Transplanting tumors: When cancer cells from a breast cancer patient are implanted into a mouse, the cells quickly grow and spread. In this image, the pink cells are human tumor cells, while the purple cells are from the mouse. Researchers are using this technique to study the progression of human cancers.
Credit: Richard Wilson

Sequencing the genomes of both healthy and cancer cells from the same patient hints at how cancer metastasizes

MIT Technology Review, April 21, 2010, by Emily Singer  –  Scientists have identified genetic clues to how a tumor spreads throughout the body. Understanding the genetic aberrations that enable the metastasis of cancers could help scientists design better prognostic tests and more effective treatments.

In the research, the scientists compared the genome sequence of a breast cancer patient with that of both her primary tumor and cancer cells that had spread to her brain. It is just one of two published papers comparing the genomic differences between a primary and metastatic tumor from the same patient, a challenging endeavor but one that allows scientists to track the cancer’s evolution. “A patient’s tumor is a living thing changing all the time,” says Matthew Ellis, an oncologist and scientist at Washington University, in St. Louis, and one of the study’s authors. “We’ve never been able to track that completely.”

Cancer results when healthy cells acquire a combination of genetic mutations that allow them to grow out of control. Scientists have identified a number of mutations that increase the risk of cancer, as well as predict its prognosis and its likelihood of responding to certain treatments. But much less is known about the genetic mistakes that enable tumor progression, especially metastasis. The new research, reported Wednesday in the journal Nature, “emphasizes that you can gain a lot from looking at the evolution of a cancer over time,” says Sam Aparicio, Canada Research Chair in molecular oncology, who was not involved in the study.

The researchers used sequencing technology from Illumina, a genomics company in San Diego, to analyze DNA from the patient’s healthy cells, from the primary tumor prior to treatment, and from the brain metastasis. They found 48 mutations unique to cancer cells, but very few mutations were unique to the metastatic brain tumor. Instead, the major difference between the two tumor types was the relative frequency of the individual mutations in each tissue sample. Twenty of the 48 mutations occurred occasionally in cells in the primary tumor but were quite common in the metastatic tumor, suggesting that a small cohort of cells present in the primary tumor drove the cancer’s spread. “It’s as if a small subset of cells broke off from the primary tumor, circulated through blood, found a new home in the brain, and began to grow wildly and out of control,” says Richard Wilson, director of the Genome Sequencing Center at Washington University and a senior author of the paper.

While researchers still need to determine which of these mutations are true drivers of metastasis and which are merely carrier mutations that don’t affect the cells, they have identified some interesting candidates. For example, the patient had normal versions of a gene called CTNNA1, which has been linked to cells’ ability to stick to each other. But both tumors samples had a large deletion knocking out both copies of the gene, an occurrence that was particularly common in the metastatic cells. This mutation might allow cancer cells to break free of the primary tumor and spread through the bloodstream.

In addition to studying tumor samples from the patient, researchers implanted some of her tumor tissue into a mouse with a compromised immune system. This approach, called a xenograft, is often used to study the properties of human cancers. Just as in the patient, the cancer cells quickly multiplied and spread. When the team sequenced DNA from these cells, they found it had a similar genetic profile to that of the metastatic tumor samples. “It was a big surprise to see so many similarities between the xenograft and the metastatic genome,” says Elaine Mardis, codirector of the Genome Center. Both cancers originated from the same primary tumor and seemed to evolve in similar ways, despite growing in completely different environments. “This is just one case and we need to study more, but this does look like an interesting model for studying metastatic cancer,” she says. If the findings are confirmed more broadly, drug developers can use this system to test new treatments on human tumor cells, knowing that the cells behave similarly in the mouse and in the human body.

Mardis, Wilson, and others aim to sequence hundreds of cancer genomes over the next year. “The capacity for sequencing instruments has been on a dramatic uptick,” says Mardis. “The biggest challenge now is, how do you do multigenome analysis, for example comparing 20 to 50 genomes at the same time from a carefully defined phenotype like drug resistance?” The researchers hope that studying this volume of DNA will give broader insight into cancer genomics, letting them identify key metabolic or signaling pathways that are affected in cancer and which might be good targets for new therapeutics. 

Credit: Gabriela Hasbun

Q&A: Paul Otellini

MIT Technology Review, May/June 2010, by David Rotman  –  As CEO of Intel, Paul Otellini knows a lot about the value of investments. And these days he’s worried that the United States, after a decade of neglecting support for education, research, and digital infrastructure, is falling behind much of the world in its ability to compete economically and technologically.

Last year, during some of the grimmest days of the recession, Otellini announced that Intel would spend $7 billion to build fabrication plants in Oregon, New Mexico, and Arizona. While the move was meant to create manufacturing capacity for its new 32-nanometer chips, the timing, which came as Congress debated President Obama’s stimulus bill, was also meant to signal its willingness to invest in the United States. This February, Otellini announced that Intel and a group of venture capital firms would supply $3.5 billion to U.S.-based technology startups over the next 18 to 24 months; a related initiative committed Intel and other high-tech companies to doubling their hiring of U.S. college graduates in 2010.

Fretting over U.S. competitiveness is nothing new: such concerns seem to make headlines every few years, peaking during poor economic times. So Technology Review editor David Rotman asked the Intel CEO why he is worried now.

TR: Why does it matter where innovation comes from? After all, about 75 percent of your revenues are from outside the U.S.

Paul Otellini: [To us] as a global company, it probably doesn’t matter. And as a multinational corporation, we have the ability to hire people from anywhere on earth. But there are still some fundamental concerns. I think that America is the best place in the world for innovation when it is done right. Historically, the infrastructure, capital markets, acceptance of failure, and the willingness to try again are uniquely American.

TR: What’s at stake for the U.S.?

PO: As a country the issue is: are we going to be prepared for the industries of the 21st century, which are fundamentally knowledge-based industries? The alternative is to go back to 19th-century industries and get back to [manufacturing] steel and those kinds of things, but then you have to do it at costs that are comparable with the lowest costs in the world. That would require a reset of the standard of living, and most Americans are not willing to do that. If you want to maintain our standard of living, you need to adapt the workforce for the jobs of the future.

TR: Do you see signs of this loss of competitiveness already?

PO: You can measure the gradual erosion with something as straightforward as how our kids are doing in math and science. It’s clear the best of the best coming out of our schools are world class. It is the average that I’m concerned about.

TR: Has this begun affecting the U.S. economy?

PO: It is so hard to tell. If we didn’t have this giant recession, you might be able to measure [the effect] more accurately. But you can surmise that if the quality of skills of the workforce is eroding, it’s a huge productivity loss.

TR: What government policies would help?

PO: Governments are best positioned to fund basic research. But there’s been a decade-long erosion in the amount of that funding. It’s now on a path to grow, and eventually the goal is to double it. But it takes a long time to do that. Secondly, we would like to see the R&D tax credit made permanent and returned to levels that are competitive with the rest of the world. Lastly, we have corporate tax rates that today are the second highest in the industrialized world.

TR: Aren’t there dangers when governments get involved in supporting innovation?

PO: One potential pitfall is government picking industries and technologies. The job of government is to fund basic research and let scientists do their work and let the innovation fall where it may. I just think there has been insufficient funding, and we need to get it back to levels that are much more consistent with our historical norms.

TR: Investing in startups is what venture capitalists are supposed to be doing. Why did they need encouragement?

PO: Yes, it is their business, but the narrowness of the focus [on clean tech and high tech] and the narrowness of the investment period was also important. We wanted to show [startup companies] that the venture capital industry was open for business.

TR: One of your recent speeches was titled “Reinventing America’s Economic Future.” What did you mean?

PO: The fifty-thousand-foot view is, it’s all about competitiveness. It is something that, as a country, we too often take for granted. We take for granted that capital will flow in, we take for granted that we will have the best workforce in the world, we take for granted that capital formation is there, that startups can have an exit through the IPO [initial public offering] market. None [of that] is to be taken for granted anymore. It was nurtured over 30 to 40 years, and for a variety of reasons it has either atrophied or been constrained. If we refocus our energies on competitiveness as a country, then other good things accrue: capital accrues, jobs accrue, investments accrue. It’s really a recipe for what makes nations prosperous.

GoogleNews.com, USAToday.com, April 21, 2010  –  A common osteoporosis drug, raloxifene, reduces breast cancer risk by 38% in women at high risk for the disease, without causing the serious side effects of similar drugs, a new study shows.

That suggests more high-risk women should consider taking raloxifene, also known as Evista, says Victor Vogel, main author of the study presented Monday at the American Association for Cancer Research meeting in Washington.

“It’s not a cure … but it’s an important protection for women who are at very high risk,” says Vogel, who followed nearly 20,000 high-risk, postmenopausal women for almost seven years.

Both raloxifene and another drug, tamoxifen, are approved to prevent breast cancer in women at high risk. Few women take them for prevention, however, because of concerns about side effects.

Tamoxifen reduces breast cancer by 50% but can also cause hot flashes and other symptoms. So about half of breast cancer patients, who often take it to prevent a relapse, stop the drug early, says study co-author Lawrence Wickerham of Allegheny General Hospital.

Tamoxifen also doubles the risk of endometrial cancer, from about one in 1,000 women to about two in 1,000, according to the National Cancer Institute, so many doctors are cautious about prescribing it.

Given these concerns, no more than 5% of high-risk women today “even consider taking” either drug, says Gabriel Hortobagyi of Houston’s M.D. Anderson Cancer Center, who wasn’t involved with the study but will participate in a panel discussion at the conference. “The impact of these drugs is huge,” he says. “The only thing that reduces the risk as much is a bilateral mastectomy.”

The new study — which shows that raloxifene doesn’t substantially increase the risk of endometrial cancer — should put those concerns to rest, says co-author Patricia Ganz, who runs a clinic for high-risk women at the University of California-Los Angeles.

“We have two very effective agents for breast cancer prevention,” Ganz says. “If women were not so risk-averse, we might actually be able to reduce the risk of breast cancer in high-risk women.”

A typical American woman has about a 12% chance of getting breast cancer in her lifetime. That risk rises to about 18% for a woman whose mother or sister has had the disease, and to 30% for a woman with a breast lesion called atypical hyperplasia, Ganz says.

Trial meets main goals

 

By Debra Sherman and Bill Berkrot

GoogleNews.com, ATLANTA – A noninvasive procedure that freezes and kills problem-causing heart tissue was nearly 10 times better at eliminating a potentially serious heart rhythm disorder than conventional anti-arrhythmic drugs, researchers said on Monday.

A clinical trial of Medtronic Inc’s (MDT.N) cryoablation system looked at 245 patients with paroxysmal atrial fibrillation, a condition marked by intermittent episodes of abnormal heart rhythm that causes the upper chambers of the heart to quiver.

A small pilot study funded by St. Jude Medical Inc (STJ.N) compared the two therapies in a sicker population of patients and also found that the procedure worked better than drugs.

Atrial fibrillation is the most common heart disorder, affecting 2.2 million Americans and 10 million people worldwide. It significantly raises the risk of stroke.

Patients in the Medtronic-sponsored trial who underwent the cryoablation procedure — which involves using a catheter to freeze away the heart tissue where the problem originates — was just as safe as drugs used to treat the condition and far more effective, meeting the study’s primary goal of eliminating atrial fibrillation one year after the procedure.

Dubbed Stop-af, the Medtronic trial showed that almost 70 percent of patients who had cryoablation remained free of the condition after one year, compared with just 7 percent of patients who received drug therapy, according to data presented at the American College of Cardiology meeting in Atlanta.

“This is the best data we have at this point in support of cryoablation (to treat atrial fibrillation),” said Dr. Douglas Packer of Mayo Clinic, the lead investigator of the study.

Over 3 percent of patients treated by cryoablation experienced a serious condition — a narrowing of the pulmonary vein in 7 out of 228 patients, one of whom required another procedure to widen the vein.

Damage or irritation to the nerve that controls the diaphragm was reported in 11 percent of the cryoablation procedures, but none of the cases was considered serious, with 98 percent resolved by the 12-month follow-up.

Complications related to the atrial fibrillation itself were also monitored. During the follow-up period, 97 percent of patients who got the procedure and 92 percent of the drug therapy patients did not suffer heart attack, stroke or death.

Less than 1 percent of patients treated with cryoablation were hospitalized for a recurrence of the disease, compared with 6 percent in the drug group.

Patients in the pilot study had advanced atrial fibrillation and tended to have other medical problems, such as high blood pressure, diabetes or coronary artery disease,

Packer, who also led the pilot study, dubbed Cabana, acknowledged that the main limitation of this study was its small size, but said it lays the foundation for a larger one.

He said the larger study, which will include 180 centers, is currently enrolling patients.

Anti-arrhythmic drugs eliminate atrial fibrillation in about half of all patients but can have adverse side effects.

Cryoablation is an alternative that is growing in popularity. Over the past decade, more patients have been referred for ablation procedures when drugs proved ineffective.

Catheter ablation involves inserting a thin tube into a blood vessel, usually through a site in the upper leg or neck, and then threading it though the body until it reaches the heart. When it reaches the area of the heart that causes abnormal rhythms, the tissue is ablated, or destroyed.

The procedure has been used to treat arrhythmias for years. The U.S. Food and Drug Administration initially cleared ablation catheters to treat arrhythmias, such as atrial flutter, but not atrial fibrillation.

Only Johnson & Johnson (JNJ.N) has an ablation device approved by U.S. health regulators specifically to treat atrial fibrillation.

The Medtronic device, which the company added to its portfolio with the 2008 acquisition of CryoCath, has been approved in Europe and Australia.

For Immediate Release: April 20, 2010
Media Inquiries: Karen Riley, 301-796-4674
karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA to Address Challenges of Using Complex Medical Devices in the Home
Agency’s Home Use Initiative to provide guidance, other measures to help caregivers, patients

The U.S. Food and Drug Administration today announced a new initiative to ensure that caregivers and patients safely use complex medical devices in the home.

Hemodialysis equipment to treat kidney failure, wound therapy care, intravenous therapy devices, and ventilators are among the medical products that have migrated to the home in recent years. And more hospital patients of all ages are being discharged to continue their medical treatment at home.

“Using complex medical devices at home carries unique challenges,” said Jeffrey Shuren, M.D., J.D., director of the Center for Devices and Radiological Health. “Caregivers may lack sufficient training, product instructions may be inadequate or overly technical, and the home environment itself may pose environmental or safety hazards that can affect the product’s functioning.

According to an FDA white paper, the initiative will develop guidance for manufacturers who intend to market a device for home use, provide for postmarket surveillance, and put in place other measures to encourage safe use of these products. In addition, the FDA is developing educational materials on home use of medical devices.

“The FDA’s Home Use Initiative will help address the potential challenges, providing greater protection and awareness for patients who are being cared for in the home,” Shuren said.

Currently, the FDA does not have a clear regulatory pathway for devices intended for home use that describes the unique factors that manufacturers should take into consideration when designing, testing, and labeling such products. The new home use guidance document that FDA intends to develop will

  • make recommendations for actions manufacturers should take to support premarket approval or clearance of these devices, including device testing with at-home caregivers and patients in a non-clinical setting
  • define circumstances under which the FDA may exercise its authority to require that certain devices cleared for marketing carry a statement in the labeling that the device has not been cleared for use in the home
  • recommend postmarket surveillance to identify and address adverse events that may occur in the home.

In addition to developing the guidance document, the FDA will launch a 10-month pilot program beginning in the summer of 2010 in which manufacturers of home use devices may voluntarily submit their labeling to the agency for posting on a central Web site repository. Posting medical device labeling in the repository will help home care patients and caregivers to quickly and conveniently access important information about the safe use of their devices.

The Home Use Initiative also contains measures for enhanced postmarket surveillance through HomeNet, a subnetwork of the FDA’s Medical Device Surveillance Network, an adverse event reporting program that includes more than 350 health care facilities nationwide.

Understanding issues experienced by home users will help the FDA develop appropriate actions to address those issues in the future. It may also identify cases in which devices intended solely for use in a health care facility are being used at home. The FDA already has collected information on safety concerns related to home hemodialysis and is now collecting similar information on the use of some wound therapy devices.

The FDA is partnering with the Community Health Accreditation Program and the Joint Commission, which evaluates and accredits 17,000 U.S. health care organizations and programs, to strengthen home health agency accreditation criteria that relate to medical device safe use practices.

Harvard Medical School, April 20, 2010  –  Most people take bladder and bowel control for granted — until something goes wrong. Then, unexpectedly, they find themselves hurrying to get to a bathroom on time, avoiding certain situations for fear of leakage, or relying on absorbent pads for protection. If you have had any of these experiences, you are not alone.

An estimated 32 million adults have incontinence, the unintended loss of urine or feces that is significant enough to make it difficult for them to maintain good hygiene and carry on ordinary social and work lives. What’s the cause? For women, it’s typically a rarely discussed but common result of childbirth and aging. For men, it’s most often a side effect of treatment for prostate problems.

Sometimes incontinence is a minor problem. But when you begin organizing your life around easy access to a bathroom or start giving up the activities that are important to you — your daily walk, travel, career, or sex — because you can’t control leakage, it may be time to take action.

Besides disrupting daily activities and nighttime sleep, incontinence can also chip away at your health. If you have stopped exercising for fear of leakage, for example, you are giving up one of the most effective strategies for maintaining health. In addition, getting up several times a night can lead to sleep deprivation and raises the risk of injury from falls. And incontinence that causes withdrawal from social interactions can contribute to depression.

Even more alarming, older women who frequently must rush to the bathroom are 26% more likely to fall and 34% more likely to break a bone. Incontinence is also a leading cause of nursing home placement, and that prospect drives some people to try to hide their condition rather than seek help.

The good news is that treatments are becoming more effective and less invasive. For example, today’s medications for urinary incontinence are easier to use than earlier ones. Exercises can help strengthen the muscles of the pelvic floor, shoring up those that control both bladder and bowel. Most people don’t require surgery, but for those who do, the options often include less invasive outpatient procedures that often work as well as older, open surgical procedures. 

