Chemotalk Newsletter, Vol. 28: August 1, 2010
I don't know where everybody lives, but I know it's not hot today in sunny California. But it will be. Around October, when you east of the Mississippi cool off, we'll be getting slammed ... Here's this month's news:
I wanted to include this story from The New York Times last month, but it came to me late in the month and I didn't think there was room. It deserves room.
FROM M.S. PATIENTS, OUTCRY FOR SURGERY
Vein-Opening Procedure Attracts Adherents, Though Theory Is Unproved
By Denise Grady
For her first appointment with Dr. Daniel Simon, Neelima Raval showed up with a rolling file cabinet full of documents. She had downloaded every word written by or about Dr. Paolo Zamboni, a vascular surgeon from Italy with a most unorthodox theory about MULTIPLE SCLEROSIS.
Dr. Zamboni believes that the disease, which damages the nervous system, may be caused by narrowed veins in the neck and chest that block the drainage of blood from the brain. He has reported in medical journals that opening those veins with the kind of balloons used to treat blocked heart arteries -- an experimental treatment he calls the "liberation procedure" -- can relieve symptoms.
The idea is a radical departure from the conventional belief that multiple sclerosis is caused by a malfunctioning immune system and inflammation.
The new theory has taken off on the Internet, inspiring hope among patients, interest from some researchers and scorn from others. Supporters consider it an outside-the-box idea that could transform the treatment of the disease. Critics call it an outlandish notion that will probably waste time and money, and may harm patients.
These critics warn that multiple sclerosis has unpredictable attacks and remissions that make it devilishly hard to know whether treatments are working -- leaving patients vulnerable to purported "cures" that do not work.
The controversy has exposed the deep frustration of many people with this incurable, disabling disease, who feel that research has let them down. It is a case study in the power of the Internet to inform and unite angry patients -- which may be a double-edged sword. Pressure from activists helped persuade the Multiple Sclerosis Society to pay for studies of Dr. Zamboni's theory, but the Internet buzz has also created an avid market for a therapy that is still unproved.
"It's eye-opening the way this group of patients has grabbed hold of the social-networking technology," said Dr. Simon, an interventional radiologist at JFK Medical Center in Edison, N.J. "They've taken this to a level I've not seen in other patients. Patients used to read an article or two. Now, they're actually seeing procedures on YouTube. Is this the future of medicine?"
Scientifically, the jury is out: Dr. Zamboni's hypothesis is being studied. It is not known whether narrowed veins are more common in people with multiple sclerosis than in others, and even if they are, whether the narrowings are a cause, or an effect, of the disease. There is no solid proof that opening the veins can help. There have been no studies with control groups -- the only way to find out whether a treatment works.
"In my view the evidence is quite scanty and the biological plausibility is low," said Dr. Stephen L. Hauser, the chairman of neurology at the University of California, San Francisco. Many neurologists agree. Dr. Hauser said there was much stronger evidence that they disease arose from genetic variations affecting the immune system.
But Dr. Adnan H. Siddiqui, part of a team at the University of Buffalo that has been studying Dr. Zamboni's theory, said that it made sense and that the data from Italy was encouraging. Still, he emphasized that more study was needed, and that patients should not be treated until the research was done.
Despite the lack of proof, many patients are captivated by the idea that multiple sclerosis might turn out to be a vascular disease. They want to believe it can be fixed with a relatively simple procedure, and they want to be tested and treated. Now.
These patients say they cannot afford to wait for research results because they will wind up in wheelchairs before the studies are done. Their only option so far has been a lifelong course of drugs with limited benefits and harsh side effects. To some, balloon treatment seems no riskier than those drugs.
Dr. Zamboni himself has said that the procedure should not yet be done outside of studies. He said in an interview that he was conducting research only and had turned down thousands of requests from people wanting to go to his clinic at the University of Ferrara.
But other doctors have set up shop. A clinic in India with a toll-free American phone number has an online advertisement for a "liberation package." Patients are posting testimonial videos and trading tips on clinics in Bulgaria, Poland and Jordan.
In the United States, where many hospitals forbid experimental treatments outside of studies, a "back alley" network of doctors willing to perform the procedure has begun to develop, said Dr. Salvatore J. A. Sclafani, chairman of radiology at Downstate Medical Center in Brooklyn. He said he knew of about a dozen. The doctors try to stay under the radar, and patients quietly pass their names to one another.
"It reminds me of abortion in 19968," Dr. Sclafani said.
He said he had treated about 20 patients at Kings County Hospital before the hospital ordered him to stop in early April. He said he had a waiting list of 300 to 400 patients.
Meanwhile, researchers are trying to answer basic questions. On June 29, the team in Buffalo is to begin the first treatment study to include a control group. The controls will be given a sham procedure, and compared with others who get the real thing. Initially, 30 patients -- only those with an early form of the disease -- will be enrolled. Thousands of people applied.
The Multiple Sclerosis Societies in the United States and Canada will spend $2.4 million over the next two years on studies at seven centers. Researchers will study veins in patients with different stages of multiple sclerosis, in healthy people and in those with other neurological diseases. The studies will not test the balloon treatment, ut are meant only to find out if the narrowings really exist, if they are related to the disease and if they are cause and effect.
