Published by
Stanford Medicine

Category

Clinical Trials

Cancer, Clinical Trials, Research, Science, Stanford News, Stem Cells

Drug may prevent bladder cancer progression, say Stanford researchers

Drug may prevent bladder cancer progression, say Stanford researchers

Bladder cancer is an insidious foe. About 70 percent of the time the condition is diagnosed while still confined to the bladder lining (in these cases, it’s known as a “carcinoma in situ,” or CIS). However, a subset of these localized cancers will go on to invade tissue surrounding the bladder and become much more deadly.

Now, developmental biologist Philip Beachy, PhD, a Howard Hughes Medical Institute investigator, and his colleagues have found that low doses of a drug called FK506 currently used to prevent the rejection of transplanted organs can prevent the progression of CIS into invasive bladder cancer in mice. Beachy collaborated with collaborated with urologist Joseph Liao, MD, and pulmonary specialist Edda Spiekerkoetter, MD, to conduct the research, which was published today in Cancer Cell. As Beachy explains in our release:

This could be a boon to the management of bladder cancer patients. Bladder cancer is the most expensive cancer to treat per patient because most patients require continual monitoring. The effective prevention of progression to invasive carcinoma would be a major advance in the treatment of this disease.

Beachy and Liao are members of the Stanford Cancer Institute. Together they’re hoping to initiate clinical trials of FK506 in people with CIS to learn whether the drug can also prevent progression to invasive cancer in humans.

The findings of the current study build upon previous research into the disease in Beachy’s laboratory and a long-time interest by Beachy in a molecular signaling pathway governed by a protein called sonic hedgehog. Beachy identified the first hedgehog protein in 1992; the protein (and the hedgehog pathway) have since been shown to play a vital role in embryonic developments and many types of cancers. Sonic hedgehog, Beachy has found, is produced by specialized stem cells in the bladder as a way to communicate with neighboring cells. They learned it’s required for the formation of CIS, but that it must also be lost in order for the cancer cells to invade other tissues. As Beachy explained in our release:

This was a very provocative finding. It was clear that these [sonic-hedgehog-expressing] bladder stem cells were the source of the intermediate cancers, or carcinomas in situ, that remain confined to the bladder lining. However, it was equally clear that sonic hedgehog expression must then be lost in order for those cancer cells to be able to invade surrounding tissue. We wondered whether the loss of this expression leads to increased tumor cell growth.

The researchers found that sonic hedgehog expression works in a loop with another class of proteins called BMPs. (You can read more about this in our release.) FK506 works by activating the BMP portion of the pathway in the absence of sonic hedgehog. Ten out of ten mice with CIS who received a low dose of the drug (low enough not to cause immunosuppression) were protected from developing invasive bladder cancer after five months of exposure to the carcinogen. In contrast, seven of nine mice receiving a placebo did develop the invasive form of the disease within the same time period.

Continue Reading »

Clinical Trials, Ethics, Genetics, NIH, Pediatrics

The promise and peril of genome sequencing newborns

NICUEven though doctors and researchers have made great strides in caring for patients in the past few decades, there are still many illnesses that are difficult to diagnose, let alone treat. Among the most heartbreaking cases are those newborns who come down with mysterious illnesses that defy medical expertise. But in recent years, doctors have turned to genetic sequencing in some of these cases to identify the culprit causes of the illnesses.

Last year, the National Institutes of Health funded four pilot projects looking into the efficacy and ethics of genetic screening for otherwise inexplicable illnesses in newborns. The first of the trials will begin next week at Children’s Mercy Hospital in Kansas City, Missouri, as reported in a recent story from Nature. The trial at Children’s Mercy Hospital will focus on rapid genome sequencing with a 24-hour turn-around. Genetic sequencing normally takes weeks, but some of these infants don’t survive that long. Doctors have used similar rapid genome sequencing to diagnose an infant with cardiac defects at Lucile Packard Children’s Hospital Stanford.

