Published by
Stanford Medicine

Category

Clinical Trials

Clinical Trials, Fertility, NIH, Research, Women's Health

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Primary ovarian insufficiency (POI), a condition affecting approximately 1 percent of women and teenage girls in the U.S., is characterized by ovaries that stop functioning normally before a woman is 40. POI may be a cause for irregular periods, reduced fertility, or health problems such as osteoporosis, and women with POI may also be at risk for depression and decreased quality of life. Treatments for POI may include hormone replacement therapy to restore estrogen and progesterone levels.

A recent study from the National Institutes of Health Clinical Center has examined the effect in women with POI of one year of hormone treatment that included testosterone.

From a release:

In the randomized, double-blind, placebo controlled study, 61 women used placebo patches and 67 women used patches that delivered 150 micrograms of testosterone a day, similar to the Intrinsa patch that was rejected by FDA as a treatment for low sexual desire in women.

After 12 months, testosterone levels were back up to normal for the women who got the treatment. The investigators saw no detrimental effects of testosterone, but they found no significant improvement either in measurements of quality of life, self esteem and mood compared with placebo.

Bringing testosterone back to normal doesn’t help these aspects of life, suggesting that it’s something other than testosterone that plays a role in mood problems for women with POI, concluded the researchers.

“This study makes an important contribution toward understanding what testosterone can and cannot do. With all the hype about testosterone and aging, it is important that the public have the facts,” NAMS Executive Director Margery Gass, MD, said in the release.

The study was published online in the journal Menopause.

Previously: An in-depth look at fertility and cancer survivorshipAsk Stanford Med: Expert in reproductive medicine responds to questions on infertility, Researchers describe procedure that induces egg growth in infertile women and Oh, baby! Infertile woman gives birth through Stanford-developed technique

Clinical Trials, In the News, Research, Science, Stanford News

The Lancet documents waste in research, proposes solutions

The Lancet documents waste in research, proposes solutions

Science is hard work. So hard, in fact, that it’s pretty disheartening to hear that much of that effort is wasted. A major series of research papers was published yesterday in The Lancet documenting five major causes of waste in research (if you’re interested, the culprits include inefficiencies in setting research priorities, inappropriate study design and analysis, problems in research regulation and management, a lack of accessibility of research results and incomplete or unusable reporting of data).

Stanford’s John Ioannidis, MD, DSci, who has studied the subject extensively, co-authored the accompanying commentary and the article “How to Increase Value When Research Priorities are Set.” He is also the first author of “Increasing Value and Reducing Waste in Research Design, Conduct and Analysis.” (Stanford health research and policy experts  Rob Tibshirani, PhD, and Mark Hlatky, MD, are senior and co-author, respectively, of the article.)

It’s not all doom and gloom, however. The series does suggest ways to overcome these seemingly pervasive obstacles. From the opening article:

How might things be different? One protection from these distorting drivers would be the creation of a set of balancing counter-influences. So, instead of being judged on the basis of the impact factors of the journals in which their work is published, academics might be judged on the methodological rigour and full dissemination of their research, the quality of their reports, and the reproducibility of their findings. If these factors were to contribute substantially to promotion, funding, and publication decisions, institutions might even go so far as to audit the performance of their staff and, when substandard, pay more attention to continuation of professional development and appraisal of the research workforce.

Previously “U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis, Shaky evidence moves animal studies to humans, according to Stanford-led study and Neuroscience studies often underpowered, say researchers at Stanford, Bristol

Clinical Trials, Neuroscience, Research, Stanford News, Surgery, Technology

Stanford conducts first U.S. implantation of deep-brain-stimulation device that monitors, records brain activity

Stanford conducts first U.S. implantation of deep-brain-stimulation device that monitors, records brain activity

DBS team - 560

Mark down October 30 and November 20, 2013, as medical mileposts.

On Oct. 30, a Stanford surgical team led by neurosurgeon Jaimie Henderson, MD, implanted a next-generation deep-brain-stimulation (or DBS) device into a Parkinson’s disease patient’s brain. On the order of 100,000 nearly but not quite identical procedures have been performed worldwide in the past decade or so, to relieve symptoms of not only Parkinson’s but epilepsy, chronic pain and more. Making what took place just over a month ago unique wasn’t the surgery itself but, rather, the nature of the device that was implanted – the first time ever in the United States. (In August, a patient in Germany received such a next-generation DBS device, although for a different indication.)