Some patients complain that the society has been too slow to consider the new idea. A splinter group -- the Reformed Multiple Sclerosis Society -- has formed to increase the availability of the vein treatment.
Joyce Nelson, the president of the Multiple Sclerosis Society in the United States, said, "I wasn't aware of how thin the veneer was and how close to the surface the frustration was."
"'We can't wait' has resounded," Ms. Nelson said. But she added, "There isn't a way to rush the work that needs to be done."
As a procedure has caught on in some places, few serious complications have been reported. But at Stanford University, a woman, 50, treated with stents (wire-mesh tubes used to hold blood vessels open) and blood thinning drugs, died of a brain hemorrhage after returning home, and another patient needed heart surgery after a stent placed in a neck vein came loose and was swept into the heart. The procedures were stopped.
Dr. Michael Dake, who treated the patients, declined several requests for an interview, but said by e-mail that he hoped to discuss "a number of exciting developments" about the procedure "in the near future."
Dr. Philip Pizzo, the deal of Stanford's medical school, said the vein theory "deserves to be explored" -- but only in studies. A study with a control group is being planned.
About 400,000 people in the United States have multiple sclerosis; world-wide, there are 2.1 million. (The disease is more common in temperate zones than in the tropics, and affects more women than men and more Caucasians than members of other groups.) It usually begins in young adults, with fatigue, vision problems, numbness, bladder trouble and difficulty with walking, balance and coordination. The disease eats away a fatty substance, myelin, that coats nerves, and gradually scars the nerves. The damage is thought to occur because the immune system, for unknown reasons, mistakenly attacks myelin.
Most patients, 85%, start out with a form called relapsing-remitting. In about half of those the disease becomes progressive, harder to treat and more disabling. Ms. Raval, who is 38 and has had multiple sclerosis for 13 years, implored Dr. Simon to test her for narrowed veins and, if he found any, to open them.
Dr. Simon regularly uses balloons and stents to open bile ducts and blood vessels. He was impressed with Ms. Raval's determination, her trove of information and her background. She has a degree in Toxicology and works for a drug company. But he was also familiar with Dr. Zamboni's work -- and deeply skeptical of it.
"My initial take was, it doesn't make any sense," Dr. Simon said.
But Ms. Raval had high hopes. She said she believed that the balloon treatment would be "the next best thing to a cure." The usual drugs have not worked for her. Her 5-year-old son is eagerly awaiting the day when she can run with him, but she is finding it harder and harder even to walk.
Theory Born of Experience
Dr. Zamboni, 53, (no relation to the inventor of the ice-rink machine) began studying the medical literature on multiple sclerosis in 1995 when his wife learned she had the disease.
"What I found was like a detective story," he said.
He discovered reports of vein abnormalities and of brain lesions forming around veins. But the research had been abandoned. Vein disorders are his specialty; he has been studying them for 25 years. He began using ultrasound and other imaging techniques to examine veins, and found narrowings in the neck and chest veins in people with the disease but not in healthy ones. He suspected that abnormal blood flow and pressure in the veins -- not just narrowing alone -- might cause minute amounts of bleeding in the brains, leading to an immune reaction and inflammation that damaged myelin and nerves. Iron deposits could also form, and add to the damage. He wondered if opening the narrowed areas might help.
In 2006 he began using balloons to treat patients, including his wife, whose symptoms went away and, he says, have not come back. Other patients who, like his wife, had relapsing-remitting disease, also recovered fully, he said but some did not respond at all. In those with progressive disease, fatigue improved, but not mobility problems, according to a pilot study he published in December in The Journal of Vascular Surgery. And in half the treated patients, the neck veins closed up again. The study did not have a control group, and the patients were also taking drugs to treat multiple sclerosis. More rigorous trials will start in Italy this summer, Dr. Zamboni said.
Another doctor, Marian Simka, who has been performing the procedure in Pszcyna, Poland, has reported that it has made symptoms worse in some patients.
Researchers in Buffalo have confirmed (but not yet published) that narrowed veins and abnormal blood flow are more common in people with multiple sclerosis. But, while Dr. Zamboni found them in all patients and no healthy people, the Buffalo team found them in about 60% of patients and 15% of healthy controls.
Granting a Patient's Wish
Dr. Simon sensed that Ms. Raval would have no peace unless she could learn whether she had narrowed veins, and he wanted to help her.
So he offered to perform a test to find out, a venogram. It involves passing a tube into a vein in the groin and up to the neck and chest, and then injecting dye to take X-rays of the veins. He felt sure there would be no blockages.
"And then she would be able to stop obsessing over this and move on with her life and get some kind of conventional treatment," he said.
But he was stunned to find narrowings, right where Dr. Zamboni's theory predicted: in the jugular vein in the neck and the azygous, a vein in the right side of the chest.
Mrs. Raval was elated. She felt certain that opening up those veins would solve her problems. Dr. Simon agreed to try.
Although it was, technically an experimental procedure, Dr. Simon said he did not have to ask his hospital for permission to perform it. The details were similar to other procedures that interventional radiologists do every day. It is not uncommon for them to take a device approved for one purpose and use it for another, like putting a bile-duct stent into a blood vessel -- a practice called "off-label" use, which the Food and Drug Administration allows. Interventional radiology, Dr. Simon said, Is an "off-label specialty" that depends on innovation and adaptability.
On March 24, as Ms. Raval lay on a padded table in a treatment room, Dr. Simon passed balloons to the pinched spots in her right jugular and azygous, and dilated them.
The procedure took less than an hour. In the recovery room, Ms. Raval said she felt better already.
Over the next days and weeks, she noticed remarkable improvements. Her fatigue went away. She walked and climbed stairs more easily, and the color in her face brightened. Her husband and co-workers saw the changes, too, she said.
Was it real, or just one giant, communal placebo effect? Ms. Raval posted exuberant Facebook messages naming her "most amazing doctor." Other patients began calling Dr. Simon.
Within a month, Ms. Raval again had trouble walking. She felt sure her veins had closed again. Another venogram showed they had. Dr. Simon rep=opened them.
Ms. Raval felt better -- and then deteriorated again. On June 18, another venogram, her fourth invasive procedure in three months, suggested that the narrowings had recurred. She struggled over what to do. She could not keep having balloon procedures again and again. Dr. Simon consulted Dr. Dake, his former mentor, who recommended stents.
Initially, Ms. Raval and Dr. Simon had thought stents too risky. Unlike balloons, which are inserted briefly and removed, stents are permanent. They can migrate to somewhere they do not belong, like the heart, as occurred in Dr. Dake's patient. Or tissue growth can clog them.
But Dr. Simon and Ms. Raval could see no other option. On June 23, he implanted a stent in her two jugular veins.
"I really have a good feeling on this one," Ms. Raval said a few hours after the procedure. "I think this is the resolution, long0-term. Let's wait and see."
In the meantime, Dr. Simon had conducted venograms on about 20 other patients with multiple sclerosis. He found narrowed veins in all but one. He said he was going to ask the hospital's ethics panel for permission to perform balloon procedures in those patients. But the hospital would have to figure out how to get paid: insurance might cover venograms, but not an experimental treatment. The total charge for the procedure, including both hospital and doctor fees, would be about $10,000, Dr. Simon said.
He and his partner, Dr. Noam Eshkar, said they knew many researchers thought patients should not be given unproven treatments outside of clinical trials. They said they did not disagree. But they also sympathized with patients who had progressive diseases and who felt they did not have the time to wait. "In the real world," Dr. Eshkar said, "things happen at the edge of scientific proof."
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WHEN CANCER PATIENTS OPT FOR SURGERY
Most LUNG CANCER patients who undergo surgery are still alive three years later, compared with just 10% of those who do not. Yet at least one-third of patients choose not to have the operation. Why?
That was the question Dr. Samuel Cykert sought to answer when he and fellow researchers asked 386 new lung cancer patients who were eligible for the operation, called resection, to fill out detailed questionnaires about their backgrounds and access to health care.
The results varied by race. Sixty-six percent of the white patients eventually had the operation; the percentage for blacks was 55, said Dr. Cykert, an internist at Moses Cone Hospital in Greensboro, North Carolina, and the author of a paper published in The Journal of the American Medical Association.
Patients who reported feeling that they did not communicate well with their doctors were less likely to have the operation, as were those who thought they would not necessarily be better off a year later if they had surgery. Back patients were also less likely to opt for surgery if they had other chronic diseases besides cancer.
Having a regular doctor also influenced patients to have surgery. "If you go back to your primary care doctor and he or she says, 'When's your surgery?' and you say 'I'm not sure I'm going to have it,' your doctor will try to get you back in the system," Dr. Cykert said. By contrast, he continued, if a patient does not have a regular doctor, "you disappear into space and nobody tells you to reconsider."
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And more about lung-related news, this having to do with transplantation ...
LONGER ANTIVIRAL THERAPY REDUCES LUNG TRANSPLANT COMPLICATIONS
Extended antiviral treatment after a LUNG TRANSPLANT may help prevent dangerous complications and organ rejection, a new study from Duke University Medical Center shows.
A common cause of infection in lung transplant recipients is cytomegalovirus (CMV), which often causes mild effects but can be life-threatening for transplant patients. Standard preventive therapy involves taking the drug valganciclovir (Valcyte) for up to three months. But even with this treatment, most lung transplant patients develop CMV infections within a year.
The Duke study included 136 patients who completed three months of oral valganciclovir and then received either an additional nine months of placebo (66 patients) or an additional nine months of oral valganciclovir (70 patients). Since it was a double-blind, placebo-controlled randomized study, researchers compared two groups of randomly selected patients at 11 different centers (one group of which received the additional medication and a control group that received the placebo, with neither the researchers nor the participants knowing who was in the control group).
Researchers found that CMV infection occurred in 10% of the extended treatment group, compared to 64% of the placebo group. Pneumonia caused by CMV virus occurred in 4% of the extended-treatment group and in 32% of the placebo group.
"We found that 12 months of oral valganciclovir was extremely effective and led to a dramatic reduction in the rate of CMV infection and disease," Dr. Scott Palmer, scientific director of the Lung Transplant Program at Duke University Medical Center, said in a university news release.
Potential side effects of valganciclovir include nausea, diarrhea, anemia and other blood disorders, retinal detachment, headache, fever, vomiting, mental changes and other problems. However, the study "showed that there was no increased or added toxicity with the extended course of treatment," Palmer said. "In addition," he added, "the study examined viral resistance mutations and demonstrated that extended therapy did not lead to increased drug resistance, a potential concern with longer courses of treatment."
The study, published in the Annals of Internal Medicine, was funded by Roche Pharmaceuticals, which makes Valcyte.
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ORGAN-REJECTION DRUG LINKED TO HIGHER CANCER RISK AFTER LIVER TRANSPLANT
Cyclosporine, a drug commonly used to prevent organ rejection following a TRANSPLANT, has been linked to a significantly increased risk of developing cancer after liver transplant, new Dutch research reveals.
The study was done in part to examine what role drugs that suppress the immune system might play in the development of cancer in liver transplant patients, whose long-term survival rates have improved little over the past three decades. Cancer is one of the leading causes of late death, and appears to be directly related to the intensity and cumulative doses of immunosuppressive drugs, according to researchers.
The Dutch study compared cyclosporine and tacrolimus -- the cornerstone of immunosuppressive drug therapy -- in the occurrence of de novo (new) malignancies after transplantation. To do so, researchers analyzed the records of 385 liver transplant patients who had the procedure between 1986 and 2007, and tracked all the patients through 2008 for signs of de novo cancer (defined as the onset of cancer other than a recurrence of primary liver cancer).
Of the study participants, 13% were found to have developed at least one de novo cancer.
Lead author Dr. Harold Metselaar and his colleagues found that compared to TAC therapy, cyclosporine appeared to be the most important risk factor for new cancer following a liver transplant. The higher cancer risk was not found in all patients treated with cyclosporine, however; it was specific to patients who had undergone a transplant more recently (2005 to 2007) and to those under the age of 50.
In addition, compared to tacrolimus, cyclosporine was more likely to spark aggressive types of cancer, those with a one-year survival rate of less than 30%. Metselaar and his team theorized that the increased risk among patients transplanted since 2005 may have something to do with a change in the way cyclosporine dose monitoring was structured from that year onward.
"Strikingly, [cyclosporine-treated] patients transplanted from 2005 on showed a 9.9-fold higher de novo cancer risk in the early phase after liver transplant compared to patients treated with tacrolimus," he noted. In addition, cyclosporine was associated with cancer types that had a worse prognosis, Metselaar said.
The study, conducted by researchers from the Erasmus MC University Medical Center in The Netherlands, appears in an issue of Liver Transplantation.
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...And on the other side of the liver transplant story:
EXPERIMENTAL LIVER TRANSPLANT APPROACH SHOWS EARLY PROMISE
A new approach to liver transplantation is making headway in preliminary work with rats, researchers say. Their work at the Center for Engineering in Medicine at Massachusetts General Hospital (MGH-CEM) could ultimately point the way toward engineering fresh, functioning and transplantable liver organs out of discarded liver material, the researchers suggest.
The research, reported in Nature Medicine, is just at the "proof-of-concept" stage, but the team believes it has successfully fashioned a laboratory method to take stripped down structural liver tissue and essentially "reseed" it with newly introduced liver cells. The seed cells are then coaxed to adhere to the host scaffolding, so that they grow and eventually re-establish the organ's complex vascular network. Although the highly complex technique is still far from the point at which it might be applicable to humans, the prospect is hopeful news for the liver transplant community. Because of a drastic shortage of donor organs, about 4,000 Americans are deprived of potentially life-saving liver transplants each year.
"There is great potential for constructing full-fledged liver lobes containing animal or human cells," said study co-author Dr. Martin Yarmush, director of MGH-CEM. "But several thorny issues must first be tackled. Given enough careful work, this approach could ultimately revolutionize tissue engineering and provide real working grafts for the liver and other complex tissues."
The authors pointed out that building liver tissue is particularly challenging, given that each of the organ's cells are essentially metabolic factories that must be in constant contact with the intricate vascular system. The team sought to build on prior work that targeted the rebuilding of rat heart tissue, which is much less delicate in structure than liver tissue.
Efforts to remove living cells from rat livers until the organs were stripped to their structural base were effective, followed by more success when the team synthetically reintroduced the cells to their correct functional locations in order to reconstitute blood vessel networks. Subsequent attempts to reintroduce the prime motors of liver function cells -- called hepatocytes -- also worked.
Grafts of such rebuilt liver tissue were then reattached to organ tissue in live rats, although so far the team has only been able to demonstrate normal tissue function for several hours following such transplantation.
Senior author Korkut Uygun nonetheless described the work to date as "a great start." It's important to note that, while the new findings could prove significant, research with animals often fails to yield benefits for humans.
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BLOOD TEST MAY PREDICT COLON CANCER SPREAD
Researchers Identify Proteins That May Be Used as Biomarkers for Aggressive Colon Cancer
A blood test may soon be able to predict which COLON CANCERS are likely to spread to other parts of the body, according to a new study. Researchers found two proteins in the blood that may serve as potential biomarkers of colon cancers that are more aggressive and likely to spread.
Colon cancer is a leading cause of cancer death in the U.S. with more than 50,000 deaths reported each year. Surgery is the main treatment for the disease, but almost half of those treated for colon cancer experience a recurrence of the disease within five years due to cancer cells spreading to other parts of the body. Researchers say determining which colon cancers will spread is difficult because there are no reliable chemical markers in the body for predicting its spread, known in medical terms as metastasis.
In the study, published in the Journal of Proteome Research, Chinese researchers compared proteins produced by the original colon cancer tumor cells to those of metastasized cells from a single person with colon cancer. The results highlighted two proteins that occurred at much higher levels in the metastatic cells than in the original colon cancer cells. Although further research is needed to confirm these findings, researchers say the proteins may bring them a step closer to understanding the disease.
"The identified candidate proteins," write researchers Hua Xue of Zhejiang University in Hangzhou, China, and colleagues, "will facilitate our understanding toward the molecular mechanism of colorectal cancer metastasis as well as providing useful biomarkers for cancer prevention, detection and intervention in the future."
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CANCER CAREGIVERS SHARE PATIENT STRESSES
Emotional Highs and Lows Similar for Cancer Patients, Caregivers Ed Grace's journey as a caregiver began in December of 2004 when his wife, Diana, a nonsmoker, was diagnosed with stage IV lung cancer.
Over the next 2 1/2 years, the semi-retired aerospace engineer experienced many of the same emotional highs and lows as his wife as she underwent endless rounds of chemotherapy. Grace, who had worked on the Apollo moon program, says he initially approached his wife's illness as a problem to be solved, just as he would tackle an engineering problem. He quickly learned that her cancer had its own agenda. In a diary he later published online, Grace writes about trying to stay upbeat while fighting anxiety, depression, and stress during the toughest days of his wife's illness.
"We were told Diana would live for just three or four months, but we fought it hard and she lived for almost three years," he said. "There were many good times, but it was also very stressful for both of us."
Grace's story is reflected in new research finding that family caregivers often experience the same feelings of well-being, distress, and depression as patients with a terminal cancer.
In earlier work, palliative care researcher Scott A. Murray and colleagues of Scotland's University of Edinburgh identified four critical times that are particularly stressful for patients -- diagnosis, following initial treatment, at cancer recurrence, and during the terminal stage of the illness. The researchers found these times to also be the emotional low points for caregivers in their new study.
Murray and colleagues conducted 42 interviews with lung cancer patients and 46 interviews with their family caregivers. The interviews took place every three months for up to a year or until the patient died. He said that the caregivers reported feeling overwhelmed and depressed more often during these key times, as if they were riding an emotional roller coaster.
"Caregiver support initiatives that target these key periods may prove to be most effective," he says.
The American Cancer Society's (ACS) ongoing 'National Quality of Life Survey' periodically asks cancer patients and their caregivers about their experiences in an effort to identify psychological stresses and unmet needs. ACS research analysis Rachel Spillers Canady says it is clear from the responses that interventions designed to ease the burden on caregivers are needed across the trajectory of illness.
She says that caregivers are particularly vulnerable to stress early in the illness as they are assuming the new role. And after initial treatment ends, patients and caregivers often report depression.
"That is when the waiting game begins," she says. "The patient and caregiver have been through the treatment and there is nothing else to do."
Women with children at home caring for a sick parent seem to be particularly at risk for caregiver-related stress and depression. Somewhat surprisingly, women in this situation who also worked outside the home tended to report less stress.
"It is almost like their job is a stress buffer or an escape," she says. Caregiver advocate Betty Garrett says almost two out of three caregivers will experience some degree of depression and isolation following a loved one's cancer diagnosis. When her husband Gene was diagnosed with esophageal cancer in April of 2003, she did not ask for much help as the couple negotiated chemotherapy, radiation, and later surgery.
It was only after her husband's cancer returned in the spring of 2004 that she knew she couldn't do it all alone. "He had gotten a clean bill of health, but then we found out the cancer had returned with a vengeance," she says. "I felt like I had been kicked in the gut. I knew I didn't have the energy and emotional stamina to keep doing it all by myself."
The Irving, Texas businesswoman looked for a caregiver support group. When she found there wasn't one at Baylor University Medical Center, where her husband was being treated, she worked with the staff to develop one. She also wrote the book From Hiccups to Hospice: A Survival Guide for the Cancer Caregivers to help others experiencing what she went through.
"There are many things I wish I had known at the beginning of this process," she says. "It is a roller coaster ride and you might as well go ahead and accept it. And you need to ask for help from family and friends."
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The following first appeared in March, 2010, but is important enough to include, even at this late date:
VACCINE FOR ASBESTOS-RELATED CANCER LOOKS SAFE
An investigational vaccine for the asbestos-related CANCER MESOTHELIOMA is safe, according to a new study. Researchers in the Netherlands tested the vaccine -- which infuses a patient's own dendritic cells with antigen from the patient's tumor -- on 10 patients and found that it induced an immune T-cell response against mesothelioma tumors.
This is the first time DC-based immunotherapy has been tested in patients with mesothelioma, which typically occurs in the lungs but can arise at other body sites. The study was published in the American Journal of Respiratory and Critical Care Medicine.
Asbestos has been banned in developed countries for decades, but the incidence of mesothelioma is expected to continue to increase until 2020. Median survival after mesothelioma diagnosis is about 12 months. The standard chemotherapy treatment improves survival by about three months.
"The possibility to harness the potency and specificity of the immune system underlies the growing interest in cancer immunotherapy," said study author Dr. Joachim Aerts, a pulmonary physician at Erasmus Medical Center. "One such approach uses the patient's own dendritic cells to present tumor-associated antigens and thereby generate tumor-specific immunity."
Dendritic cells are a form of immune system cell. "The major problem in mesothelioma is that the immunosuppressive environment caused by the tumor will negatively influence our therapy so we are now working on a method to lower this immunosuppressive environment," Aerts said. "We hope that by further development of our method it will be possible to increase survival in patients with mesothelioma and eventually vaccinate persons who have been in contact with asbestos to prevent them from getting asbestos related diseases."
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I'm including the following story as a matter of fairness. The study was legitimate. Many doctors are now using the test, and patients are making decisions based upon its results. BUT ... Personally, I wouldn't base my survival on a genetic test that may, or may not be accurate in my particular case:
SKIP THE CHEMO? GENE TESTS HELP BREAST CANCER PATIENTS MAKE THE DECISION
Ask any woman with breast cancer if she'll do all that it takes to prevent a recurrence, and chances are she'll say, "Of course!" Yet she probably wouldn't choose to have chemotherapy ‹ and the hair loss, nausea, fatigue, and potentially serious medical complications that come with it ‹ if told that it probably wouldn't do much to lower an already low risk of relapse.
Turns out, a genetic test called Oncotype DX that predicts a woman's chances of recurrence is, indeed, affecting doctors' and patients' decisions when it comes to chemotherapy, according to a study published in the Journal of Clinical Oncology. About one third of the time, oncologists in the study changed their treatment recommendations after seeing the test result and about one quarter of the patients chose not to have unnecessary chemotherapy.
The test, which looks at 21 genes involved in determining the risk of recurrence, is most useful for those with stage 1 or 2 tumors that are small, respond to estrogen, and haven't spread to the lymph nodes; those with these tumors who take an antiestrogen drug like tamoxifen (which is separate from chemotherapy) typically have a 15 percent chance of recurrence after 10 years. But some have a risk lower than that, while others have a risk that's greater. The Oncotype test ‹ now routinely covered by Medicare and most insurance companies ‹ analyzes various gene mutations and assigns a score that indicates low risk, medium risk, or high risk.
For example, a woman with a score of 14 has a 9 percent risk of recurrence in 10 years and is classified as low risk, explains study author Shelly Lo, an assistant professor of medicine at Loyola University Medical Center in Maywood, Ill. Oncologists usually agree that this woman wouldn't benefit much from chemotherapy and can skip the infusions, she adds. On the other hand, a high-risk score above 31, which translates into a recurrence risk higher than 15 percent in the next 10 years, would indicate a good candidate for chemo. "For women at medium risk," Lo says, "it's not clear whether the risks of chemotherapy outweigh its benefits." Six women out of the study's 89 participants fell into this category, with just one choosing to have chemotherapy.
Interestingly, nearly 1 in 4 oncologists in the study didn't routinely order the Oncotype test, so women with early-stage breast cancer should ask for it themselves before opting for or against chemotherapy. Those with estrogen-receptor-negative tumors, however, need chemotherapy regardless of the test result, says Lo, because they don't benefit from other adjuvant therapies like tamoxifen.
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$1.85 MILLION GRANT EXPLORES NEW TREATMENT FOR RHEUMATOID ARTHRITIS Affecting more than 1.3 million people in the United States alone, RHEUMATOID ARTHRITIS (RA) is a debilitating disease that causes pain, swelling, and stiffness in the joints. Dr. Laura Mandik-Nayak, Assistant Professor at the Lankenau Institute for Medical Research (LIMR), received a five-year, $1,856,250 National Institutes of Health (NIH) grant for a research project entitled: IDO in inflammatory pathogenesis and treatment of rheumatoid arthritis.
The exact cause of RA is unknown. Although drugs to treat RA exist, there is a need to prevent and find new ways to treat this disease. In this research project, Dr. Mandik-Nayak is examining the role of an immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO), which has been implicated in the inflammatory process associated with tumor formation.
Because IDO is thought to be immunosuppressive, it has been generally assumed that inhibiting IDO would make classic autoimmune disorders such as RA worse. However, research data has suggested the opposite, that IDO activity may actually be associated with the development of disease symptoms and inhibiting IDO alleviated arthritis symptoms in an animal model of RA. This project is exploring the complex role of IDO in inflammation with the long-term goal of defining the mechanism by which IDO modulates the immune response and providing new insights into strategies that can be used to manipulate this pathway to reduce or prevent RA. If successful, this could lead to a new approach for the prevention and treatment of RA and other autoantibody mediated diseases.
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SMALL ADVANCES AGAINST PANCREATIC CANCER
Rarely it said that someone is lucky to have had cancer. But Justice Ruth Bader Ginsburg of the Supreme Court might be one such person.
Justice Ginsburg was treated successfully for COLON CANCER in 1999 and is examined each year at the National Institutes of Health, where in January 2009 a routine CT scan revealed a very small cancer in the center of her pancreas.
While the life expectancy for most people found to have PANCREATIC CANCER is usually a year or less, Justice Ginsburg has apparently been well after she recovered from surgery to remove the tumor, about the smallest that can be detected by a CT scan -- one centimeter, or less than half an inch, wide.
A Challenging Disease
Pancreatic cancer has proved to be one of the most challenging malignant diseases, the 11th-most-common cause of cancer but the fourth-leading cause of cancer deaths. It affects a life-sustaining organ that sits atop the stomach in the center of the abdomen, where cancer can develop and spread before it produces recognizable symptoms.
The disease is detected and treated at a potentially curable stage in fewer than 20% of patients. For that reason, its overall five-year survival rate is less than 5%.
Pancreatic cancer will be diagnosed in about 42,000 people this year in the United States; some 35,000 people will die of it. It is primarily a disease of older people, with 90% of cases occurring in those over 55 and 80% in those over 65. The disease became increasingly common in the last half century as cigarette smoking rose in popularity. Toxic chemicals in cigarette smoke and smokeless tobacco are thought to cause a gradual accumulation of gene mutations that allow cancer cells to form and spread rapidly; users have two to three times the risk of developing pancreatic cancer. Only now has a slight decline in incidence begun, thanks to the recent drop in smoking rates.
Other risk factors include obesity. Type 2 diabetes and lack of physical exercise, as well as occupational exposure to certain pesticides, dyes and chemicals used in metal refining. Less well-defined risks include chronic pancreatitis, cirrhosis of the liver, gallbladder removal, heavy alcohol consumption, a diet high in fat and cholesterol and, possibly, infection with the hepatitis B virus.
Men and women are equally at risk, although there are somewhat more cases among men, probably because more men smoked. The disease is also more common among African-Americans than whites, partly because black men have higher rates of smoking and diabetes, and black women higher rates of obesity.
A Genetic Component
Five to 10% of pancreatic cancer patients have a family history of the disease and are presumed to carry mutations that impair their body's ability to repair damage to DNA. Several such mutations have been identified and linked to an increased risk of developing pancreatic cancer. In families where four or more members have had the disease, the risk to others in the family can be as high as 57 times that of people with no such family history, Dr. Manuel Hidalgo of Johns Hopkins University School of Medicine reported in the New England Journal of Medicine.
In a rare heredity example, researchers led by Dr. Teresa A. Brentnall of the University of Washington School of Medicine described a family in which nine blood relatives had died of pancreatic cancer, some at young ages. Through detailed molecular detective work, they identified a mutation in a gene called Palladin in all those with cancer or precancer of the pancreas that was lacking in other family members. A still-healthy relative with this mutation chose to have his pancreas removed when it was found to harbor precancerous changes, and he has remained cancer-free for more than 14 years.
In an interview, Dr. Brentnall said that unraveling how the Palladin mutation works helped explain why this cancer is usually so deadly. "Pancreatic cancer cells are surrounded by a dense layer of fibroblasts," she said, adding that in nonfamilial pancreatic cancer, the Palladin protein "makes the fibroblasts grow little feet filled with poisonous enzymes that create holes through which the cancer cells can escape and invade blood vessels very early in the disease, before the tumor is of significant size."
Thus, the cancer is typically metastatic and incurable by the time it is diagnosed.
Adding to the problem of early diagnosis is the lack of a reliable screening test and the vagueness of early symptoms if any. Without a family history that might prompt a doctor to suspect pancreatic cancer, patients are often first checked for problems like chronic reflux, gallbladder disease and bowel disorders.
For those with a family history of pancreatic cancer, Dr. Brentnall and other experts at leading medical centers now offer screening tests, including an endoscopic ultrasound exam, to look for abnormalities in the pancreas that may herald precancerous changes. But such exams are not cost-effective screening tools for the general population.
As with patients with the Palladin mutation, those on the verge of developing cancer are offered surgery to remove the pancreas, which results in diabetes and a lifetime dependence on daily insulin injections.
Dr. Eileen M. O'Reilly, a pancreatic cancer expert at Memorial Sloan-Kettering Cancer Center in New York, says there are six or seven known genetic factors involved in pancreatic cancer, including the BRCA1 and BRCA2 mutations more commonly associated with an increased risk of cancers of the breast, ovary, colon and prostate. Screening might also be considered in families with such traits, she said, as well as in the much larger number of families, like the family of former President Jimmy Carter, in which the genetic link is now known. Mr. Carter's father, mother, two sisters and brother were afflicted.
A Hint of Progress
Dr. James L. Abbruzzese of the M. D. Anderson Cancer Center in Houston said some progress had been made in treating the disease. Radical surgery, called the Whipple operation, remains the mainstay of therapy, but only a small minority of patients -- whose cancers have not yet invaded surrounding blood vessels -- have traditionally been eligible for surgery.
Now, he explained, 10% to 20% more patients can undergo surgery after receiving treatment with radiation and chemotherapy to reduce the extent of disease, enabling the surgeon to remove the cancer and be sure the tissue around it is cancer-free. However, Dr. Abbruzzese said, "many still have lymph node involvement" that leads to eventual spread of the disease. "We still need to identify better systemic therapies" to attack these escaping cancer cells.
"The median survival for surgical patients is two to three years, with maybe 10% to 15% who live longer," he said. "It's not a home run yet."
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And finally ...
CANCER SURVIVAL DEMANDS STEADY PROGRESS
By Jane E. Brody
I continue to find reasons to be hopeful that one day, though probably not within my lifetime, medical researchers will overcome the challenges that thwart efforts to cure or at least contain most CANCERS, especially the more common ones.
My guarded optimism stems from the progress made in devising treatments for several less well-known malignancies. For many patients with cancers like CHRONIC LYMPHOMA, CHRONIC MYELOCYTIC LEUKEMIA and now MULTIPLE MYELOMA, longevity lies in the ability of science to remain one step ahead of the malignancy by unraveling its genetic and molecular underpinnings and producing treatments tailored to counter them.
One Patient's Struggle
Janet Battaile, 63, now in her 10th year with multiple myeloma, said her retirement-age oncologist at the Mayo Clinic in Rochester, Minn, Dr. Philip R. Greipp, told her, "I can't bring myself to retire because it's too exciting."
Ms. Battaile, a former reporter and editor for The New York Times, is a living testimonial for Dr. Greipp's enthusiasm. At the time of the diagnosis, she said in an interview, "the average live expectancy for people with my disease was two or three years." Though living in Maryland, she was advised to consult the experts at Mayo, who have long been at the forefront of refining the diagnostic features of myelomas and testing therapies based on the particular characteristics of patients and their cancers.
In December (2009), the clinic's 22-member team of myeloma experts issued new treatment guidelines for multiple myeloma, the second most common blood-based malignancy (after lymphoma). It affects about 20,000 new patients each year.
In its updated review of management strategies, published in The Mayo Clinic Proceedings, the team noted that "during the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life."
A major advance, the team stated, has been unraveling the genetic characteristics that underlie the disease and how these factors influence patient outcome. Along with other previously known factors that affect the success of treatment, the newly identified genetic abnormalities are making it possible to predict how a patient will respond to treatment and to tailor therapy "in an individualized manner."
Ms. Battaile, for example did not have on genetic characteristic -- a missing piece of Chromosome 13 in her cancer cells - that is associated with more aggressive disease and poorer chances of survival. She was treated at first with thalidomide, an orally administered immune stimulant that also blocks blood flow to tumor cells. Better known for causing birth defects in the children of women who took it for morning sickness, it has found a second life as a cancer drug. It kept her disease at bay for three years.
After a relapse, Ms. Battaile underwent a stem cell transplant using her own stored cells. A second relapse a year later was treated with bortezomib (Velcade), a drug that inhibits division of plasma cells, and dexamethasone, a steroid, which worked for two more years. Then came treatment with a successor to thalidomide, lenalidomide (Revlimid), also taken orally, which gave her three more years in remission.
Now, faced with a fourth relapse, she is battling her insurance company, United Healthcare, to cover her participation in a trial of another specially designed cousin of thalidomide, pomalidomide (Actimid).
"I hope this third-generation drug will work for me, but even if it doesn't, there are amazing drugs out there and so many new things coming," Ms. Battaile said. She noted that through the Multiple Myeloma Research Consortium -- started by Kathy Giusti, herself a myeloma patient -- "about 15 medical centers are doing collaborative research" on new treatments.
Symptoms and Diagnosis
Multiple myeloma is a cancer of the plasma cells in the bone marrow, a vital part of the immune system. When these cells grow out of control, they crowd out normal blood-forming cells, causing anemia and an increased risk of infection, bleeding and bruising. But the most common symptom of the disease, bone pain and fractures, results from a protein produced by myeloma cells that causes bones to dissolve.
Thus, the first symptom experienced by Dr. Martin Fisher, a retired dentist living in Brooklyn, was extreme pain, "like a third-rail electric shock," caused by bone damage. After the diagnosis, in 1007, Dr. Fisher was treated for six months with Revlimid and dexamethasone, which put his disease in remission for nine months.
His second drug, Velcade, given by intravenous injection, has kept him healthy so far. Last October, stem cells were harvested from his blood and frozen in liquid nitrogen in case they are needed in the future to replenish normal bone marrow cells. He is also treated with medication to counter bone loss.
Myeloma is a disease of many stages, including one called smoldering or somnolent that is rarely treated unless it starts to progress. Some patients have no symptoms; their diagnosis may follow a routine test revealing low levels of blood cells, high levels of calcium or excess protein in the urine. The most common symptoms are bone pain, weakness, shortness of breath, frequent infections with prolonged recovery, excessive bruising or bleeding, unusual thirst, loss of appetite, severe constipation and nerve pain.
Diagnostic tests typically include blood and urine analyses, CT scan, M.R.I., PET scan and bone marrow biopsy, which together can reveal the extent of disease. In addition, genetic studies are done to help determine a patient's chances of prolonged survival. Taken together, the results can help doctors choose the most effective therapies, based largely on the Mayo Clinic guidelines.
According to the Mayo experts, all patients with multiple myeloma should undergo a risk assessment before having treatment. About 75% of new patients face a "standard risk" of survival based primarily on the genetic characteristics of their cancer cells, they wrote. Like Dr. Fisher, their treatment could start with the oral drug Revlimid or the intravenous treatment, Velcade, followed by stem cell collection.
The remaining 25% have a more aggressive version of the disease, which the experts said should be treated more aggressively from the start, with Velcade followed by stem cell collection.
As new drugs come along, no doubt these regimens will be revised as well. With no cure in hand, the goal for most patients with multiple myeloma is to keep treating relapses as long as treatments are available.
But for new treatments to be developed, patients and their insurers must be willing to participate in well-designed clinical trials. Ms. Battaile is willing. But what about her insurance company?
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Enjoy your summer!
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