Earlier this year, I had the opportunity to report on a rare genetic mutation that leads young infants to develop inflammatory bowel disease. I spoke with some parents of children with the mutation, which was identified by sequencing the children’s exome – just the protein-producing part of the genome – as part of a new project (separate from the NIH trials) at the University of Toronto in Canada. As I explain in the piece, getting a bone marrow transplant early enough can help alleviate symptoms and save the child’s life.

The parents were uniformly grateful for the sequencing technology that made it possible to understand what was causing their baby’s illness, even in cases where the child didn’t survive long after diagnosis. One mother mentioned that realizing some of the best doctors in the country didn’t know what was ailing her daughter made the experience even more frightening. After months of worried confusion about their young children’s deteriorating health, for these parents to have an answer was a relief.

But because the technique is so new, several ethical details still need clarification – which the NIH study hopes to answer. From the Nature news story:

Misha Angrist, a genomic-policy expert at Duke University in Durham, North Carolina, says that although the 24-hour genome process is impressive, it is not clear whether genomic sequencing of newborns will soon become standard practice. Many questions remain about who will pay for sequencing, who should have access to the data and how far clinicians should go in extracting genome information that is unrelated to the disease at hand. Then there is the question of how informative the process is. “I think it’s really important that we do these experiments so that we start to see what that yield is,” Angrist says.

All four teams will include an ethicist who will be responsible for dealing with questions like the ones Angrist raises. The other three trials at Boston Children’s Hospital, the University of North Carolina in Chapel Hill, and at the University of California, San Francisco are still awaiting approval from the Federal Drug Adminstration.

Previously: Stanford patient on having her genome sequenced: “This is the right thing to do for our family” When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside Whole genome sequencing: The known knowns and the unknown unknowns
Photo by kqedquest

Clinical Trials, History, Immunology, Infectious Disease, Research

Stanford scientists strive to solve centuries-old puzzle: Why are young children so vulnerable to disease?

Stanford scientists strive to solve centuries-old puzzle: Why are young children so vulnerable to disease?

512px-Gabriël_Metsu_-_The_Sick_Child_-_WGA15091

Several months ago, Stanford immunologist Mark Davis, PhD, went for a stroll in Union Cemetery in Redwood City, Calif. (not far from the Stanford campus). Graves there date from the Civil War-era and Davis, who’s currently immersed in a study of childhood immunity, was intrigued.

“In the early years, you see entire families — mom, dad, and then a whole bunch of children’s headstones,” Davis told me. “It really brought home to me how differently we live now that we just take for granted a kid will survive and grow up.”

Vaccines arrived and childhood survival rates soared. Yet young children remain much more vulnerable to infectious diseases than adults. Why?

Davis and his team think vaccines trigger a set of changes that strengthens children’s immune systems — allowing them to ward off diseases they haven’t even heard of before. That’s why the researchers are conducting a group of studies, all focused on revealing new details about the immune system’s response to the flu vaccine. They need participants, particularly young children who have never received a flu vaccine before. They also need older children and twins. All participants will receive a licensed flu vaccine that will help protect from influenza this coming winter.

Davis and colleagues plan to investigate the children’s development of two types of immune cells — memory T and B cells — that are specialized to recognize certain foreign invaders. Interestingly, adults have T cells that spot diseases they’ve never been exposed to, such as HIV, Davis said. Yet newborns lack these specialized cells, leaving them vulnerable to infection.

“Somewhere between birth and adulthood we see the appearance of these memory T cells without having the particular disease,” Davis said. “It’s a real puzzle.”

Davis suspects that routine vaccines and infections may spur the development in children of a broad spectrum of memory T cells, ones that recognize all sorts of diseases. One study plans to follow children for several years, perhaps revealing how, and when, the children develop a full compliment of these memory T cells, Davis told me.

The studies are possible thanks to the development of new analytical techniques, according to virologist and immunologist Harry Greenberg, MD, who is working with Davis on the influenza studies.

“We’ve been studying influenza for half a century, but these new assays developed in the last five years offer hope we can develop better ways of protecting more people,” Greenberg told me.