With current DBS technology, a fine, insulated wire is threaded into the brain so that its lead, containing four electrodes, impinges on the relevant brain area. (In Parkinson’s, for instance, the targeted area would be key brain regions that participate in the generation of spontaneous involuntary tremors characteristic of that disease). In a second procedure, a pacemaker-like device called a neurostimulator is placed under the skin, typically near the collarbone. The neurotransmitter transmits signals – at frequencies, amplitudes and durations programmed by a neurologist – to the leads, which accordingly fire electrical impulses counteracting the aberrant brain signals producing the physical symptoms in question. Over time, the neurostimulator’s impulse-transmission pattern is optimized via a trial-and-error process involving extensive patient-neurologist interaction.

Stanford neurologist and Parkinson’s specialist Helen Bronte-Stewart, MD, routinely sees patients a few weeks after their DBS devices have been implanted. They come in having not taken their medications for a while, so she can observe their symptoms and watch how they respond to different DBS frequencies and intensities.

But the new device, manufactured by the same company (Medtronic, Inc.) that makes the existing one, has an additional capability. It can not only transmit signals to the brain but, in addition, monitor and record the brain region of interest’s electrical output.

This will let Bronte-Stewart remotely capture vast amounts of information about a particular patient’s brain-firing patterns to discern that patient’s “neural signature” – and ultimately, it is hoped, be able to develop algorithms for automating the device’s signaling program so that it changes in response to changes in brain activity. (The goal, in engineering vocabulary, is a “real-time negative-feedback loop.”)

On Nov. 20, after recovering from the surgery, the patient and Bronte-Stewart, a noted expert in movement disorders, embarked on the first of a series of groundbreaking sessions during which Bronte-Stewart will download data from the implanted device for thorough analysis. While brain-activity data has been downloaded from Parkinson’s patients while they’re lying still on the operating table after the initial electronic-lead implantation, the recorded data has by necessity reflected only activity in the brain while the patient is at rest. Now Bronte-Stewart will be able to identify the neural signatures of not only the resting state but also voluntary movement, task performance and the tremor itself, and to see how those neural signatures change in response to her manipulations of DBS frequency and voltage output.

Stanford has received 10 of the new “two-way” DBS devices from Medtronic, and is recruiting Parkinson’s patients who, while they may not benefit directly from the ongoing study, wish to make a difference in how this disease’s symptoms are treated.

Previously: Revealed: The likely role of Parkinson’s protein in the healthy brain, Mind-reading in real life: Study shows it can be done (but they’ll have to catch you first), Positive results for deep-brain stimulation trial for epilepsy and Stanford neurologist discusses advances in research on movement disorders
Photo courtesy of Jaimie Henderson

Autism, Clinical Trials, Neuroscience, Pediatrics, Research, Stanford News

Volunteers sought for autism drug study

Volunteers sought for autism drug study

There is no known cure for autism, and there are no medications approved for treating the social aspects of the condition, such as difficulty interpreting nonverbal cues in face-to-face conversations, or maintaining eye contact.

The only medications approved for treating autism are antipsychotics, which don’t target the social deficits.

But efforts are underway to explore whether certain molecules used by neurons in the brain to communicate with one another - called neuropeptides – might have a moderating effect on some of the behavioral traits that characterize autism.

I recently talked with Dean Carson, PhD, a postdoctoral research fellow in the Department of Psychiatry and Behavioral Sciences, who told me that one neuropeptide, oxytocin, is currently being studied as a treatment for autism in a number of studies around the world. Some early stage, single dose trials showed oxytocin was effective in moderating the social deficits of people with autism, but so far subsequent studies haven’t produced a consensus.

Carson also told me about a study that he’s involved with looking at another neuropeptide, vasopressin, which is closely related to oxytocin. Carson thinks vasopressin has some promise, as it’s been shown to enhance social functioning in laboratory mice with a genetically induced form of autism. It’s already approved for use in humans by the FDA and has been shown to improve social cognition and memory in people who do not have autism.

Researchers are currently seeking volunteers – children ages 6 to 12 years old - for this trial. If you’re located near Stanford and interested in learning more, this link provides details. I also explain more in a press release.

Previously: Greater hyperconnectivity in the autistic brain correlates to greater social deficits, More Stanford findings on the autistic brain, Director of Stanford Autism Center responds to your questions on research and treatment and New autism treatment shows promising results in pilot study

Cancer, Clinical Trials, Research, Stanford News

Guidance on improving Asian-American participation in cancer clinical trials

Guidance on improving Asian-American participation in cancer clinical trials

Much has been written about the need to involve more ethnic minorities in clinical trials. Now, the Stanford Cancer Institute is offering help to researchers in the form of a free online course called “Practical tips to improve Asian American participation in cancer clinical trials.” As described on the course website:

Racial and ethnic diversity is critical to the success of cancer clinical trials. Asian Americans, like other ethnic groups, have low recruitment, accrual and retention rates in cancer clinical trials. This represents a significant challenge on a national level for health advocates, healthcare institutions and the National Cancer Institute… This online course will educate healthcare providers and allied health professionals about cancer clinical trials and cultural humility skills as well as provide educational resources and tips for reinforcing change in practice to improve outcomes in Asian American clinical trial participation.

Kim Rhoads, MD, MPH, is director of the course, which can be taken for Continuing Medical Education (CME) credit. Rhoads’ research focuses on racial disparities in cancer outcomes, a topic she addressed during a 1:2:1 podcast a few years back.

Previously: NPR explores the need for improving diversity in clinical trials, Survey confirms that small number of U.S. adults, children participate in research studies, Patients share clinical trial experiences at Stanford, What motivates people to participate in clinical trials?, Not enough cancer doctors refer patients to clinical trials

Cancer, Clinical Trials, Research, Stanford News, Women's Health

Common drug class targets breast cancer stem cells, may benefit more patients, says study

Common drug class targets breast cancer stem cells, may benefit more patients, says study

ab18038.jpg  Woman having a mammogramRecently there have been intriguing suggestions that breast cancer patients whose tumors appear insensitive to a class of drug known as anti-HER2 (the drug trastuzumab, marketed as Herceptin, is a well-known example) may somehow still benefit from treatment with the medication. Although there’s an ongoing clinical trial to determine if trastuzumab, given in combination with other treatments, really is beneficial to more patients than previously thought, the reason why it could be helpful is unknown.

Now research from the laboratory of Stanford radiation oncologist Max Diehn, MD, PhD, has started to answer some of these questions. The research was published recently in Cancer Research.

Typically, only tumors in which the cells express abnormally high levels of a receptor molecule on their surface called HER-2 — about 25 percent of all breast cancer cases — seem to shrink in the presence of the drugs, which bind to and inactivate the receptor. As a result, only these patients are given anti-HER2 agents. As Diehn explained in an e-mail:

Trials of anti-HER-2 agents like Herceptin in metastatic patients with HER-2 negative tumors haven’t shown tumor shrinkage or improved outcomes, which is why these drugs are only approved for use in HER-2 positive tumors. However, more recent clinical analyses have indicated that patients with microscopic disease remaining after treatment for earlier stage disease may see improved survival from anti-HER-2 agents regardless of their HER-2 status.

Diehn and Cleo Yi-Fang Lee, PhD, wondered why this could be. How could trastuzumab and other anti-HER-2 agents effectively fight tumors that didn’t overexpress HER-2? They hypothesized that perhaps the drugs were targeting only a few very important cells in the tumor: the cancer stem cells. Also called tumor initiating cells, or TICs, cancer stem cells are able both to renew themselves and to generate all the cells of the original tumor. Killing them is vital to ensure that a tumor does not recur after seemingly successful treatment with chemotherapy, radiation or surgery. Unfortunately, however, these cancer stem cells are uncommonly resistant to normal cancer therapies. According to Diehn:

Our hypothesis was that the clinical observations described above could be explained if the anti-HER2 drugs work against microscopic deposits of cancer stem cells in at least a subset of HER2-negative tumors. Patients with visible metastatic disease do not show responses since only a small proportion of cells in tumor deposits are cancer stem cells. However, if most of the tumor has been killed or removed through standard approaches, anti-HER-2 drugs may effectively target remaining cancer stem cells and possibly prevent recurrence.

To understand how this could occur, Diehn, Lee and their colleagues studied mouse and human breast cancer cells. They learned that, in a subset of HER-2-low tumors, the stem cells produce high levels of a molecule called neuregulin 1. Neuregulin 1 works by activating HER-2 in these cancer stem cells to promote their growth and self-renewal. Blocking HER-2 or another molecule in the pathway, EGFR, together or separately inhibited the growth of breast cancer cells grown in the laboratory and after transplantation into mice. It also made the stem cells more sensitive to the types of radiation used in cancer therapies.

The researchers hypothesize that a similar mechanism may exist in other types of cancers. Diehn said:

Anti-HER2 therapies are already being used for esophageal and gastric cancers and they have been explored for use in other cancers like those of the head and neck. It will be interesting to see if there is a similar dependence by cancer stem cells on HER2 signaling in the absence of HER2 amplification in some of these tumors.

Previously: Weakness in lung cancer stem cells identified by Stanford scientists and Red Sunshine: One doctor’s journey surviving stage 3 breast cancer
Photo by Tips Times

Chronic Disease, Clinical Trials, Stanford News

At risk for diabetes? Participants sought for study of vitamin D as treatment

At risk for diabetes? Participants sought for study of vitamin D as treatment

vitamin dTwenty research institutions – including Stanford – are recruiting 2,500 patients for the first large clinical trial testing vitamin D supplementation’s effectiveness in slowing the onset of type-2 diabetes.

So why vitamin D? As explained in a press release:

Vitamin D helps the body absorb calcium and is important for the functioning of bones, nerves, muscles and the immune system. Because the body needs sunlight to synthesize vitamin D, recent increases in vitamin D deficiency may be due in part to skin-cancer-prevention recommendations to limit sun exposure. Population-level studies have shown associations between low levels of vitamin D and type-2 diabetes, autoimmune diseases and cancer. But more research is needed to determine whether increasing vitamin D levels can help prevent such diseases.

Stanford researchers are hoping to enroll 150 participants for their portion of the trial, called d2d:

Participants should be at least 30 years old and have several risk factors for type-2 diabetes, including higher-than-normal results on fasting glucose and glucose-tolerance tests, as well as a body mass index in the overweight to obese range. For all eligibility criteria, visit http://www.d2dstudy.org.

Study participants will take 4,000 international units of vitamin D per day, which is above the typical intake of 600-800 IU but considered safe based on other studies. Participants randomized to the control group will receive a placebo. Glucose tolerance will be monitored every year to test for progression to type-2 diabetes. The study is expected to continue for about four years, or until enough participants have developed diabetes to gauge the effect of vitamin D.

Previously: Nature/nurture study of type 2 diabetes risk unearths carrots as potential risk reducers, Critically ill kids often vitamin D deficient, study finds, Avoiding sun exposure may lead to vitamin D deficiency in Caucasians and What’s the deal with vitamin D?
Photo by bradley j

Clinical Trials, Events, Medicine X, Stanford News, Videos

Videos from Medicine X now available

Videos from Medicine X now available

One of the challenges presented by Stanford Medicine X, said an attendee sitting next to me last weekend, was having to select only one session to attend when multiple choices were offered at a time. Fortunately, Medicine X is a technology conference, and the organizers filmed and uploaded footage of many sessions as well as supplementary material on their YouTube channel. You can watch Jack Andraka‘s opening keynote and Vinod Khosla‘s closing address, The Buzz interviews by Hayley Goldbach with participants, and panel discussions such as #Whatifhc.

In the video above, Roni Zeiger, MD, Google’s former chief health strategist, explains how he developed Smart Patients to connect people to information and each other. ”The most important thing about the design of this product, this platform, is that it’s meant to enable people to learn not just from those that are within their defined community, their label, but across silos,” Zeiger said. Much like Medicine X.

More news about Stanford Medicine X is available in the Medicine X category.

Previously: “You belong here”: A recap of Stanford Medicine XLive tweeting Jack Andraka’s Medicine X keynoteMedicine X’s “What if health care…” seeks tweets and How a “culture of permission” prevents doctors from being active in social media

Cancer, Clinical Trials, Mental Health, Research, Science, Stanford News

Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study

Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study

applesandorangesMy colleague Bruce Goldman has written elegantly here before about how large biological databases (a phenomenon commonly known as “big data”) are a treasure trove of information – for those who know where to look for it. Bruce has referred to the computerized technique, which pairs existing drugs with human diseases (sometimes vastly different from the conditions for which the drugs were originally developed) as a molecular Match.com. And although the hook-ups are sometimes apples-and-oranges odd, they’re showing lots of promise.

Last night, Stanford researchers Atul Butte, MD, PhD, and Julien Sage, PhD, published a study in Cancer Discovery (subscription required) describing how they’ve used this algorithm developed in the Butte lab to identify a possible new treatment for small cell lung cancer, which is particularly deadly. And because the drug, an antidepressant called imipramine, is already approved by the Food and Drug Administration for use in humans, they’ve been able to quickly and (relatively) inexpensively move into human trials.

As Butte, the director of the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital at Stanford described in our release:

We are cutting down the decade or more and the $1 billion it can typically take to translate a laboratory finding into a successful drug treatment to about one to two years and spending about $100,000.

How exactly does it work? More from our release:

The pipeline works by scanning the hundreds of thousands of gene-expression profiles (gathered by multiple researchers and stored in large databases) across many different cell types and tissues — some normal and some diseased, some treated with medications and some not. Alone, these profiles may not mean much to any one investigator or group, but when viewed together, researchers can pick out previously unsuspected patterns and trends.

For example, if a particular molecular pathway is routinely activated (as indicated by an increase in the expression levels of the genes involved) in a cancer cell, and a drug is shown to block or suppress that same pathway (by decreasing the expression of genes in the pathway), it’s possible the drug could be used to treat that type of cancer — regardless of the disease for which it was originally approved.

Continue Reading »

Behavioral Science, Clinical Trials, Research, Science Policy, Stanford News

“U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis

"U.S. effect" leads to publication of biased research, says Stanford's John Ioannidis

pressuregaugeThe life of a scientist can be filled with pressure – pressure to publish, pressure to obtain funding, pressure to support the people in his or her lab. It’s no surprise that some would-be researchers *cough, me, cough* choose instead to pursue other careers (science writing FTW!).

Now new research by Stanford study-design expert John Ioannidis, MD, DSc, and Daniele Fanelli, PhD, from the University of Edinburgh, suggests that such pressures may lead to more than just sleepless nights. Their results, published today (subscription required) in the Proceedings of the National Academy of Sciences, conclude that, at least in areas of “soft” science that measure behavioral changes, studies with researchers from the United States are more likely to report that the intervention they were testing had an extremely positive outcome than studies whose authors hail from elsewhere. As Ioannidis explained to me last week:

One possible explanation for the pattern that we are seeing is that scientists from the United States are under higher pressure to generate extreme results. This could be for various reasons: to obtain funding, to justify a promotion or to advance one’s career.

Ioannidis isn’t suggesting that scientists are falsifying their results intentionally. Rather, some fields of research are more difficult to quantify than others. “In the behavioral sciences, results are presented with more leeway and creativity than in other ‘hard’ sciences like genetics, when, for example, there’s less room for error when sequencing a gene,” he explained.

For the study, the researchers analyzed more than 1,000 primary outcomes of 82 meta-analyses published in genetics or psychiatry published between 2009 and 2012. And, as Ioannidis points out, things could have changed since that time:

Our study shows what has happened in the past. It’s possible that this phenomenon is becoming more global. Unfortunately, there’s no “investigative pressure meter” we can use to directly compare the policies governing scientific research in various countries.

Previously: Shaky evidence moves animal studies to humans, according to Stanford-led study, Neuroscience studies often underpowered, say researchers at Stanford, Bristol and NIH funding mechanism “totally broken,” says Stanford researcher
Photo by William Warby

Stanford Medicine Resources: