A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on June 30, 2005 under Uncategorized | 
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Fireworks explode over tallships sailing in the Solent off the coast of Portsmouth, southern England, during events to mark the 200th anniversary of the Battle of Trafalgar June 28, 2005. Britain’s Queen Elizabeth on Tuesday conducted the world’s biggest naval review, off the southern English coast, to commemorate British naval hero Horatio Nelson’s victory at the Battle of Trafalgar 200 years ago.
Posted by rob on June 29, 2005 under Uncategorized | Be the First to Comment
Fireworks light up the Gran Turk in the Solent off the coast of Portsmouth, England, during a re-creation of a typical 1800’s naval battle, during the Trafalgar Day celebrations.
Posted by rob on June 28, 2005 under Uncategorized | Be the First to Comment
Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D
Nat Med. 2005 Jun 26;
The Poxviridae family members vaccinia and variola virus enter mammalian cells, replicate outside the nucleus and produce virions that travel to the cell surface along microtubules, fuse with the plasma membrane and egress from infected cells toward apposing cells on actin-filled membranous protrusions. We show that cell-associated enveloped virions (CEV) use Abl- and Src-family tyrosine kinases for actin motility, and that these kinases act in a redundant fashion, perhaps permitting motility in a greater range of cell types. Additionally, release of CEV from the cell requires Abl- but not Src-family tyrosine kinases, and is blocked by STI-571 (Gleevec), an Abl-family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Finally, we show that STI-571 reduces viral dissemination by five orders of magnitude and promotes survival in infected mice, suggesting possible use for this drug in treating smallpox or complications associated with vaccination. This therapeutic approach may prove generally efficacious in treating microbial infections that rely on host tyrosine kinases, and, because the drug targets host but not viral molecules, this strategy is much less likely to engender resistance compared to conventional antimicrobial therapies.
Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases.
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MELBOURNE, Australia, and MENLO PARK, Calif. and GENEVA, June 27 /PRNewswire-FirstCall/ — ChemGenex Pharmaceuticals Limited (ASX: CXS, Nasdaq: CXSP), based in Melbourne, Australia and Menlo Park, California, U.S.A., and Stragen Pharma S.A., based in Geneva, Switzerland, today announced an international alliance to accelerate the clinical development of ChemGenex’s lead anti-cancer therapeutic, Ceflatonin®.
Ceflatonin® is currently in a Phase 2 Clinical Trial at the M.D. Anderson Cancer Center in Houston, Texas treating chronic myeloid leukemia (CML) patients who are resistant to Gleevec®. In addition to CML, Ceflatonin® has established clinical activity in other hematological malignancies (blood cell cancers) including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
ChemGenex and Stragen will combine their respective strengths to pursue clinical approval of Ceflatonin® in the US, Europe, Australia and other territories. ChemGenex provides expertise in drug development and clinical trial management while Stragen offers GMP manufacturing, distribution, and marketing expertise.
Stragen has a patented manufacturing process for a semi-synthetic highly purified form of homoharringtonine, the active molecule in Ceflatonin® and has patented a suite of derivative molecules of homoharringtonine. ChemGenex will exclusively license the global rights to Stragen’s manufacturing process and novel analogues under the terms of the alliance.
Under the terms of the alliance ChemGenex will be responsible for the global clinical development of Ceflatonin®, as well as registration and marketing in North America and Asia-Pacific. Stragen will be responsible for drug production and global supply, as well as facilitating regulatory approvals within Europe. In addition, ChemGenex will engage Stragen’s established European clinical network to accelerate the development of Ceflatonin®. Once Ceflatonin® is approved in Europe, the alliance partners will market the product under the ChemGenex brand. The eventual profit split of sales in this territory will be shared ChemGenex 49%, Stragen 51%.
“The alliance with Stragen is a great opportunity for both companies to capitalize on our respective strengths and to accelerate the development of Ceflatonin® as a potential new therapy for chronic and acute leukemia,” said Greg Collier, Ph.D., chief executive officer and managing director of ChemGenex Pharmaceuticals. “This alliance expands ChemGenex’s global presence and gives us an outstanding partner with whom to progress regulatory approval and eventual marketing of Ceflatonin® in Europe.”
“We are very pleased to be able to partner with ChemGenex on the development of this promising anticancer drug,” said Jean-Luc Tetard, president of Stragen Pharma. “Stragen’s manufacturing capabilities and established European drug distribution and marketing network, combined with ChemGenex’s strong clinical development and pharmaceutical marketing capabilities make this an ideal partnership for the development and commercialization of Ceflatonin®.”
Benefits of the alliance
— Access to a European investigator network to accelerate clinical
development.
— A strong combined patent portfolio around homoharringtonine and
related analogs to provide broader and longer market exclusivity.
— Leverages each party’s respective strengths in clinical development,
marketing and manufacturing.
— Establishes a commercial infrastructure for ChemGenex in Europe.
About ChemGenex Pharmaceuticals Limited (http://www.chemgenex.com)
ChemGenex Pharmaceuticals is a gene-based pharmaceutical company dedicated to improving the lives of patients by developing therapeutics in the areas of oncology, diabetes, obesity, and depression. ChemGenex currently has two compounds in Phase 2 clinical trials, Ceflatonin® for leukemia and Quinamed® for solid tumors, and has a significant portfolio of anti-cancer, diabetes, obesity and depression programs. The company’s diabetes and obesity program is partnered with Merck KGaA and the depression program is partnered with Vernalis plc. ChemGenex currently trades on the Australian Stock Exchange under the symbol “CXS” and the NASDAQ exchange under the symbol “CXSP”.
Safe Harbor Statement
Certain statements made herein that use the words “estimate,” ‘project,” “intend,” “expect,” “believe,” and similar expressions are intended to identify forward-looking statements within the meaning of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements involve known and unknown risks and uncertainties which could cause the actual results, performance or achievements of the company to be materially different from those which may be expressed or implied by such statements, including, among others, risks or uncertainties associated with the development of the company’s technology, the ability to successfully market products in the clinical pipeline, the ability to advance promising therapeutics through clinical trials, the ability to establish our fully integrated technologies, the ability to enter into additional collaborations and strategic alliances and expand current collaborations and obtain milestone payments, the suitability of internally discovered genes for drug development , the ability of the company to meet its financial requirements, the ability of the company to protect its proprietary technology, potential limitations on the company’s technology, the market for the company’s products, government regulation in Australia and the United States, changes in tax and other laws, changes in competition and the loss of key personnel. These statements are based on our management’s current expectations and are subject to a number of uncertainties that could change the results described in the forward-looking statements. Investors should be aware that there are no assurances that results will not differ from those projected.