More information about the flu vaccine studies and the Stanford-LPCH Vaccine Program is available here or (650) 498-7284.

Becky Bach is a proud graduate of the UC Santa Cruz Science Communication Program (go Banana Slugs!) and a science-writing intern at the Office of Communications and Public Affairs.

Previously: Q&A about enterovirus-D68 with Stanford/Packard infectious disease expert, Gut bacteria may influence effectiveness of flu vaccine and Side effects of childhood vaccines are extremely rare, new study finds
Photo by Gabriel Metsu

Cancer, Clinical Trials, In the News, NIH, Patient Care, Research

National Cancer Institute looking for “Exceptional Responders”

OLYMPUS DIGITAL CAMERAHope is a powerful force in cancer treatment. For patients and their families, the hope is that, no matter how unlikely, the treatment plan will cure the patient and eradicate the disease. Sadly, this is sometimes a long shot. But sometimes, against all odds, the therapy is unusually successful. Now the National Cancer Institute is trying to learn why.

This week the institute launched a study into the phenomena of “Exceptional Responders” – that is, cancer patients who have a unique response to treatments (primarily chemotherapy) that have not been effective for most other patients. As they describe in a Q&A about the effort:

For this initiative, exceptional responders will be identified among patients enrolled in early-phase clinical trials in which fewer than 10 percent of the patients responded to the treatments being studied; patients who were treated with drugs not found to be generally effective for their disease; patients who were treated in later-phase clinical trials of single agents or combinations; and even patients who were treated with established therapies. In this pilot study, malignant tissue (and normal tissue, when possible) and clinical data will be obtained from a group of exceptional responders and analyzed in detail. The goal is to determine whether certain molecular features of the malignant tissue can predict responses to the same or similar drugs.

The researchers would like to obtain tumor samples, as well as normal tissue, from about 100 exceptional responders. They’ll compare DNA sequences and RNA transcript levels and other molecular measurements to try to understand why these patients were such outliers in their response to treatment. In at least one previous case, an exceptional responder with bladder cancer led researchers to discover a new molecular pathway involved in the development of the disease, and suggested new therapeutic approaches for other similar patients.

Do you know someone who might qualify for the study? More from the Q&A:

Patients who believe they may be exceptional responders should contact their physicians or clinical trialists to see if they can assist in submitting tissue for consideration. [...] Investigators who have tissue from a potential exceptional responder should send an email to NCIExceptionalResponders@mail.nih.gov. The email should include a short description of the case, without patient identifiers; information about whether tissue collected before the exceptional response is available; whether informed consent was given to use tissue for research; and the patient’s vital status.

Photo by pol sifter

Clinical Trials, Immunology, Pain, Research, Stanford News, Surgery, Technology

Discovery may help predict how many days it will take for individual surgery patients to bounce back

Discovery may help predict how many days it will take for individual surgery patients to bounce back

pandaPost-surgery recovery rates, even from identical procedures, vary widely from patient to patient. Some feel better in a week. Others take a month to get back on their feet. And – until now, anyway – nobody has been able to accurately predict how quickly a given surgical patient will start feeling better. Docs don’t know what to tell the patient, and the patient doesn’t know what to tell loved ones or the boss.

Worldwide, hundreds of millions of surgeries are performed every year. Of those, tens of millions are major ones that trigger massive inflammatory reactions in patients’ bodies. As far as your immune system is concerned, there isn’t any difference between a surgical incision and a saber-tooth tiger attack.

In fact, that inflammatory response is a good thing whether the cut came from a surgical scalpel or a tiger’s tooth, because post-wound inflammation is an early component of the healing process. But when that inflammation hangs on for too long, it impedes rather than speeds healing. Timing is everything.

In a study just published in Science Translational Medicine, Stanford researchers under the direction of perioperative specialist Martin Angst, MD, and immunology techno-wizard Garry Nolan, PhD, have identified an “immune signature” common to all 32 patients they monitored before and after those patients had hip-replacement surgery. This may permit reasonable predictions of individual patients’ recovery rates.

