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Clinical Trials

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

Clinical Trials, Health Disparities, Medicine and Society, Research

High rates of incarceration among black men could be skewing study results

High rates of incarceration among black men could be skewing study results

prison bars

Few headlines have grabbed my attention like this one did today: “Doctors can’t research the health of black men, because they keep getting sent to prison.” The Vox article focused on a new Yale study that, in the words of writer Dara Lund, “suggests that some of the biggest medical studies of the last few decades may have seriously distorted data on African-American men.”

For the study, researcher Emily Wang, MD, MAS, and colleagues examined fourteen long-term trials that began enrolling participants between 1972-2000. They concluded that the high rates of incarceration among black men at this time (as of 2001, one in six black men had been incarcerated) “may have accounted for up to 65 percent of the loss to follow-up among black men in these studies.” Why is this important? As the researchers describe in the paper, which appears in Health Affairs:

The implications of having a disproportionate number of black men drop out of prospective cohort studies because of incarceration are significant, even though the differences between loss to follow-up are not always large or significantly different between black men, white men, black women, and white women. Conditions such as cardiovascular disease and sickle cell disease are more common in black men than in white men and have complex factors that influence morbidity and mortality. This makes it important for analysts to have access to a large number of cases so that they can adjust for possible confounders.

And:

The likely high association between imprisonment and being lost to follow-up in these studies may yield underpowered and biased estimates for black men. Furthermore, participants who are incarcerated are more likely to be sick than are participants who have never been incarcerated. This difference increases the likelihood that disease rates and progression of disease in blacks and black-white disparities will be underestimated.

One possible solution, Wang and her co-authors note, is for incarcerated people to be allowed to continue their participation in a study. But Lind reports that “for now, there doesn’t appear to be much momentum behind [this].”

Previously: NPR explores the need for improving diversity in clinical trials, Study shows deaths from acute leukemia higher in minority patients, A conversation with Augustus White, a pioneer for underrepresented minorities and Surgeon’s memoir calls for an end to health disparities
Photo by Martin Fisch

Chronic Disease, Clinical Trials, Pediatrics, Research

New research shows how to keep diabetics safer during sleep

New research shows how to keep diabetics safer during sleep

sleeping girlLife with type 1 diabetes requires an astonishing number of health-related decisions – about 180 per day. But patients’ vigilant monitoring of their daytime blood sugar, food intake, insulin and activity levels is perhaps less exhausting than the worries they face about getting a safe night’s sleep. During sleep, diabetics often fail to sense when their blood glucose veers too low. Low blood sugar levels can cause seizures and even, in rare cases, death.

“At night you lose control,” said Bruce Buckingham, MD, a pediatric endocrinologist who treats children with diabetes at Lucile Packard Children’s Hospital Stanford. “It’s when things can happen.” Among children with diabetes, about 75 percent of hypoglycemic seizures occur at night, he said.

That’s why Buckingham and his colleagues across the United States and Canada have been testing various methods to automate blood sugar control during sleep. Our press release on their new research describes an approach that could make a big difference – automated shut-offs of patients’ insulin pumps to keep their sugar levels above the hypoglycemia danger zone:

The new study, which [appeared] online May 7 in Diabetes Care, coupled a glucose sensor worn under the skin to an insulin pump that was connected wirelessly to a computer at the bedside. The computer ran an algorithm that calculated when a low blood-sugar level might occur and then temporarily suspended insulin delivery until the sugar level was trending upward. This occurred without waking the patient. The shutoffs reduced the cumulative time patients spent with low blood sugars during sleep by 81 percent, with only a minimal increase in nighttime glucose levels.

“A system like this should dramatically decrease diabetics’ risk of having a seizure overnight,” said Bruce Buckingham, MD, professor of pediatric endocrinology at Stanford, who led the trial and is a co-author of the study. “Patients and parents will be able to have a better night’s sleep, knowing that there is a much lower risk of severe hypoglcyemia at night.”

During the study, the researchers monitored close to 2,000 nights of sleep in 45 people with type 1 diabetes. The patients, who were 15 to 45 years of age, slept in their own homes and didn’t know ahead of time which nights their insulin pumps could be shut off by the computer and which nights their pumps operated normally. Several measures of hypoglycemia indicated that patients were safer on treatment versus control nights. Morning blood sugar levels were slightly higher after treatment nights, but still within the healthy range.

To get a sense of what the results mean for patients and their families, I spoke with Jack Leguria, whose 14-year-old daughter, Rosa, has had type 1 diabetes for almost 10 years. Rosa participated in the second phase of Buckingham’s research, which is now testing whether the benefits his team documented for older teenagers and adults will extend to children as young as 3. Seeing the new technology in action was exciting for Rosa and her parents.

“This is going to be life-altering for us,” Leguria said. “In four years, Rosa will be ready for college. For a child with type 1 diabetes who is not able to recognize low blood sugar at night, that’s a very difficult prospect for us.”

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Applied Biotechnology, Clinical Trials, FDA, Public Health, Research, Stanford News

The best toxicology lab: a mouse with a human liver

The best toxicology lab: a mouse with a human liver

of mice and menA few years ago, Stanford pharmacogenomic expert Gary Peltz, MD, PhD, collaborating with researchers in Japan, developed a line of bioengineered mice whose livers were largely replaced with human liver cells that recapitulate the architecture and function of a human liver. Now, in a recent study published in PLoS Medicine, Peltz’s team has shown that routine use of this altered lab mouse in standard toxicology tests preceding clinical trials would save human lives.

Among the liver’s numerous other job responsibilities, one of the most important is chemically modifying drugs in various ways to make them easier for the body to get rid of. But some of those chemical products, or metabolites, can themselves be quite toxic if they reach high levels before they’ve been excreted.

The Food and Drug Administration requires that prior to human testing, a drug’s toxicological potential be assessed in at least two mammalian species. But we humans metabolize things differently from other mammals, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen liver toxicity, said Peltz, a former pharmaceutical executive who is intimately familiar with established preclinical testing procedures in the industry.

That’s what happened in 1993 when, after a short safety trial of a drug called FIAU concluded without incident, the comp0und was placed in a phase-2 clinical trial of a drug for hepatitis B. FIAU belongs to a class of drugs that can interfere with viral replication, so it was considered a great candidate for treating virally induced infections such as hepatitis B.

As I wrote in my release about the new study:

“FIAU was supposed to be a revolutionary drug,” Peltz said. “It looked very promising in preclinical tests. In phase 1, when the drug was administered to subjects for a short period of time, the human subjects seemed to do fairly well.” But the phase-2 trial was stopped after 13 weeks, when it became clear that FIAU was destroying patients’ livers.

In fact, nearly half the patients treated with FIAU in that trial died from complications of liver damage. Yet, before advancing to clinical trials FIAU had been tested for as long as six months in mice, rats, dogs and monkeys without any trace of toxicity. An investigation conducted by the National Academy of Sciences later determined that the drug had shown no signs of being dangerous during those rigorous preclinical toxicology tests.

In Peltz’s new study, though, FIAU caused unmistakable early signs of  severe liver toxicity in the bioengineered mice with human livers. This observation would have served as a bright red stop signal that would have prevented the drug from being administered to people.

Bonus item: Using bioengineered mice with human livers instead of mice with murine ones would no doubt result in the clinical and commercial success of some drugs that never got to the human-testing stage because they caused liver toxicity in mice.

Previously: Fortune teller: Mice with ‘humanized’ livers predict HCV drug candidate’s behavior in humans, Alchemy: From liposuction fluid to new liver cells and Immunology escapes from the mouse trap
Photo by erjkprunczyk

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