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Source: ChemGenex Pharmaceuticals Limited
ChemGenex and Stragen Pharma Create Alliance to Accelerate Clinical Development and Commercialization of Ceflatonin(R)
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Monday, June 27, 2005
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Cancer Drug Slows Poxvirus in Mice
Mice given a relatively new cancer drug can survive an otherwise lethal dose of vaccinia virus, a relative of smallpox virus, report scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The findings, say the investigators, suggest that Gleevec or similar drugs might be useful in preventing adverse side effects of smallpox vaccine. The classic smallpox vaccine is made from live, weakened vaccinia virus and is not recommended for people with compromised immunity, except in emergency situations where they may have been exposed to smallpox virus.
“This study helps illuminate the cellular machinery used by poxviruses to exit infected cells, and also provides new support for the concept of treating viral infections by targeting specific host cell molecules rather than the viruses themselves,” says NIAID Director Anthony S. Fauci, M.D.
The senior author of the paper, published online this week in the journal Nature Medicine, is Daniel Kalman, Ph.D., of Emory University School of Medicine in Atlanta.
Like all viruses, poxviruses co-opt various cellular molecules and processes to enter a cell, replicate and then spread to uninfected cells. Using lab-grown cells, Dr. Kalman and his colleagues identified specific cell proteins vaccinia uses to detach from an infected cell and move toward an uninfected cell. The proteins, members of the Abl-family (pronounced “able”) of tyrosine kinases, are well known to cancer investigators because mutation of one family member, Abl, causes a rare form of cancer known as chronic myelogenous leukemia (CML). Gleevec inhibits Abl-family tyrosine kinases and has proved very useful in treating CML.
To learn whether Gleevec could prevent or lessen vaccinia’s ability to spread in a living organism, the researchers treated mice with either saline solution or with Gleevec at a dose equivalent to that given to humans being treated for CML. Next, they exposed the mice to ordinarily lethal amounts of vaccinia. All of the Gleevec-treated mice survived, while 70 percent of the untreated mice died.
This finding, if confirmed in additional animal model studies, suggests that Gleevec might play a role in addressing a public health emergency in the event of a smallpox outbreak, Dr. Kalman says. Specifically, Gleevec might be useful as a preventive against adverse effects of smallpox vaccine, enabling clinicians to use the vaccine even in people who otherwise could not take it. Given for a short period, Gleevec theoretically could hamper the cell-to-cell spread of virus and allow the body’s immune system to mount a successful defense, he explains. Experiments to test whether Gleevec might work against smallpox virus as well as against vaccinia virus are now being planned, Dr. Kalman says. “The approach of fighting disease by targeting drugs to cellular molecules rather than to disease agents themselves may be applicable to a wide variety of pathogenic microorganisms,” he says.
Routine vaccinations for smallpox ended in this country in the early 1970s, and the World Health Organization declared smallpox eradicated in 1980. Nevertheless, concern remains that smallpox virus could be unleashed through an act of bioterror. For this reason, scientists are working to better understand the mechanisms of smallpox disease and to develop new and improved smallpox treatments and vaccines.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Reference: PM Reeves et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinasas. Nature Medicine DOI: 10.1038/nm1265 (2005).
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A sunflower in a field near Serpa, Alentejo, 220 km east of Lisbon.
Posted by rob on June 27, 2005 under Uncategorized | Be the First to Comment
The hidden big business behind your doctor’s diagnosis
You walk into your doctor’s office for a physical exam and step on the scale. Last year, the doctor said you were overweight. Now he says you are obese — at the same weight.
A nurse takes your blood pressure. You have hypertension — with the same previously healthy reading you’ve had for years.
The doctor scans your wrist bone. You have a condition called “osteopenia” — with the same bone density that was fine last time you were measured.
You mention you are not enjoying sex as much as you used to. Diagnosis: a new kind of sexual dysfunction.
You leave the office with a head full of worry and a fistful of new prescriptions, joining more than 40 percent of Americans who take one or more prescribed drugs daily in the effort to stave off more serious trouble.
You are suddenly sick, simply because the definitions of disease have changed. And behind those changes, a Seattle Times examination has found, are the companies that make all those newly prescribed pills.
The Times found that:
• Pharmaceutical firms have commandeered the process by which diseases are defined. Many decision makers at the World Health Organization, the U.S. National Institutes of Health and some of America’s most prestigious medical societies take money from the drug companies and then promote the industry’s agenda.
• Some diseases have been radically redefined without a strong basis in medical evidence.
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• The drug industry has bolstered its position by marketing directly to the health-conscious consumer, leading younger and healthier people to consider themselves at risk and to start taking medications.
Every time the boundary of a disease is expanded — the hypertension threshold is lowered by 10 blood-pressure points, the guideline for obesity is lowered by 5 pounds — the market for drugs expands by millions of consumers and billions of dollars.
The result? Skyrocketing sales of prescription drugs. Soaring health-care costs. Escalating patient anxiety. Worst of all, millions of people taking drugs that may carry a greater risk than the underlying condition. The treatment, in fact, may make them sick or even kill them.
Dartmouth Medical School researchers estimate that during the 1990s, tens of millions more Americans were classified as having hypertension, high cholesterol, diabetes or obesity simply because the definitions of those diseases were changed.
Today, three of every four Americans technically have at least one of those diseases. But millions of them are not truly sick and may never be, even without medication. The Dartmouth researchers said it was unknown whether those people would benefit from early detection and treatment, while it is “an open question” whether branding them diseased and feeding them drugs may be causing significant physical or psychological harm.
The medical profession’s term for these people is “the worried well.” They are otherwise healthy people who have risk factors, such as high blood pressure or high cholesterol, but may never suffer a heart attack or stroke.
Dr. Alfred Berg, chairman of family medicine at the University of Washington and a past chairman of a federal task force that fights drug-industry influence on disease and treatment guidelines, said the best advice for many people at risk of so-called “lifestyle diseases” is to simply change their lifestyles.
“Diet and exercise and righteous living — but nobody wants to hear that,” Berg said.
Instead, he says, a “commercial prevention” industry has emerged, focused on selling drugs to people who don’t really need them but who can pay for them.
“We have a system that nobody but Big Pharma is happy with,” says Dr. John Kitzhaber of The Foundation for Medical Excellence in Portland, who was Oregon’s governor from 1995 to 2003.
But the drug companies can’t do it alone. They need, and receive, support from much of the world’s medical establishment.
Treatment guidelines established by international and national health organizations instruct physicians on diagnosis and treatment of disease and are meant to be scientifically pristine. But many of those groups lack any process for preventing or disclosing conflicts of interest.
The Times found that for a broad spectrum of diseases, the experts writing the treatment guidelines had drug-company ties ranging from research contracts to consultancies to stock ownership.
Berg’s group, the U.S. Preventive Services Task Force, flatly prohibits any conflicts of interest, either in money or previous research. As a result, it is consistently more conservative in its recommendations than other medicalguideline-writing groups and pushes fewer drugs.
Dr. H. Gilbert Welch, a Dartmouth medical professor and editor of Effective Clinical Practice, a journal of the American College of Physicians, agrees that his profession shares the blame for what he sees as an overdose of preventive medicine.