In my news release on this study, I wrote:

The Stanford team observed what Angst called “a very well-orchestrated, cell-type- and time-specific pattern of immune response to surgery.” The pattern consisted of a sequence of coordinated rises and falls in numbers of diverse immune-cell types, along with various changes in activity within each cell type.

While this post-surgical signature showed up in every single patient, the magnitude of the various increases and decreases in cell numbers and activity varied from one patient to the next. One particular factor – changes, at one hour versus 24 hours post-surgery, in the activation states of key interacting proteins inside a small set of “first-responder” immune cells – accounted for 40-60 percent of the variation in the timing of these patients’ recovery.

That robust correlation dwarfs those observed in earlier studies of the immune-system/recovery connection – probably because such previous studies have tended to look at, for example, levels of one or another substance or cell type in a blood sample. The new method lets scientists simultaneously score dozens of identifying surface features and goings-on inside cells, one cell at a time.

The Stanford group is now hoping to identify a pre-operation immune signature that predicts the rate of recovery, according to Brice Gaudilierre, MD, PhD, the study’s lead author. That would let physicians and patients know who’d benefit from boosting their immune strength beforehand (there do appear to be some ways to do that), or from pre-surgery interventions such as physical therapy.

This discovery isn’t going to remain relevant only to planned operations. A better understanding, at the cellular and molecular level, of how immune response drives recovery from wounds may also help emergency clinicians tweak a victim’s immune system after an accident or a saber-tooth tiger attack.

Previously: Targeting stimulation of specific brain cells boosts stroke recovery in mice, A closer look at Stanford study on women and pain and New device identifies immune cells at an unprecedented level of detail, inside and out
Photo by yoppy

Clinical Trials, Ethics, Health Policy, Stanford News, Videos

Video explains why doctors don’t always know best

Video explains why doctors don’t always know best

“Over 85 percent of our major medical guideline recommendations are not based on high-quality evidence,” said Robert Califf, MD, director of the Duke Translational Medicine Institute, in an article I recently wrote for Inside Stanford Medicine.

This was the inconvenient truth that Stanford bioethicist David Magnus, PhD, had to explain to patients during focus groups, as he began developing policy recommendations for conducting ethical comparative-effectiveness research within physician practices.

“We had to dispel the myth that doctors always know which treatments are most effective for individual patients,” Magnus told me. “The truth is, in the absence of good evidence, these choices are often influenced by advertising, insurance coverage and local preferences.”

Gathering better treatment evidence is a key objective of the Affordable Care Act’s health-care reform mandate. It provides incentives for medical practices to continually evaluate the relative effectiveness of competing medical interventions as a way of delivering better, less costly care to more people. The widespread adoption of electronic medical records is enabling researchers to conduct these head-to-head comparisons in more automated ways, reducing the time and expense associated with the highly controlled clinical trials used to evaluate new drugs and devices.

A communications challenge with these new approaches, however, is how to explain the risks and rewards of participation to patients. In focus groups, Magnus found that no meaningful discussions could take place until his research team had educated patients on some fundamental concepts of medical research, such as standards-of-care, randomization and informed consent. To help with this process, his team produced three short, animated videos that would rapidly get everyone up to the same level of understanding. Magnus and his collaborators are making these videos available to all for educational purposes.

The first video, “Which Medication is Best?,” explores the influences and uncertainty associated with physicians’ prescribing preferences. “Research on Medical Practices” explains medical record reviews, study randomization and randomization of clinics and hospitals; and “Informing or Asking” describes ways to explain study participation to patients.

Magnus and his bioethicist collaborators from the Seattle Children’s Research Institute and University of Washington expect to publish their final ethics policy recommendations later this year.

Previously: Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical researchStanford biomedical ethicist discusses Choosing Wisely Initiative and Will new guidelines lead to massive statin use?
Videos by Booster Shot Media

Big data, Chronic Disease, Clinical Trials, Health and Fitness, Public Health

Stanford to launch Wellness Living Laboratory

Stanford to launch Wellness Living Laboratory

1200px-Female_joggers_on_foggy_Morro_Strand_State_BeachIf you’re the kind of person who wears a heart monitor while jogging, tracks your sleep with an app or meditates to lengthen your lifespan, then a new Stanford project, called WELL, just might be for you.

WELL, which stands for the Wellness Living Laboratory hasn’t started quite yet — it will launch in 2015 — but when it does, it will unleash a variety of cutting-edge tools in an effort to define health.

Health seems like a no-brainer, but it is more than the absence of disease, says John Ioannidis , MD, DSc, the head of the Stanford Prevention Research Center. Ioannidis wants to find out how people can be “more healthy than healthy.”

To do that, he secured $10 million and laid out plans for the project. WELL plans to enroll thousands of volunteers — who Ioannidis calls “citizen scientists” — in two initial locations: Santa Clara County, Calif., and China, with plans to expand to other sites in the future.

Participants may be able to select which health factors to track and to report much of their information remotely and digitally, although some in-person visits may be required. Participants will also have the opportunity to enroll in a variety of clinical trials to test various interventions, such as nutrition counseling or smoking cessation programs.

The program will focus on wellness, rather than diseases, with the hypothesis that promoting wellness thwarts diseases, Ioannidis said.

Volunteers who would rather not provide health information will also have the opportunity to benefit from access to a program-wide social networking effort that will spread news of successful practices, he said. “This outer sphere could reach out to tens of millions of people,” Ioannidis told me.  Stay tuned to learn how to sign up.

The $10 million came as an unrestricted gift to Stanford University from Amway’s Nutrilite Health Institute Wellness Fund.

Previously: Medicine X explores the relationship between mental and physical health, Stanford partnering with Google [x] and Duke to better understand the human body, New Stanford center aims to promote research excellence and Teens these days smoking less but engaging in other risky behaviors
Photo by: Mike Baird

Clinical Trials, Patient Care, Research, Science, Stanford News

Re-analyses of clinical trial results rare, but necessary, say Stanford researchers

Re-analyses of clinical trial results rare, but necessary, say Stanford researchers

The results of large clinical trials are used to make important clinical decisions. But the raw data on which these results are based are rarely made available to other researchers, perhaps due to concerns about intellectual property or giving a leg up to competitors in the field. But a new study by Stanford’s John Ioannidis, MD, DSci, shows that the re-analysis of such data by independent research is critical: About one third of the time it leads to conclusions that differ from those of the original study.

The research was published today in the Journal of the American Medical Association.

Clearly, data sharing is an important step in making sure research is conducted efficiently and renders reproducible results

For the study, Ioannidis and his co-authors surveyed about three decades of research cataloged in the National Library of Medicine’s PubMed database looking for re-analyses of previously published clinical-trial data. They found fewer than 40 studies that met their criteria (reanalyses using the original data to investigate a new hypothesis, or meta-analyses of several studies were not included) and, as I wrote in a release:

Thirteen of the re-analyses (35 percent of the total) came to conclusions that differed from those of the original trial with regard to who could benefit from the tested medication or intervention: Three concluded that the patient population to treat should be different than the one recommended by the original study; one concluded that fewer patients should be treated; and the remaining nine indicated that more patients should be treated.

The differences between the original trial studies and the re-analyses often occurred because the researchers conducting the re-analyses used different statistical or analytical methods, ways of defining outcomes or ways of handling missing data. Some re-analyses also identified errors in the original trial publication, such as the inclusion of patients who should have been excluded from the study.

Clearly, data sharing is an important step in making sure research is conducted efficiently and renders reproducible results – goals shared by the recently launched Meta-Research Innovation Center at Stanford (or METRICS), which Ioannidis co-directs. More from our release:

The fact that researchers conducting re-analyses often came to different conclusions doesn’t indicate the original studies were necessarily biased or deliberately falsified, Ioannidis added. Instead, it emphasizes the importance of making the original data freely available to other researchers to encourage dialogue and consensus, and to discourage a culture of scientific research that rewards scientists only for novel or unexpected results.

“I am very much in favor of data sharing, and believe there should be incentives for independent researchers to conduct these kinds of re-analyses,” said Ioannidis. “They can be extremely insightful.”

Previously: John Ioannidis discusses the popularity of his paper examining the reliability of scientific research, New Stanford center aims to promote research excellence and “U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis

Cancer, Clinical Trials, Pediatrics, Public Health, Research

Researchers call for broader age limits for cancer trials to increase participation of teenage patients

Researchers call for broader age limits for cancer trials to increase participation of teenage patients

Findings published today in the Lancet Oncology highlight the need to increase the flexibility of age limits for cancer trials so that more teenage patients have access to experimental treatments. “Right now too many of our young patients are needlessly falling through the gap between paediatric and adult cancer trials,” said Lorna Fern, PhD, who led the study and co-ordinates research for the Teenage and Young Adult Clinical Studies Group of the UK-based National Cancer Research Institute.

In the study (subscription required), researchers examined strategies to boost participation of teens and young adults diagnosed with cancer in clinical trials. The study involved 68,275 patients, aged 0-59 years, who were diagnosed with cancer within a five-year window. According to a release:

The study showed [trials designed with broader age limits] led to a 13 per cent rise in 15-19 year old cancer patients taking part in clinical trials between 2005 and 2010 (from 24 to 37 per cent), and a five per cent rise in 20-24 year olds (from 13 to 18 per cent). Children under 14 taking part in trials rose by six per cent (from 52 to 58 per cent).

This rise was due to the increase in availability and access to trials for young people, increased awareness from healthcare professionals, patients and the public about research and importantly the opening of trials with broader age limits which allow older teenagers and young adults to enter trials.

Fern added, “By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

Previously: High rates of incarceration among black men could be skewing study results, Stanford researchers examine disparities in use of quality cancer centers and NPR explores the need for improving diversity in clinical trials

Clinical Trials, Nutrition, Parenting, Pediatrics, Research, Women's Health

Stanford study investigates how to prevent moms from passing on eating disorders

Stanford study investigates how to prevent moms from passing on eating disorders

veggie-stirfryResearchers have known for some time that women who have previously had eating disorders face a special set of challenges when they begin feeding their own children: They may unintentionally pass on problematic eating behaviors to their kids.

Now a Stanford research team is studying how to help these moms. They are recruiting families with a child between the ages of 1 and 5 whose mother had anorexia nervosa, bulimia nervosa or binge-eating disorder in the past. In the 16-week study, the researchers will work with both the mother and her partner to build healthy family interactions around food.

From our announcement about the study:

“The data on feeding practices of mothers who have had eating disorders are very worrying,” said Shiri Sadeh-Sharvit, PhD, a visiting scholar at Stanford who is leading the new study. “These mothers are good parents who want only the best for their children, but they struggle with eating-disorder thinking. It’s something that comes and blurs their parenting.”

Prior research has shown that mealtime conflict is more common in families in which the mother has had an eating disorder. These mothers may overfeed or underfeed their children, though underfeeding is more predominant. They also have more difficulty recognizing hunger and fullness cues in themselves and their children, which makes it harder for them to help their kids learn to respond to these sensations. Children whose mothers have had eating disorders are more likely than other kids to be dissatisfied with their bodies and engage in emotional eating, binge eating or restrictive eating.

Sadeh-Sharvit is collaborating with James Lock, MD, PhD, who has a long track record of demonstrating the effectiveness of eating-disorder treatments that involve the patient’s family in the treatment process.

Local families who are interested in participating in the research can contact Sadeh-Sharvit at (650) 497-4949 or shiri_sade@yahoo.com for more information. Stanford’s Eating Disorders Research Program also maintains an online list of all of their eating-disorder studies that are currently seeking participants.

Previously: Promoting healthy eating and a positive body image on college campuses, A growing consensus for revamping anorexia nervosa treatment and Story highlights need to change the way we view and diagnose eating disorders in men
Photo by Indiana Public Media

Stanford Medicine Resources: