to study it more closely and figure out exactly what it does in the body. "Since BRCA2 is such a large protein, it has a lot of different domains and it has never really been clear how the different domains work together," explained Wolf-Dietrich Heyer, senior author of a paper appearing online in the journal Nature Structural & Molecular Biology and co-leader of the Molecular Oncology Program at the University of California, Davis, Cancer Center. "With having the entire protein purified now, one has a chance to actually understand the whole protein," he said. "It's a huge protein. People were studying individual pieces but never got the full picture. Now we can really start to analyze its mechanisms." That analysis should help illuminate the underpinnings of breast and ovarian cancers and point the way, someday, to better prevention and treatment. Heyer's paper joins two other papers, one also in Nature Structural & Molecular Biology and one in Nature, which detail the findings. Although the BRCA1 and BRCA2 genes were discovered some 15 years ago, scientists have had trouble deciphering their inner workings. "Everybody has a BRCA gene. You need it because it functions as a tumor-suppressor gene," explained Dr. Julia Smith, director of the Breast Cancer Screening and Prevention Program at NYU Cancer Institute in New York City. "Abnormal cells that could become tumor cells are popping up all the time and we have lots and lots of repair mechanisms and corrective mechanisms to bump off those cells so they can't divide and behave badly." Under normal circumstances, the BRCA gene would automatically correct those problems. "But if you have certain mutations in the BRCA gene, then one of the mechanisms of repair - the BRCA gene - is not functioning properly, so that cell is allowed to proliferate and grow out of control," Smith said. Over the course of several, often frustrating years, these scientists were able to purify the protein, which consists of 3,418 amino acids, to reveal some of its inner workings. As it turns out, BRCA2 binds with another protein, RAD51, in a specific way to make sure that any breaks in the DNA get fixed correctly. It's a basic science discovery but it has many implications," said Stephen Kowalczykowski, senior author of the paper appearing in Nature and distinguished professor of microbiology and molecular and cellular biology at the University of California, Davis. "One would be that since we now know how the protein works, we can try to screen for therapeutic agents that could mitigate some of these problems." "This illuminates a function of BRCA2 that's going to give new ideas to people who are involved in translational [lab-to-bedside] work," added Dr. Priscilla A. Furth, a professor of oncology and medicine at Lombardi Cancer Center of Georgetown University in Washington, D.C. "This is good, solid, basic science that is going to put us on a firm ground as we now look at why we get cancers from the loss of BRCA2." "The more we can understand where the defect is the more we can try to correct it. RAD51 could be a molecule that we could target to make DNA repair actually effective in BRCA patients," Smith added. "That's the import of this work. It's not going to help us right now but we're moving more and more towards targeted therapy, designing treatments that target specific molecular abnormalities." * * * Patients who have a heart transplant to correct the most common type of genetic heart disease -- hypertrophic cardiomyopathy -- have better long-term survival rates than those who have transplants for other heart diseases, a new study finds. In patients with hypertrophic cardiomyopathy (HCM), the pumping chamber of the heart, known as the left ventricle, thickens over time. This makes it stiff and less able to relax in order for blood to fill the heart chambers. This serious, potentially fatal condition affects about 500,000 people in the United States. In the new study, published in the journal Circulation: Heart Failure, U.S. researchers analyzed data from 26,706 adult heart transplant patients included in the United Network of Organ Sharing Registry. HCM patients account for about 1% of all heart transplants performed nationwide. One year after transplant, the survival rate was 85% for patients in the hypertrophic cardiomyopathy group and 82% for those with other heart diseases. The survival rates were 75% and 70%, respectively, after five years, and 61% and 49%, respectively, after 10 years. "Patients with this disease who are undergoing transplant can expect
reasonable long-term survival rates -- that's a crucial clinical message for
this small but important subgroup of patients," said lead author Dr. Martin
S. Maron, an assistant professor of medicine, director of the Hypertrophic
Cardiomyopathy Center and co-director of Advanced Cardiac Imaging at Tufts
Medical Center in Boston. * * * NOTCH INHIBITORS MAY OFFER BREAKTHROUGH ON BRAIN CANCER Cancer researchers are hailing a preclinical proof-of-concept study demonstrating the effectiveness of a combo therapy in targeting and eliminating BRAIN CANCER cells, an important new strategy for defeating a lethal case of glioblastoma. Researchers at the University of Massachusetts Medical School found that by combining an experimental Notch inhibitor with the chemotherapy drug temozolomide they could slow tumor growth and recurrence in mice and tissue more effectively than either agent alone. "Either drug used individually only transiently slowed tumor growth," they report. That's good news for Merck and Eli Lilly, both of which have Notch inhibitors in the pipeline, according to Reuters. Glioblastoma is one of the toughest cancers to beat. The cancer has a tendency to go into remission temporarily before it comes back as an even more lethal tumor. Temozolomide is a chemotherapy drug of choice for glioblastomas, and the results of our preclinical study represent a potential promising new approach to combat an extremely difficult tumor," said lead researcher Alonzo Ross (photo). "The effect of the two together is very dramatic." Results of this study are published in Cancer Research. "These results help lay the groundwork for future clinical research and are yet another stepping stone towards a future era dominated by 'precision therapeutics' designed to specifically target the underlying molecular drivers of cancer growth and spread," said Patrick O'Connor, chief scientific officer of Selexagen Therapeutics. * * * RESEARCHERS CREATE CANCER-FIGHTING CLUSTER BOMB Delivers drugs directly into cancer cells Scientists in Israel have come up with a way to target cancer without damaging healthy cells. Two researchers at Tel Aviv University developed a nano-vehicle that carries tiny particles of CHEMOTHERAPY drugs through the body. The drugs are released when the nano-vehicle comes into direct contact with cancer cells. Dr. Dan Peer of Tel Aviv University's Department of Cell Research and Immunology and the Center for Nano Science and Nano Technology and Professor Rimona Margalit of the Department of Biochemistry and Molecular Biology invented the tumor-targeting device. "The vehicle is very similar to a cluster bomb," explains Peer. A sugar molecule recognized by many cancer cell receptors is used to create the outer coating of the cluster. The microscopic nano-device is wrapped in this sugary coating -- which serves as a trojan -- tricking the cancer cells. "When the nano-vehicle interacts with the receptor on the cancerous cell, the receptor undergoes a structural change and the chemotherapy payload is released directly into the cancer cell," said Peer. The direct release leads to more focused treatment against the cells. As a result, this nano-vehicle can be used to treat various types of cancer and increases the benefits of chemotherapy while reducing side effects. Since the nano-vehicle is made from organic materials, it is safer than current therapies and according to Peer and the materials decompose once its function is complete. Peer and Margalit are said to be working with a pharmaceutical company in the United States with expected trials to being within the next two years. The Tel Aviv team's breakthrough is published in the most recent edition of the Biomaterials journal. * * * ROCHE BACKS NEW METHOD FOR DRUGS By Duff Wilson, New York Times The Swiss pharmaceutical giant Roche is throwing its weight behind an experimental technology that could be used to treat a number of diseases. The company has agreed to pay $25 million now and up to $1.1 billion later to Aileron therapeutics of Cambridge, Mass., for developing a new type of drug technology called "stapled peptides." They are expected to announce the agreement on Thursday (8/26). Aileron, which holds patent rights from Harvard and the Dana-Farber Cancer Institute, hopes to start clinical trials next year. It is testing a stabilized form of peptides, a small protein, to deliver medicine inside cells for a variety of medical conditions, including Roche's priorities like treatments for CANCER and inflammation. "This is a significant commitment by a very smart pharmaceutical company betting they're finally goig to unlock the power of peptides as a superclass of drugs," said Joseph A. Yanchick III, the chief executive of Aileron. The synthetic peptides, developed by a Harvard chemical biologist, have been described as a type of magic bullet that can deliver particularly potent doses of drugs at the cellular level. They are stabilized in a helical shape that stays active longer in the body. Mr. Yanchik said they have been successfully tested in animals. He said the company started preliminary talks with the Found and Drug Administration in June. The F.D.A. Must approve an investigatory new drug applicaion before any human testing. Dr. Jean-Jecques Garaud, Roche's global head of pharmaceutical research and early development, said stapled peptides could open new horizons in medicines. "One of the challenges the industry is facig is not to identify new targets, but to be able to reach the target that we would like to reach with the right therapeutic benefit, particularly inside the cell," he said in a phone interview. He emphasized, however, that they are years from proving it will work in patients. "Obviously no one knows yet, but it is worth exploring as a tool," Dr. Garaud said. Richard D. DiMarchi, a professor and former chairman of the chemistry department at Indiana University, who is not involved with Aileron, said the deal shows that big pharmaceutical companies are embracing the novel peptide and protein technologies. "Peptide molecular medicine is a very hot area, and this concept of stapled peptides is a new area of great promise," he said. Professor DiMarchi co-founded Marcadia Biotech in 2005 and signed a licensing deal with Merck in 2008 to pursue other forms of stablilized peptides to treat diabetes and obesity. He said those materials, which work outside cells, are now in clinical trials. Roche and Aileron said they would focus on five target diseases. Citing proprietary reasons, they would not identify the diseases but said they call among Roche's priorities of cancer, viruses, inflammation, metabolism and the central nervous system. Aileron's lead research aims at cancer. Dr. Garaud said Roche's chief executive has approved the deal with
Aileron. Mr. Yanchik said the companies signed the deal last week. Such new technologies are fraught with possible setbacks, however, on the path from laboratory bench to bedside. Monoclonal antibodies, for instance, have yet to live up to expectations. In another example of innovative biology that companieshoped would provide new therapeutics, Roche has invested heavily in technology called RNA interference. Roche has made two bog deals to advance the RNA technology. It agreed in 2007 to pay up to $1 billion to Alnylam Pharmaceuticals of Cambridge and in 2009 to pay up to $50 million to Tekmira Pharmaceuticals of Canada. The company, however, is not meeting its goal of starting a clinical trial this year, a spokesman said. Existing peptide products, without the stapling, include Forteo of Eli Lilly for osteoporosis and Byetta from Amylin and Lilly for Type 2 diabetes. So far the peptides must be injected; they do not come in pill form. Roche, based in Basel, is the world's largest biotech company and bought Genentech last year. Roche recently reported a $5.35 billion profit for the first six months of the year. Aileron, founded in 2005, has about 40 employees. * * * Until next month... * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at jesmer_e@pacbell.net Elaine Jesmer
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