The problem begins, he said, with the expanding definitions of disease.
“You can’t tell me that three-quarters of my population is sick before I start,” he said. “That just doesn’t pass the laugh test.
“Our business is in a hard place right now,” Welch said. “A lot of docs know it’s not right.”
Duff Wilson reported and co-wrote this story while working for The Seattle Times. He now reports for The New York Times. Send comments to suddenlysick@seattletimes.com or call Susan Kelleher: 206-464-2508.
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Paul Spracklen leaned down and touched his daughter’s hair, thick and blond, and long enough to drape past the middle of her back. “Yeah, I know, honey,” he said gently. “We knew that would happen when you started the chemo.” Caitlin paused. “Well, do you think you could do me a favor and brush it all out?” Spracklen looked at his daughter blankly. “What do you mean?” he asked. “Well, if we brush it, we can save it, and we can send it to the wig company, and some other little girl can have it who might need it.” For a moment, Spracklen just stared at his daughter as they stood in her room in the children’s ward of Balboa Military Hospital in San Diego. Finally, nodding, he said “Yeah, let’s do that, honey.” Spracklen sat down behind his daughter and began pulling the brush through her hair in careful, tender strokes. His eyes rimmed with tears as hair came out in threads and clumps. He felt shattered by this girl of his whose little body was waging a fierce war with the leukemia inside her. This girl who, facing a likely death, still managed to think about some other kid down the road who might need a wig. Tears trailed down his face. Spracklen wept as his daughter’s hair fell in strands through his fingers. — As told by Lt. Paul Spracklen In March 2002, when Caitlin was first diagnosed with leukemia — cancer of the blood — the Spracklens thought of it as a horrible, but isolated, incident. They would soon learn this, tragically, wasn’t the case. In the months following Caitlin’s diagnosis, Spracklen would learn of more than 10 other children who had been diagnosed with leukemia and other rare cancers. Some survived; others did not. What did all those children have in common? They had all lived in military housing areas on Guam. The Spracklens had lived in the Apra Heights military housing complex in Santa Rita from 1998 to 2000 while Spracklen, a lieutenant in the Navy, served on the USS Frank Cable. When his orders changed, the family moved to San Diego, and they were still living there when Caitlin got sick. After Spracklen began to learn about other sick children, he asked the Defense Department’s investigations arm to do a study on the incidence of leukemia among families who had been stationed on Guam. After a prolonged and sometimes arduous effort on Spracklen’s part, the Navy finally released the results of that investigation. In their initial search through the military’s medical databases, the Navy had found some 17 military children whose families had been stationed on Guam and who were later diagnosed with leukemia. However, after looking at the 17 cases more carefully, investigators eliminated all but seven of those children from the study for a variety of reasons, such as their parents were Air Force, not Navy; the diagnosis had been changed; their parents had since retired from the Navy; or a Guam duty station couldn’t be established for some reason. But even with the seven cases retained, the Navy’s Bureau of Medicine and Surgery said the incidence could be defined as a “cancer cluster” because it was higher than the national average. The Navy’s Surgeon General asked the Air Force to do a similar study for Air Force dependents. In October 2003, an Air Force office in Texas produced a memorandum on the results of that investigation. The Air Force calculations suggested “that Air Force children on Guam were three times more likely to develop ALL (Acute Lymphocytic Leukemia) than the national average.” However, there were not enough cases included in the study to be statistically significant, the memo concluded. At the same time the Navy released the results of the investigation, it also published a fact sheet summarizing the results. The fact sheet stated that the leukemia incidence on Guam “was not large enough to indicate that a problem or an unusually elevated leukemia rate exists.” Spracklen doesn’t agree. He believes something really wrong may be going on in the military housing areas on Guam, something that has taken children’s lives. When Lt. Spracklen learned of his daughter’s diagnosis, he was on an aircraft carrier floating in the North Arabian Sea. Spracklen had just gotten off watch when a friend on board called telling him to contact his wife because one of the Spracklen kids was apparently in the emergency room. “Oh, great,” Spracklen recalls thinking. “My boy’s gone and broken his leg again.” But when he reached his wife in the children’s ward of Balboa, he wasn’t met with a groaned story of a roughhousing little boy. He was met instead with a choked silence. His wife could barely talk. Finally, she passed the phone to a doctor. No, no broken bones, he learned. And it wasn’t spunky 7-year-old Michael or his toddler Sabrina, who had just turned 3. It was his eldest, 10-year-old Caitlin. Caitlin of the boundless energy, Caitlin of the tea parties with dolls and daddy, Caitlin of the thick blond hair and quick, wide grin. Caitlin’s red blood cell count was significantly low, and she had virtually no functioning white blood cells or platelets left in her small body. Spracklen knew what that meant: he’d worked as a chemistry and radiological controls assistant on a nuclear-powered aircraft carrier and had been trained in blood chemistries. He knew that a low red blood count and no immune system meant only one thing, and the news sideswiped him, leaving him feeling frazzled, horrified, scared, devastated. “So you suspect it’s cancer or leukemia?” he asked the doctor. The doctor replied that he did. Spracklen waited three torturous days for the ship to dock in Bahrain and took the first flight home. He spent those three days combing through everything he could get his hands on about leukemia. When he wasn’t reading, he prayed, hard. Spracklen had been home for only a few days when he got the first inkling that something bigger may be going on. Caitlin was already tired of the hospital food, so he went downstairs to pick up some McDonalds. As he was walking back into the children’s ward in Balboa, fries in hand, he saw a woman that looked familiar. “I dropped off the food and went back out and said, ‘Do I know you? You look familiar to me,’ and she said ‘Yeah, I’m Cathy Baughman. We were neighbors on Guam.’ That’s when I found out that her 4-year-old son Will had leukemia,” he said. “That struck me as really weird, that we would live on the same street and both of our children had leukemia now.” Will was lucky. He had acute lymphocytic leukemia, or ALL, which is the less deadly of the two most common forms of the disease. About 85 percent of children with ALL survive, according to the National Cancer Institute. Will’s leukemia was already in remission. Caitlin, the Spracklens had just learned, was not so fortunate. She had acute myelogenous leukemia, or AML. Without a bone marrow transplant, only about one in four AML patients survive, the Spracklens learned. When they met their former neighbors in Balboa, the Spracklens were in the midst of an anxious two-week wait for a test that would tell them whether anyone in the family was a genetic match with Caitlin’s bone marrow — which could determine whether she lived or died. A bone-marrow transplant would basically double Caitlin’s chances of survival, but it was a dice-roll whether anyone in the family would be a close enough bone-marrow match to donate. Each of her two siblings had about a 25-percent chance at matching the four out of six proteins necessary for a safe transplant, he said. “That was a very, very long two weeks,” Spracklen said afterward, his brow furrowing at the memory. “A very long two weeks.” After meeting Will’s mom, Spracklen called and e-mailed Naval Hospital Guam to see if the hospital had been treating other children for ALL or AML, but officials there said they hadn’t noticed any recent increase in leukemia cases. The coincidence still seemed strange to Spracklen, but soon it was stashed at the back of his mind because suddenly he had something more pressing to think about: namely, the care for not just one, but both of his daughters. Miraculously, 3-year-old Sabrina was found to be a perfect, six-for-six blood-marrow match for her older sister. News of the third case came in August, right after Sabrina underwent the long needle of a surgeon and her bone marrow was dripping into Caitlin’s blood stream through an intravenous tube. Caitlin’s body hadn’t immediately rejected Sabrina’s bone marrow, which seemed to be a good sign. Spracklen was on the computer in the playroom of the children’s ward one afternoon when he got the e-mail from his old friend Ken Thompson. Thompson’s teenaged son was real sick, the e-mail read. He had been diagnosed late with AML. The prognosis did not look good. The news shook Spracklen deeply. He’d known Thompson from way back, and they had later served together on Guam. He’d known his kid, Richard, too. He was a bright, athletic teenager, his father’s only child. “I immediately thought that there has to be some link with Guam. There was no way that I was the only person who knew the only three leukemia cases on Guam — that just couldn’t be right,” Spracklen said. That same day, he called the Department of Defense Inspector General hot line and asked them to begin an investigation into Guam’s leukemia rates. In the months thereafter, he began doing a bit of his own nosing around. He talked to friends and colleagues who’d also served on Guam and began sifting through the latest research on childhood leukemia. When they’d lived on Guam, the Spracklens and the Baughmans had lived in Old Apra Heights in Santa Rita, toward the south of the island. But the Thompsons, who were on Guam from 1998 to 2000, lived at the north end of the island, in NCTAMS — the U.S. Naval Computer and Telecommunications Area Master Station housing area — also known as Finegayan. In his research, Spracklen had learned of studies going on about a childhood leukemia cluster that had sprung up in Fallon, Nev., near a naval air station. Researchers were looking into the possibility that benzene, a component of jet fuel, could have factored in to the cluster. Both Finegayan and Old Apra could theoretically be in the flight paths of Guam’s airports, Spracklen thought. Could there be a connection?, he wondered. Spracklen also learned that Guam has unusually high rates of radon, a naturally occurring, odorless, colorless gas that emits radiation as it breaks down. Radon is known to cause cancer if it accumulates in homes. It was in the midst of this research that the fourth case surfaced. This one hit him like a sucker punch to the gut: The girl had been just a year or two older than Caitlin. Her family had lived down the street in Old Apra. As it happened, he learned of her illness the day she was buried — dead of complications with ALL. It was then that Spracklen’s doubts ended and his mission began. “Once is a terrible tragedy, twice is a horrible coincidence, three times is enemy action and four times is inexcusable,” he wrote friends and colleagues in a mass e-mail the day he learned of the girl’s death. He sent the e-mail to everyone he knew, explaining the remarkable, tragic coincidence that he had discovered, warning parents to keep an eye out for symptoms and asking for help in spreading the word. The mass e-mail met a forceful response. Within a few weeks, as the e-mail circulated through the ranks of service members and their dependents who had been stationed on Guam, Spracklen learned of four more cases of leukemia and an additional three cases of other rare childhood cancers, including two sarcomas and one brain tumor. All had occurred in the two neighborhoods on Guam. He also received e-mails from concerned families currently stationed on or moving to Guam: Should they be worried for their children? How could they protect their family from such a horrendous misfortune? To these, Spracklen and his wife replied as sensitively and as honestly as they could, dispensing information about what signs to look out for, and also about how little is known about the disease and its causes. “There are lots of kids out there who were on Guam who are just fine,” Spracklen wrote to one woman who was worried about moving to Guam with her husband and children. “My other two kids are a prime example. Right now, it’s just a huge, tragic coincidence.” As Spracklen was learning more and more through his own research, he was also beginning to hit walls as he asked the military to investigate the situation. About two weeks after first filing his inquiries with the Department of Defense Inspector General in August 2002, he called back, asking what the status of the investigation was. The response was that the investigation hadn’t begun and would be handled in the order that it was received. Spracklen recalls feeling the blood rushing to his face. “So you mean to tell me that no matter what the case is, you take it in the order it was received? You’ll give a case where a sailor hit his thumb with a hammer the same priority as a case where kids are popping up with leukemia and it could be because they were stationed on Guam?” he answered angrily. “Oh no, sir. We’ll get right on this,” the DOD official replied, humbled, Spracklen recalled. They may have gotten right on it, but the investigation and its results eventually found their way into a bureaucratic quagmire, Spracklen said. The DOD Inspector General forwarded the inquiry on to the Naval Inspector General, who sent it on to the Navy’s Bureau of Medicine and Surgery — better known to sailors as BuMed. BuMed’s Navy Environmental Health Center conducted the study. The study was completed in March 2003, after which it was sent up to the BuMed chief, who added a few recommendations and forwarded it back to the Navy’s IG in May. “The Naval Inspector General considers this case closed,” the deputy naval inspector general wrote in a letter to the DOD IG that June. The case may have been closed, but it would take Spracklen nearly nine more months to convince them to give it to him. After calling and e-mailing the DOD IG multiple times and finally submitting a formal status request, he received an e-mail in September 2003 stating the case had been closed. In order to get more specific information about it, Spracklen would have to submit a formal written request under the Freedom of Information Act. “All right, I’ll play their game,” Spracklen thought, and he sent the written request. Several weeks later, he received the reply. The IG sent back every document associated with the case, including all the information Spracklen himself had submitted, responses to him and a couple of internal memos. They had sent him every document associated with the report, with the exception of the report itself. After more inquiries and calls, Spracklen still hadn’t received what he was looking for. Finally, at the end of January 2004, nearly a year and a half after first filing his complaint with the Department of Defense Inspector General’s hotline, Spracklen wrote one last letter, this time trying to make an appeal from one parent to another. “I would like to see a final copy of the Navy Surgeon General’s report,” he wrote. “If you have children, I would like for you to take a moment to envision them with a tube implanted into their side. This tube runs under the skin, up their side, across their shoulder and into the main artery that exits the heart. This tube is there to ease the number of needle sticks they will be required to receive for all the chemotherapy, blood transfusions, medications and intravenous solutions they will be given. “Your child has already lost their hair,” he continued. “They are pasty white in complexion, they have no energy and thankfully sleep most of the time when they aren’t awake and in pain from sores they develop on the rear and in their mouth as their (intestinal) tract lining disappears from the chemo. They lose a lot of weight. They run the risk of bleeding to death internally due to low platelets counts. “Since they have no immune system, the doctors give them antibiotics that are so powerful they send your child into seizures if the doctor doesn’t first medicate them,” he wrote. “You get to watch as your child receives over 40 pints of blood over a year’s period and 30 units of platelets.” Spracklen concluded that he felt he had been “very patient with the process.” “Please see what you can do about getting me a copy of the Navy Surgeon General’s report. I’d really like to know how many cases they were able to find. I’m certain there are more than eight leukemias, three sarcomas and one brain tumor,” he wrote. “I just want to know the facts.” A month later, he received the report. The Navy’s investigation confirmed at least a few of Spracklen’s suspicions: There was, it concluded, a leukemia cluster among Navy kids who had lived on Guam. According to the report that Spracklen finally had in his hands, the investigators had begun by searching the military’s medical databases for Navy children who had lived on Guam and were diagnosed with leukemia from 1993 to 2002. In their initial search, the investigators found 17 children who seemed to fit this description. Of those, four had been diagnosed with AML – the more deadly of the two most common childhood leukemias, which Caitlin and Richard had been diagnosed with. Thirteen had been diagnosed with ALL, the more common and typically less lethal childhood leukemia, which 4-year-old Will was being treated for and Caitlin’s playmate had later died of. Investigators explained that they had looked at the rates of the two diseases separately. After getting the initial pool of 17 children with the disease, investigators looked more closely at each case to see if they should be counted in the study. Most of those cases ended up being excluded from the study. Of the 13 cases of ALL, the investigators ultimately retained only five in their study and excluded eight: s Four cases were excluded because they were Air Force dependents, not Navy. s One case was excluded because the child’s sponsor retired before the date of diagnosis. s In one case, the diagnosis was confirmed not to be ALL, and in another case, it “could not be confirmed” whether the child had lived on Guam, the report said. s The eighth case of ALL was excluded, the report said, because the child had been diagnosed before the study period began. As for the four AML cases that had been identified, only two were retained. The other two were excluded because, the report said, “a Guam duty station could not be confirmed.” The investigation did not identify where on the island the children lived. The report used the retained cases to determine whether there was a leukemia “cluster,” using the CDC’s definition as a greater-than-expected number of cancer cases in a group of people, in a geographic area or over a period of time. The Navy used different models to look at the rates and determine whether there was a cluster. One model found that the ALL rate was nearly five times higher than estimated national averages, while another model found a rate about seven times higher than the estimated national averages. But compared to Navy rates — which are about twice national estimated averages — the leukemia rate on Guam seemed “significantly but only slightly higher than expected” in one model, the report said, and not noticeably higher in the others. Ultimately, the cluster was determined not large enough to merit further investigation, wrote BuMed Chief M.L. Cowan in a memo to the Naval Inspector General. “Although the rate met the definition of a cluster, it was not as high as in many other clusters that have occurred in the United States in the past,” Cowan wrote. “Prior studies by the CDC on ALL clusters significantly larger than this one have all failed to make an environmental link to the disease. “Because of the smaller size of this cluster and the transient nature of the Naval population with the resulting low probability of finding a cause, the CDC was not requested to attempt to find an environmental link,” Cowan concluded. At almost precisely the time the Navy finally released the report to the Spracklens, the same office that had conducted the investigation published a “fact sheet” summarizing the investigation’s results. The fact sheet, posted on the Navy’s Guam Web site and made available to anyone who inquired about leukemia on Guam, stated in bold and italicized font that “living in Guam does not appear to have increased the risk of leukemia among Navy children studied.” “The results indicate that Navy children who have lived on Guam have a similar incidence rate of both ALL and AML as other Navy children world-wide,” the pamphlet reads in another highlighted section. The pamphlet states that rather than compare the rates to the National Cancer Institute’s “estimate of the cancer rates for the U.S. population,” a better comparison is to other Navy children. “(The Navy Environmental Health Center) concluded that other Navy children are the best comparison group for this study because the study group is a subset of this much larger, but similar group,” the pamphlet read. Also put on the Web was a Question and Answer about the leukemia study. One question was “Do Navy children have a higher rate of leukemia than children in the general U.S. population?” The answer was direct: “There is no evidence or reason to believe that Navy children have higher rates or risks for leukemia than any other children in the U.S. population,” the answer read. When Spracklen saw this fact sheet on the Navy’s Web site, he was enraged. “I don’t know how they got from ‘there is a cluster’ to ‘there is no increased risk.’ Or from the fact that Navy kids have twice the leukemia incidence of the national average to ‘there’s no evidence of higher rates,’” he said, shaking his head. “What they’re really saying is ‘We don’t believe there’s a problem because we don’t want to alarm you,’” he said. But the Navy scientists who did the study and wrote the fact sheet said that it was “unfortunate” that the rate had been described as a cluster because they don’t believe it truly is. “We apologize if our statements were misleading,” said Capt. Christopher Rennix in a written response to questions about the fact sheet. Rennix was among the epidemiologists from the Navy Environmental Health Center who worked on the investigation. “In retrospect, it is unfortunate that BuMed chose to use the word ‘cluster’ to describe this study. The statement in the fact sheet is accurate because we believe the evidence so far indicates that there was no cluster. The fact sheet was designed to present all the results in this very technical study report in plain language.” Rennix went on to explain that the five cases of ALL that were retained for the study were spread over 10 years, with only two in a one-year period. A more classic cluster has a few cases over one or two years, and then a period where there are several cases, and then it slows down again. This is how it occurred, for example, in Fallon, Nev., he said. When asked about the fact sheet’s statement that “there is no evidence or reason to believe” Navy children have higher rates of leukemia than other children, Rennix replied the national averages used are simply estimates, whereas the Navy rates are “actual.” “The (estimated) rates do not include information on every person in the (United States). They are averages calculated using a portion of the U.S. population,” Rennix wrote. “Navy children are special populations when compared to the rest of the (United States) in that they are highly mobile, very young, and have almost 100 percent access to health care. “The only thing that can be inferred is that the Navy population is different than the general population,” he said. So were the high leukemia rates on Guam caused by random chance or is there really something on Guam making children sick? This is a question that, unfortunately, we may never know the answer to, according to epidemiologists who looked at the study. Part of the problem, said Beverly Kingsley, an epidemiologist for the CDC in Atlanta, Ga., is that no one knows precisely what causes childhood leukemia in the first place. The best guesses now are that it’s caused by a complex interaction between environmental and genetic factors. And it’s entirely possible that there are natural cancer clusters, she said, not unlike the grouping of pool balls on a table. But most experts believe that some things in the environment can increase a person’s likelihood of getting leukemia. For example, some scientific evidence point to radiation, tobacco smoke and benzene as possible factors, Kingsley said. The reality is it’s been very difficult for scientists to link leukemia clusters to specific causes in the environment, she said. “There have probably been thousands of cancer cluster studies and there probably have been one or two that have actually been able to link something environmental going on,” she said. Making things complicated is that there’s usually a lag time of years or even decades between when a person is exposed to a chemical and when they actually get the cancer. By the time the cancer shows up, it’s nearly impossible to “go back in time” and measure what was in the environment when the cluster began, she said. “It’s almost impossible with the science that we have now to assess what was in the environment when the disease was starting or initiated,” Kingsley said. The mobility of military families complicates the situation as well, because they may be exposed to many environments for just a few years at a time, she said. When asked whether the community should worry about the increased rates, Kingsley paused to think for a moment. “I understand that they might be upset or thinking that there’s something wrong, but at the same time, clusters pop up everywhere, either because of statistical chance or because there might be something going on environmentally. Either way, they do pop up everywhere,” she said. “So you could be concerned, you could move somewhere else, and then a year down the road, someone could say we have a cluster in this new town. Is it a real cluster? Not a real cluster? Very hard to discern,” she said. There was a moment, Spracklen recalls, when he realized the enormity and precariousness of what his family was living through. It was right before the surgeries that would take bone marrow out of toddler Sabrina’s little body and put it into Caitlin’s. “I can still remember, I was sitting there holding Sabrina, making sure she understood that she was gong to be a hero and save her big sister, and I remember thinking …,” he paused, hesitating to say aloud the unthinkable. “It’s just that sometimes things happen, you know? Sabrina was going under anesthesia. I was running a risk right then of losing both of my girls. Not just one, but possibly both. What do you do there? What decision do you make?” he asked. He shook his head. “I just put my faith in God and went ahead with it, but still, what do you do?” At the time, the Spracklens were counting life in potential tragedies. Today, nearly three years after that agonizing moment, they’re counting life in miracles. The first miracle occurred long before Caitlin ever got sick: when Sabrina came into the world. Sabrina had been the Spracklens’ surprise baby: She wasn’t supposed to happen. After the Spracklens had Caitlin and then their boy, Michael, Spracklen had had a vasectomy. Needless to say, he and his wife were shocked and unprepared when, four years later, against all probability, they learned they were expecting another baby. And what a miracle it turned out to be: Caitlin’s brother’s bone marrow was not closely enough matched to Caitlin’s to be a viable donor, nor was anyone else in the family. Without Sabrina, Caitlin’s prognosis could have been terribly, tragically different. Another miracle Spracklen counts is that Caitlin’s leukemia was caught early. A few weeks, he said, can mean the difference between life and death, or the difference between “a hard fight and a very, very, very hard fight.” One of the biggest gifts has been that the family has drawn closer to its faith. “We couldn’t have gotten through this without God,” he said. “I’m not even sure we would still be a family without God.” Other miracles occur daily. Sometimes he thanks his lucky stars that he can nag his daughter to do her homework or argue with her over daily chores. “I get to yell at my daughter. Praise be to God,” he said, smiling. Today, all three Spracklen kids are healthy. In a few months, Caitlin will be entering the ninth grade. Other children have not been so lucky — a reality Spracklen is acutely aware of. Spracklen said he still is searching for answers about what happened on Guam: Whether the cluster was a statistical anomaly, as the Navy maintains, or whether there may have been an environmental factor involved. He acknowledges these may be answers he’ll never get. In the meantime, however, he will be taking no chances with his family. When asked if he would ever live in military housing on Guam again, Spracklen sat lost in thought for a moment. “If the Navy gave me orders, I would return,” he finally said. “But there is no way in God’s green earth that I would move my family back to Guam, because I believe there is a risk there. I’m certainly willing to put myself at risk for my country, but I can’t do it to my children again.”
Originally published June 27, 2005 http://www.guampdn.com/apps/pbcs.dll/article?AID=/20050627/NEWS01/50627003/1002
Father waits for answers to son’s death
By Katie Worth Pacific Daily News kworth@guampdn.com
At the start of a recent interview on leukemia rates among military dependents on Guam, Lt. Ken Thompson was asked how many children he has.
His reply was terse:
“I had one.”
That one was Richard Thompson, who died a year and a half ago at the age of 15.
Before getting sick and being diagnosed late with acute myelogenous leukemia, Richard was about as all-American as you can get: He played four sports in high school; he was an avid student, especially in math and science; he was popular among his peers and mature enough for adults to enjoy talking to; he thought he might want to go to the Massachusetts Institute of Technology or some other top-notch science school, if he could get in.
He never got the chance to try.
From 1998 to 2001, Richard lived on Guam as a dependent of his father, a lieutenant in the Navy.
In the summer of 2002, about nine months after the Thompsons moved to Key West, Fla., Richard started getting sick. He’d had his wisdom teeth removed in May and had an infection that seemed to take forever to get better. He went to Washington to spend the summer with his mother, and in July he got a bad case of strep throat that he just couldn’t kick.
Finally, after returning to Key West in August, he went to get his annual physical for school.
The results weren’t good. After a few additional tests, he was diagnosed with leukemia.
“About three hours later a helicopter showed up and he was on his way to Miami Children’s Hospital,” said his father. “Seventeen months later he was dead.”
Richard had AML — the more lethal of the two most commonly diagnosed forms of childhood leukemia. For more than a year, he endured chemotherapy, radiation and a bone-marrow transplant. None of it helped.
“Initially, all the treatments were very promising — it looked like everything was fine, but then everything went south. Finally all that was left was experimental treatments. But my son said, ‘No, I’ve had enough. I’m not being a lab rat.’ And a few months later he passed away,” Thompson said.
Thompson was an old friend of Lt. Paul Spracklen, and he knew that Spracklen, whose own daughter had been diagnosed with leukemia, had asked the Department of Defense to investigate the incidence of leukemia among Navy children who’d lived on Guam. Thompson decided to wait for the investigation to be completed before jumping to any conclusions.
However, he said, he was not satisfied with the answer he received. The investigation stated that there was a higher-than-expected rate of leukemia when compared to national estimated rates, but the rate was not higher than expected when compared to Navy rates.
“My issue was, they find how many kids — more than 10 kids on the Navy base — who get sick over a few years’ period, and that just seems like a pretty high rate to me, and I was not very happy with the answer we got from the Navy’s internal investigation,” he said.
He noted that several of the children found in the Department of Defense investigation had been disqualified from the study because they were Air Force dependents, their parents were no longer in the Navy or the investigator couldn’t confirm that they’d ever lived on Guam.
“When they discount like that, that’s an excuse of convenience,” he said. “If they were ever on Guam, there’s a record of that, and if you look hard enough, you’ll find it. Maybe somebody’s just being lazy because they could have found those records if they had looked.”
When asked if he had any theories about the cause of his son’s fatal illness, Thompson said he had no idea, but the number of sick children seemed too high to simply be a statistical anomaly.
“I have no idea what caused it, but what I do know is there’s a lot of dead kids, and the only thing they have in common was they were living on Navy property in Guam,” he said.
“The odds that all these kids from Guam would just naturally get sick at the same time, that’s a billion-to-one shot. And I really think we owe it to our kids and especially to the families that have served. We owe them a straight answer. I don’t think we’ve gotten that straight answer yet,” he said.
Originally published June 27, 2005
http://www.guampdn.com/apps/pbcs.dll/article?AID=/20050627/NEWS01/506270302/1002
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A nightingale cools off with tap water in Islamabad.
