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Clinical Trials, Imaging, Neuroscience, Research, Stanford News, Women's Health

Estradiol – but not Premarin – prevents neurodegeneration in women at heightened dementia risk

Estradiol - but not Premarin - prevents neurodegeneration in women at heightened dementia risk

bottle of pillsWomen near the age of menopause and at elevated risk for dementia – owing, say, to a family history of Alzheimer’s disease, a personal history of major depression, or a genotype positive for the infamous Alzheimer’s-predisposing gene variant, ApoE4 – may want to consider talking to their doctor about estrogen-based hormone therapy.

In a brain-imaging study just published in PLOS ONE, hormone therapy protected key “early warning” brain regions from metabolic decline in women who fit that description – but only if they started therapy shortly after reaching menopause, and only if the pill they took contained just estradiol, the dominant female sex-steroid hormone. Premarin, a more widely used hormone-therapy formulation derived from the urine of pregnant mares, was far less protective.

Premarin contains more than 30 substances, with estradiol accounting for only about 17 percent. Other components exert various endocrinological effects on different tissues. In my release on the new study, I wrote:

More than 20 million women in the United States are between 45 and 55 years old – an age range at which many once were considered prime candidates for Premarin. Hormone therapy… was… widely heralded as protecting postmenopausal women from heart disease, osteoporosis and even cognitive decline.

Indeed, from 1992 through 2001 Premarin was the most widely prescribed drug in the United States. Then came the deluge. Here’s the backstory:

In July 2002, a large multicenter study of hormone therapy’s effects was abruptly halted when – contrary to expectations – woman assigned to PremPro (Premarin plus progestin, a synthetic version of progesterone, another important female steroid hormone) developed more cardiovascular disease than those getting a placebo. Within 18 months, about half of American women who’d been on hormone therapy abandoned it. Its use has since plunged considerably further.

Then in 2003, an ancillary study called WHIMS (“Women’s Health Initiative Memory Study”) reported that dementia incidence among 65- to 79-year-old women randomly assigned to PremPro was double  that of women on placebo. This disappointing finding was widely covered in the media.

But Rasgon and her colleagues’ findings are consistent with other analyses indicating that women initiating hormone therapy within five years of their last menstrual cycle experienced beneficial brain effects. In fact, major differences in trial design may explain the discrepancy between WHIMS’s decidedly negative results and the new study’s more nuanced ones.

The WHIMS women were older, on average, than those in Rasgon’s study and were beginning hormone therapy after a long hiatus during which their bodies were no longer producing substantial quantities of estrodiol. Moreover, the PremPro given to women in the active arms of WHIMS contained progestin – which, the new study shows, speeds metabolic deterioration in at least dementia-prone women’s brains.

Natalie Rasgon, MD, PhD, director of the Stanford Center for Neuroscience in Women’s Health and the study’s lead author, puts it plainly. “Hormone therapy’s neurological effect on women at risk for dementia depends critically on when they begin therapy and on whether they use estradiol or Premarin.”

Previously: Hormone therapy halts accelerated biological aging seen in women with Alzheimer’s genetic risk factor, Hormone therapy soon after menopause onset may reduce Alzheimer’s risk and Study shows common genetic risk factor for Alzheimer’s disrupts brain function in healthy older women, but not men
Photo by Canned Muffins

Clinical Trials, Immunology, Pediatrics, Research, Stanford News

Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows

Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows

milk and eggsLiving with one food allergy is a challenge; living with more than one can make ordinary activities such as eating at a restaurant feel downright impossible.

That’s because the standard medical advice for the 4 million Americans with food allergies is to avoid all of your allergy triggers, all the time – and, by the way, make sure you always carry injectable epinephrine in case you accidentally eat something contaminated with a food that triggers anaphylactic shock.

So it will be welcome news to these food-allergy sufferers to hear that a Stanford team is making progress on a new way to help them. In research published today in the journal Allergy, Asthma & Clinical Immunology, a team led by Kari Nadeau, MD, PhD, found that an experimental treatment already being widely tested for single food allergies, called oral immunotherapy, could be modified so that patients can be desensitized to multiple food allergens at the same time. The results now being reported are the products of a pair of phase-1 safety trials.

In our press release about the findings, Nadeau explained why she wanted to develop the new therapy:

“Parents came up to me and said things like, ‘It’s great that you’re desensitizing children to their peanut or milk allergies, but my daughter is allergic to wheat, cashews, eggs and almonds. What can you do about that?’” said Kari Nadeau, MD, PhD, associate professor of pediatrics at the medical school and an immunologist at Stanford Hospital & Clinics and Lucile Packard Children’s Hospital Stanford. Nadeau is the senior author of the new study.

… [O]ral immunotherapy is still experimental and quite slow: In prior studies, patients took as long as three years to become desensitized to one food. Being desensitized to several foods, one at a time, could prospectively take decades. Yet Stanford researchers succeeded in safely desensitizing patients to several food allergens at once and were able to speed up desensitization by supplementing oral immunotherapy with injections of omalizumab (brand name Xolair).

With omalizumab, patients were desensitized to up to five of their allergens in a median of 18 weeks; without the medication, the same process took a median of 85 weeks, the research team found. The published results add weight to the anecdotal findings from three of Nadeau’s patients who participated in the trial and shared their experience in a story in the New York Times magazine last spring.

The researchers stress that the treatment is still experimental and must be performed in a hospital setting, but they are excited by the next step in the process: a phase-2 trial to evaluate the therapy more rigorously in a larger number of patients. The phase-2 trial will be conducted at Stanford, where recruitment of new patients has already begun, and at four other centers across the country, which will begin recruiting patients in the coming months. Individuals who are interested in learning more about participating in the new studies can check the federal clinical trials website for opportunities in their region.

Previously: Researchers show how DNA-based test could keep peanut allergy at bay, A mom’s perspective on a food allergy trial and Searching for a cure for pediatric food allergies
Photo by Logan Brumm Photography and Design

Clinical Trials, Genetics, In the News, Stanford News

Huntington’s therapy discovered at Stanford shows positive results in humans

Huntington's therapy discovered at Stanford shows positive results in humans

There are definite perks to sticking with the same job for several years. For me, it means the chance to see the progression of research findings I first wrote about in their infancy actually enter human testing. Last week Raptor Pharmaceuticals, based in Novato, Calif., reported positive results in a clinical trial of a possible treatment for Huntington’s disease called RP103. RP103 is a delayed-release cysteamine – a compound first identified in 2002 as a potential therapy in the Stanford laboratory of Lawrence Steinman, MD. As I wrote in my release at that time (courtesy of the way-back machine):

By enhancing the brain’s natural protective response to the disease, researchers were able to alleviate the uncontrollable tremors and prolong the lives of mice with a neurological disorder that mimics Huntington’s. Their finding suggests that a similar treatment strategy may be effective in humans.

Raptor (a company which Steinman advises and in which he holds stock options) enrolled 96 patients in an 18-month-long double blind trial pitting RP103 against a placebo, followed by an 18-month period in which all the participants would receive RP103. Eighty-nine patients completed the first 18-month period; those who received the drug appeared to show slower progression in their disease than those who received the placebo.

It will likely still be years before we know whether the potential treatment will clear the necessary hurdles and become clinically available. But as Steinman said to me in a e-mail last week, “It’s very exciting to see this moving forward in humans.”

Previously: Drug found effective in two mouse models of Huntington’s disease, Amyloid, schmamyloid: Stanford MS expert finds dreaded proteins may not be all bad and Potential therapeutic target for Huntington’s disease discovered by researchers in Taiwan, Stanford

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

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