 
April 20, 2010

 

Training your bladder

Better Bladder and Bowel Control

Bladder or bowel incontinence is surprisingly common. It has a number of causes including the complications of surgery, childbirth, or injury. Middle-aged and older people are particularly susceptible to these conditions, but there are a variety of treatments available, including exercise programs, medications, and surgery.

Click here to read more »                                 

Treatment choices for urinary incontinence range from lifestyle changes to surgery. Your treatment will depend on the underlying problems causing the incontinence. But keep in mind that no treatment works perfectly, and you may have to try more than one approach before you find the one that best suits your needs. Treatments may be different for men and women. Because there are a variety of options, your preferences are important in developing a plan.

For example, a woman may be a candidate for either injections of bulking agents or a sling procedure. If she is in her 40s and likes to do kickboxing for exercise, she may not be dry enough with the injections and may choose sling surgery. A woman with similar exam and test results but a less active lifestyle might get along fine with injections.

It’s also important to know that less invasive treatments, such as biofeedback or pelvic floor exercises, are a good first step and can be helpful, but may not be as effective as some surgical procedures. You and your physician need to decide which is most appropriate for you. Check with your health plan to find out which therapies are covered. Treatment for urinary incontinence is an area of active research, and new approaches are under development.

Bladder training

You might be teaching your bladder some bad habits—habits that can gradually result in incontinence or frequent bathroom breaks. For example, if you routinely urinate before your bladder is full, it learns to signal the need to go when less volume is present. That can set up a vicious cycle, as you respond to the new urges and teach your bladder to cry “run” when less and less urine is present.

Luckily, old bladders can learn new tricks. Bladder training, a program of urinating on schedule, enables you to gradually increase the amount of urine you can comfortably hold. Bladder training is a mainstay of treatment for urinary frequency and overactive bladder in both women and men, alone or in conjunction with medications or other techniques. It can also help prevent or lessen symptoms of overactive bladder that may emerge after surgery for stress incontinence. You can try it on your own or with the guidance and support of a health professional. Because bladder training is low-cost and low-risk, your clinician may encourage you to try it first, even before specific diagnostic tests are performed.

Step-by-step bladder-training technique

  • Keep track. For a day or two, keep track of the times you urinate or leak urine during the day.
  • Calculate. On average, how many hours do you wait between urinations during the day?
  • Choose an interval. Based on your typical interval between urinations, select a starting interval for training that is 15 minutes longer. If your typical interval is one hour, make your starting interval one hour and 15 minutes.
  • Hold back. When you start training, empty your bladder first thing in the morning and not again until the interval you’ve set. If the time arrives before you feel the urge, go anyway. If the urge hits first, remind yourself that your bladder isn’t really full, and use whatever techniques you can to delay going. Try the pelvic floor exercises sometimes called Kegels, or simply try to wait another five minutes before walking slowly to the bathroom.
  • Increase your interval. Once you are comfortable with your set interval, increase it by 15 minutes. Over several weeks or months, you may find you are able to wait much longer and that you experience far fewer feelings of urgency or episodes of urge incontinence.

Keeping a bladder diary

  • Complete the information for two consecutive 24-hour periods. Record both day and night.
  • Begin with first urination upon arising.
  • Record intake amount in ounces and type of fluid (for example, coffee, juice, water, etc.).
  • Record approximate urine output and time of urination.

 

Whether sitting on an airplane, attending a business meeting, or just gardening in the yard, the sudden or urgent need to get to a bathroom is a distressing and all-too-frequent disruption in the lives of millions of people. Bladder or bowel incontinence is surprisingly common. It has a number of causes including the complications of surgery, childbirth, or injury. These and other causes can interfere with the muscles, nerves, and other tissues that work together for urinary and rectal function. Middle aged and older people are particularly susceptible to these conditions. But there are a variety of treatments available including exercise programs, medications and surgery. This Special Health Report, Better Bladder and Bowel Control, describes the causes of urinary and bowel incontinence and treatments tailored to the specific cause.   

Better Bladder and Bowel Control was prepared by the editors of the Harvard Health Publications in consultation with May M. Wakamatsu, M.D., assistant professor of obstetrics gynecology and reproductive biology at Harvard Medical School and Massachusetts General Hospital, and Joseph A. Grocela, M.D., Instructor in Surgery, Harvard Medical School and Massachusetts General Hospital; and Liliana Bordeianou, M.D., Instructor in Surgery, Harvard Medical School, Massachusetts General Hospital. 47 pages. (2009)