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David Nason
June 27, 2005
THE battling Victorian coastal city of Geelong is best known for the collapse of the Pyramid Building Society and for the mercurial footballer Gary Ablett.
But now a little biotech company with big dreams is set to give this oft-maligned community a morale boost when it this week becomes just the 12th Australian company to list on the Nasdaq.
ChemGenex Pharmaceuticals, a company based at the Geelong campus of Deakin University, is working on the development of new drugs to treat cancer, diabetes, obesity and depression.
It will list on the Nasdaq tomorrow night, a move designed to maximise the investment potential of the company, which was formed last year when Deakin’s AGT Biosciences merged with San Francisco-based ChemGenex Therapeutics.
ChemGenex will join a mixed bunch of Nasdaq-listed Australian companies. The roll call includes big players such as condom and glove maker Ansell, paper and packaging group Amcor and petroleum company Santos, along with ambitious smaller biotech companies such as the nanotechnology-focused Psivida, which earlier this year was the last Aussie to list.
Shares in ChemGenex have been rising steadily since managing director Greg Collier this year announced that the company’s anti-cancer drug, Ceflatonin, was entering phase-two human trials at the Anderson Cancer Centre in Texas.
The shares closed at 68c on Friday but expect them to go higher. The word on the street is that Dr Collier has another big announcement to coincide with the Nasdaq listing, one related to the company’s efforts to build a profile in Europe. If that announcement happens to have anything to do with Bill Gates, look out.
News last week that the Gates-funded Foundation for Innovative New Diagnostics was to collaborate with the Sydney-based biotech Proteome Systems to fast-track the development of a rapid antigen-based diagnostic test for TB sent the Australian company’s share price through the ceiling.
Proteome closed on Friday at 35c, up from 15c a week earlier, giving the struggling biotech sector a desperately needed dose of positive news. After a miserable 2004, biotech stocks have continued in the doldrums, with stocks down an average of more than 20 per cent in 2005.
On of the worst performers has been Prana Biotechnology, a company whose fortunes nose-dived when forced to abandon its clinical trial of an Alzheimer’s drug because of its toxic side effects.
Prana listed on the Nasdaq in 2002, which proves that heading to the US is no guarantee of success.
But for ChemGenex and Ceflatonin the prospects appear bright. Ceflatonin is a drug intended for the estimated 50 per cent of patients who develop a resistance to Gleevec, the most effective drug available to treat the blood cancer chronic myelogenous leukemia in its advanced stages.
Last year Gleevec, which costs US patients about $US2500 ($3248) a month, reportedly earned its owner, Novatis, $US1.6 billion from worldwide sales.
ChemGenex, however, is not putting all its eggs in one gilt-edged basket. It has also discovered and patented a number of genes related to depression, type-2 diabetes and obesity and has products being worked up for trial.
It also has another oncology drug, Quinamed, in stage-two trials for the treatment of solid tumour prostate, ovarian, breast and colon cancers.
Investors generally show most interest in companies that have more than one product in clinical trials.
The Australian: A tiny piece of Geelong on the Nasdaq [June 27, 2005]
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A ballerina watches dancers from the backstage of the Bolshoi theater in Moscow during the 10th International Ballet Competition.
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Moles MP, Landry J, Roche-Lestienne C, Godon A, Schmidt-Tanguy A, Gardembas M, Le Clech C, Verret JL, Zandecki M, Blanchet O
Ann Biol Clin (Paris). 2005 May-Jun ; 63(3): 317-22
Idiopathic hypereosinophilic syndrome is characterised by chronic hypereosinophilia leading to tissue damage, and after exclusion of reactive eosinophilia. Until recently no specific or efficient therapeutic was available. In 2003, a recurrent interstitial deletion 4q12 leading to the fusion of the FIP1L1 and PDGFRA genes was detected in hypereosinophilic syndromes. The resulting protein has constitutive tyrosine kinase activity which explains clinical and cytological remission of hypereosinophilic syndrome after treatment by a specific tyrosine kinase inhibitor, imatinib mesylate or Glivec, usually used in chronic myeloid leukaemia. Here we report a patient with hypereosinophilic syndrome associated to peculiar morphology of neutrophilic series and the 4q12 deletion. He presented clinical and haematological remission since the introduction of imatinib mesylate therapy.
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Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I, Bolton AE, Racine-Poon A
Br J Clin Pharmacol. 2005 Jul ; 60(1): 35-44
Aims This study was designed to investigate the biochemical and physiological covariates or comedications that affect the pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia (CP CML). Methods Pharmacokinetic data were analyzed in 371 patients receiving 400 mg imatinib once daily during a phase III trial of imatinib vs interferon-alfa plus cytarabine for the treatment of newly diagnosed CP CML. Covariates included age, weight, sex, ethnicity, haemoglobin (Hb) concentration, white blood cell (WBC) count, liver function, and creatinine concentration. Blood samples for imatinib analysis were taken on treatment days 1 and 29. Nonlinear mixed effects modelling was used for the population pharmacokinetic analysis. Results Population mean estimates (95% confidence interval) at day 1 for apparent clearance (CL) and apparent volume of distribution (V) of imatinib were 14 (13-15) l h(-1) and 252 (237-267) l, respectively. Modelling suggested that CL decreased by 4 (3-5) l h(-1) from day 1 to day 29, whereas V remained unchanged. Interindividual variability in CL and V was 32% and 31%, respectively. Weight, Hb, and WBC count demonstrated small effects on CL and V. Doubling body weight or Hb or halving the WBC count was associated with a 12%, 86% and 8% increase in CL, respectively, and a 32%, 60% and 5% increase in V, respectively. Comedications showed no clear effects on imatinib CL. Conclusions Population covariates and coadministered drugs minimally affected imatinib pharmacokinetics in newly diagnosed CP CML patients.
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Klein S, McCormick F, Levitzki A
Nat Rev Cancer. 2005 Jun 20;
As the signalling pathways that control cellular proliferation and death are unravelled, a range of targets have emerged as candidates for molecular cancer therapy. For their survival, cancer cells depend on a few highly activated signalling pathways; inhibition of these pathways has a strong apoptotic effect and can lead to tumour regression. But drugs that exploit this weakness, such as imatinib, have not cured patients: withdrawal of the drug leads to disease recurrence, and sustained treatment leads to the emergence of drug-resistant clones. Can cancer be cured, or will it have to be controlled as a chronic disease?
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Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G, de Boeck G, Sparreboom A, Verweij J, Nooter K
Cancer Biol Ther. 2005 Jul 9; 4(7):
Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia’s, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 muM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.
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Deconde R, Kim PS, Levy D, Lee PP
J Theor Biol. 2005 Sep 7; 236(1): 39-59
We model the immune dynamics between T cells and cancer cells in leukemia patients after bone marrow transplants, using a system of six delay differential equations to track the various cell-populations. Our approach incorporates time delays and accounts for the progression of cells through different modes of behavior. We explore possible mechanisms behind a successful cure, whether mediated by a blood-restricted immune response or a cancer-specific graft-versus-leukemia (GVL) effect. Characteristic features of this model include sustained proliferation of T cells after initial stimulation, saturated T cell proliferation rate, and the possible elimination of cancer cells, independent of fixed-point stability. In addition, we use numerical simulations to examine the effects of varying initial cell concentrations on the likelihood of a successful transplant. Among the observed trends, we note that higher initial concentrations of donor-derived, anti-host T cells slightly favor the chance of success, while higher initial concentrations of general host blood cells more significantly favor the chance of success. These observations lead to the hypothesis that anti-host T cells benefit from stimulation by general host blood cells, which induce them to proliferate to sufficient levels to eliminate cancer.
Post-transplantation dynamics of the immune response to chronic myelogenous leukemia.
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Kantarjian HM, Bueso-Ramos CE, Talpaz M, O’brien S, Giles F, Faderl S, Wierda W, Rios MB, Shan J, Cortes J
Cancer. 2005 Jun 21;
BACKGROUND: Myelofibrosis is associated historically with a poor prognosis in patients with chronic myelogenous leukemia (CML). Its significance in the recent era of effective therapy with imatinib mesylate is unknown. METHODS: The current study evaluated the significance of the degree of pretreatment myelofibrosis on response and survival with imatinib therapy in patients with newly diagnosed CML. The study group comprised 198 patients with newly diagnosed Philadelphia chromosome-positive, chronic-phase CML treated with imatinib mesylate therapy. They were analyzed for the prognostic significance of bone marrow reticulin fibrosis. RESULTS: Severe reticulin (Grade 3-4) fibrosis was observed in 75 patients (38%): Grade 3 in 46 (23%) patients and Grade 4 in 29 (15%) patients. There was a trend towards a lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis (76% vs. 89%; P = 0.07), and a significantly worse survival (estimated 3-year survival rate of 87% vs. 97%; P = 0.04). CONCLUSIONS: Although the prognostic significance of severe reticulin fibrosis in patients with newly diagnosed CML receiving imatinib therapy was better, 15% of patients with Grade 4 reticulin fibrosis still had a worse outcome. Cancer 2005. (c) 2005 American Cancer Society.
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Colijn C, Mackey MC
J Theor Biol. 2005 Jun 20;
Periodic chronic myelogenous leukemia (PCML) is an interesting dynamical disease of the hematopoietic system in which oscillating levels of circulating leukocytes, platelets and/or reticulocytes are observed. Typically all of these three differentiated cell types have the same oscillation period, but the relation of the oscillation mean and amplitude to the normal levels is variable. Given the appearance of the abnormal Philadelphia chromosome in all of the nucleated progeny of the hematopoietic stem cells (HSCs), the most parsimonious conclusion is that chronic myelogenous leukemia, and its periodic variant, arise from derangements partially involving the dynamics of the stem cells. Here, we have synthesized several previous mathematical models of HSC dynamics, and models for the regulation of neutrophils, platelets and erythrocytes into a comprehensive model for the regulation of the hematopoietic system. Based on estimates of parameters for a typical normal human, we have systematically explored the changes in some of these parameters necessary to account for the quantitative data on leukocyte, platelet and reticulocyte cycling in 11 patients with PCML. Our results indicate that the critical model parameter changes required to simulate the PCML patient data are an increase in the amplification in the leukocyte line, an increase in the differentiation rate from the stem cell compartment into the leukocyte line, and the rate of apoptosis in the stem cell compartment. Our model system is particularly sensitive to changes in stem cell apoptosis rates, suggesting that changes in the numbers of proliferating stem cells may be important in generating PCML.
A mathematical model of hematopoiesis-I. Periodic chronic myelogenous leukemia.
Posted by rob on June 25, 2005 under Uncategorized | Be the First to Comment
Banker sentenced for embezzling
Faces nearly 2 years in prison; $400,000 taken from Wamu
Saturday, June 25, 2005
By TRACY JOHNSON
SEATTLE POST-INTELLIGENCER REPORTER
A Seattle bank vice president first started embezzling money to pay for a pricey alternative treatment for his leukemia, finding himself desperate to stay on the only drug that showed much promise.
But yesterday, a federal judge in Seattle said ordinary greed helped drive Ken Dawson’s decision to keep stealing money from Washington Mutual, taking nearly $400,000 — an amount that soared far above his medical costs — by the time he was caught.
U.S. District Judge Robert Lasnik sentenced Dawson to nearly two years in prison, saying the man’s self-esteem issues — and desire to drive a fancy BMW, live in a nice Bainbridge Island house and take trips to New York City and Las Vegas — “helped accelerate him down that slippery slope.”
The judge turned down Dawson’s request for home detention, finding the crime serious enough to deserve prison time, though he agreed that the 33-year-old has mental-health problems and doled out about six months less than prosecutors sought.
Dawson was diagnosed in 1996 with acute myeloid leukemia and, after trying more traditional treatments, was accepted into a Duke University program that used an experimental drug called Gleevec.
His attorney, Kenneth Kagan, said it turned out to be a life-saving drug, but it cost roughly $10,000. A grant that paid for it ended suddenly in March 2003, devastating Dawson. That June, he started creating phony invoices and having Washington Mutual pay them.
Kagan said Dawson’s mental problems helped drive him to steal far more money than he needed for treatment. Dawson’s bipolar disorder was misdiagnosed as depression, resulting in Dawson taking the wrong medications — and ridiculously high doses of them — for several years, the attorney said.
“He got started to pay for his (leukemia) medication, and yeah, it got out of control,” he said. “He lost his moral compass, I suppose.”
Dawson, whose leukemia has been in remission for a year, told the judge yesterday that he was ailing physically and emotionally when he began taking money.
“At this time, my decision-making was at its worst,” said Dawson, who now lives with his parents in Virginia. “I ask for forgiveness and a second chance.”
But U.S. Attorney Bruce Miyake disputed the sympathetic picture of a sick, desperate man, noting that Dawson spent only a small fraction of the stolen money on treatment.
He said Dawson gave thousands of dollars to two different strippers, paying for one’s breast-augmentation surgery, and went on shopping sprees at Bloomingdale’s and Tiffany’s, took trips and paid for new landscaping at his house.
“This was a man who stole money to establish an extremely lavish lifestyle,” Miyake said. “He saw how easy it was, and he went full-bore.”
Several of Dawson’s former colleagues told the judge how disappointed, angry and embarrassed they were. They, too, said Dawson took the money simply because he liked to live extravagantly. “I feel as though he’s left a slimy spot on my soul,” said Debora Reinert. “He thought it through, he did it over a long period of time, and he got caught.”
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P-I reporter Tracy Johnson can be reached at 206-448-8169 or tracyjohnson@seattlepi.com
