Category Archives: Medical Genetics

A Younger Kennedy’s Mental Health Crusade

Patrick J. Kennedy is no longer in Congress, but he’s still campaigning passionately on behalf of mental health. In a plenary talk at the annual meeting of the American Association for Geriatric Psychiatry (AAGP), the former democratic congressman from Rhode Island described his recent mission: An organization he founded called One Mind for Research, which “brings together the science, technology, financial resources, and knowledge required to create an unprecedented understanding of brain disease.” Its goal is to increase the investment in research by $1.5 billion each year for the next 10 years and to achieve a minimum 10% reduction in the cost of brain disease per year.

Courtesy of AAGP

The initiative was launched last May 25th on the anniversary of his uncle John F. Kennedy’s “Moonshot” speech, at the suggestion of his cousin Caroline. He said he told her at the time, “Great, instead of going to outer space, we’ll go to inner space!”

On a more serious note, Mr. Kennedy drew a parallel between President Kennedy’s focus on civil rights as a moral issue and the cause of the mentally ill, telling the audience of psychiatrists “What you all do in the field of mental health is to help lessen the marginalization of too many Americans…I think we have a historic opportunity now, with the implementation of the Mental Health Parity Bill and the [Affordable Care Act] to break down the segregation of mental health from overall health.”

Referencing his own struggles with substance abuse, depression and bipolar disorder and his role in Congress as chief sponsor of the parity bill, Mr. Kennedy decried the current insurance reimbursement system as being “wholly inadequate” for treating chronic mental conditions. “If we treated diabetics the way we treat alcoholics and addicts, we’d be waiting till we were cutting off their toes and they’d lost their eyesight before we paid for treatment,” he said, to applause.

He was equally emphatic regarding the politics involved in securing funding for One Mind’s 10-year plan. “If you consider how much money we put into neuroscience today compared to the burden of [mental] illness, any CEO in the country would be kicked out of their job for not doing enough research…it just doesn’t compute,” he said, again to applause.

He acknowledged there would be challenges. “I can’t tell you we’re going to be successful, but at least I’m going to do my part to see that we try something different.”

The AAGP plenary session was supported in part by an educational grant from Lilly USA, LLC.

-Miriam E. Tucker (@MiriamETucker on Twitter)

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SABCS: Paging Biomarkers STAT

Image courtesy of NIH (public domain)

The CLEOPATRA, BOLERO-2, and AVEREL trial results generated a lot of excitement (and confusion) in San Antonio at the annual Breast Cancer Symposium. Since the results were finally released,  these trials have been hot topics.  There’s good reason.

In the CLEOPATRA trial, the addition of pertuzumab to trastuzumab and docetaxel in previously untreated patients with HER2-positive metastatic breast cancer extended progression-free survival (PFS) by 6 months compared with trastuzumab and docetaxel alone. In BOLERO-2, the combination of everolimus and exemestane extended PFS by 4 months (local review) and by 7 months (central review) in women with ER-positive, HER2-negative breast cancer that is refractory to non-steroidal aromatase inhibitors. In AVEREL, the addition of bevacizumab to trastuzumab and docetaxel in women with HER2-positive, locally recurrent metastatic breast cancer also improved PFS — by 2.8 months (local assessment) and by 2.9 months (central assessment).

This is all great news but biomarkers to identify the patients who actually benefit the most from these new regimens would be even better news. All three presenters at one press conference — Dr. Luca Gianni, Dr. Gabriel Hortobaygi, and Dr. Jose Baselga — stressed the need for these tools. All three of these trials involved exploratory components to assess potential biomarkers to predict response.

“The common theme … of our three studies is that we have a challenge with the development of new drugs in identifying biomarkers that will determine which is the group that can be enriched and will derive the lion’s share of the benefit of adding drug X,” said Dr. Hortobaygi. “None of our new drugs in this panel has such a biomarker as yet. There is much work being done in all three studies to try to identify biomarkers that will help us to do that,” he said.

“That continues to be one of the major challenges for bevacizumab. We did not have a biomarker that can tell us that we can treat less than 100% of patients to observe the benefit. I think that most of us on this panel believe that most of these drugs provide benefit to a subset of patients and not to everybody. That is an ongoing challenge and we really need to invest in and redouble our efforts, so that we can develop those biomarkers,” he added.

Dr. Gianni told me that a biomarker for bevacizumab seriously could help with drug development. “If there was a biomarker, this combination could become very, very promising and would deserve analysis, head to head with other very active treatments in the case of HER2-positive disease.”

Image courtesy of NIH (public domain)

Dr. Howard A. Burris III told me that it makes sense based on what we already know that not every patient will benefit from the same treatments. “We know that not all ER-positive women are the same. The BOLERO-2 trial looked at adding the mTor inhibitor everolimus to exemestane in patients with ER-positive breast cancer. [However], you’ve got patients that have 10% ER overexpression and some that have 100%. Then you’ve got groups of patients who relapsed after the adjuvant therapy, so they didn’t have a long-lived response, and some that have had d great response in the metastatic setting. Those patients are not at all alike,” he said.

“I think we’re going to find that there isn’t this one size fits all and I think that the closer we get to this idea of having a panel — where you’re going to find out what the various overexpressions are for these patients — the clearer we’re going to be about who should get what.” Dr. Burris is the chief medical officer and the director of drug development at the Sarah Cannon Research Institute in Nashville.

“The primary toxicity, interestingly, for many of the new biologics is the financial toxicity. So it’s perfectly acceptable to give a relatively expensive therapy to the 10% of that it’s going to benefit greatly. The shame is that you can’t treat 10 patients to help that one patient who will benefit most. Somewhere in between is a societal decision,” Dr. Burris said.

“I think we’ve got to get closer to the idea that when a woman gets her original biopsy or surgery that you learn everything you can about that patient; then, at the time of relapse — if that’s unfortunate enough to occur –- if possible get a biopsy to see what’s changed; but if not, at least your first attempt in treating that relapse is going to be in the right direction. Identifying who’s the group at highest risk for relapse or who needs to stay on therapy longer are all going to be factors that are going to be important going forward,” said Dr. Burris.

Dr. Gianni noted that it’s easy to envision that these regimens potentially could be used earlier in the disease progression for women with breast cancer, who are identified by a biomarker to respond well to one of these regimens. It makes sense that these regimens could be used earlier for women identified by a biomarker to respond well to one of these regimen, he said.

Kerri Wachter

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Video of the Week: Has the Time Come for Genetic Testing of Early-Stage Lung Cancer?

Researchers have devised and validated an 11-gene expression test that can distinguish patients with stage I or II lung cancer who have a low, intermediate, or high risk for having micrometastatic disease after primary tumor resection that requires adjuvant chemotherapy. Our reporter Mitchel Zoler asked investigator Dr. Johannes Kratz to discuss the need for and strengths of the test.

The multigene assay can outperform conventional risk factors and staging, and may lead to personalized therapies for patients with early-stage nonsquamous non–small cell lung cancer. [Dr. Krause] 

You can read a more detailed analysis of the test and its implications on the  IMNG Oncology Digital Network.

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Whose Rights Are at Stake?

The Supreme Court heard arguments Tuesday in support of the 2007 Vermont statute limiting the release of the information detailing which drugs doctors prescribe. This information is maintained by pharmacies, which sell it to data-mining agencies, that in turn sell it to drug companies, for marketing purposes. Patient information is excluded from the data, doctor’s information is not.

Under the Vermont law, this information can be released only with the consent of the doctor. However, once data collection firms like IMS Health and interested parties like Pharmaceutical Research Manufacturers of America, challenged the statute, the issue became a question of free speech.

In the case of Sorrell v. IMS Health Inc., data-mining firms claim they have First Amendment rights to buy and sell the information for their marketing use.

However, the state’s attorney’s office likened the release of the confidential information to disclosing a doctor’s tax returns, patient files, or a competitor’s business information, arguing that First Amendment rights in the case apply to protecting doctor’s information. But since the information is given away to parties including insurance companies, journalists, and law enforcement, the court wasn’t too convinced.

” … just don’t tell me that the purpose is to protect their privacy,” said Justice Antonin Scalia. “[A doctor’s] privacy isn’t protected by saying you can’t sell it but you can give it away.”

Justice John Roberts said Vermont is trying to reduce health care costs by “censoring” information doctors hear about brand-name drugs, with the intent that they will prescribe more generics, a measure Justice Scalia added was a restriction on free speech.

Vermont Assistant Attorney General Bridget Asay responded that “the purpose of the statute is to let doctors decide whether sales representatives will have access to this inside information” on the prescribing habits of physicians.

Attorneys general of several states, the federal government, AARP, medical associations, privacy groups, and the New England Journal of Medicine have filed briefs in support of the Vermont statute, according to a brief by Cornell (N.Y.) University Law SchoolThe National Association of Chain Drug Stores, the Association of National Advertisers, the Associated Press, and Bloomberg have filed in support of the data mining firms.

In an age in which personal data can mined through social networks and search engines, this case could set the precedent concerning how much personal information can be used for marketing. A decision is expected by June.

 Tell us what you think. 

–Frances Correa (@FMCReporting on Twitter)

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Genetic Diseases Lurk in All Prospective Parents

A woman and a man with no personal or family history of a severe, recessive, childhood-onset genetic disease still face a roughly 1 in 1,500 chance of giving birth to a child affected by a severe, genetic disease simply due to the chance pairing of mutations that each parent unknowingly carries.

Genetic screen result showing deletion causing Lesch-Nyhan syndrome/courtesy Stephen Kingsmore and Science Translational Medicine

Will those odds motivate prospective parents to get themselves screened before conceiving a child, to learn whether they each carry a recessive mutation in the same gene?

It’s a choice that parents-to-be may soon face, thanks to a wide-ranging carrier screening test reported today by researchers at the National Center for  Genome Resources in Santa Fe and their associates.

The team, led by Dr. Stephen F. Kingsmore, report their findings with a test that screens for mutations in 448 different genes that can each lead to a severe, recessive childhood disease. Five of these diseases already have preconception screens that are usually offered to selected, higher risk people: fragile X, cystic fibrosis, Tay-Sachs disease, Canavan disease, and familial dysautonomia. By applying a panel of state-of-the-art genetic-testing technology, Dr. Kingsmore and his coworkers expanded their screening net to include 443 additional genes and diseases, including 142 metabolic disorders, 122 neurologic defects, 46 genes that affect development, 45 with cutaneous presentations, etc. In an interview, he told me that while today’s report focuses on screening 448 genes, the actual total now possible has grown to 580 different genes and resulting disorders. I’m sure over time the list will grow even longer.

In the current paper they applied the 448-gene screen to 104 people, and found that each person carried, on average, 2.8 mutations. Although several subjects had known genetic disorders, correcting for this skewing still produced the estimate that any adult carries, on average, 2.8 recessive gene mutations even if they appear completely healthy and have absolutely no personal or family history suggesting they might be a carrier. In short, everyone harbors some genetic flaws hidden within their cells that can unexpectedly appear in their children if their partner contributes a mutation in the same gene.

Mathematically, a recessive, genetic-mutation burden of 2.8 per parent out of 448 genes works out to a 1 in 25,000 risk for having an affected child, but the actual risk is much higher because everyone has some genetic skewing that boosts the risk. For example, people with Northern European ancestry have a 2.5% rate of carrying a mutated cystic fibrosis gene. As a result, the overall risk for any seemingly healthy couple with no affected family members is one in 1,500.

With a risk as significant as that, Dr. Kingsmore and his associates call for making preconception genetic screening available to everyone, not just those with a pedigree that seems to put them at higher risk. They also noted that the tests they ran cost $378 per person, a price that could drop with higher volume. But the cost of testing also must include the added fees for test interpretation, results reporting, and genetic counseling.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Remembering the Father of Erythropoietin

Biochemist Eugene Goldwasser, who had the drive and tenacity to spend more than 20 years isolating the first minute amounts of human erythropoietin, died at 88 last Friday, December 17. After Dr. Goldwasser and his lab staff isolated a few milligrams of the protein in 1977, he  eventually decided to collaborate with Amgen and in 1980 allowed them to start using some of his precious isolate to hunt for the gene. Amgen cloned the gene in 1985, and then began marketing the gene product as Epogen in 1989.

image courtesy of Flickr user with a hook

One of his colleagues at the University of Chicago, Dr. Donald Steiner, called Dr. Goldwasser’s isolation of erythropoietin a medical landmark similar in importance to the discovery of insulin. Although erythropoietin has gone through rocky times recently, with evidence of adverse effects curbing its use and dropping sales, the various marketed forms of  erythropoietin continued this year to tally billions of dollars in sales and substantial clinical benefits in patients with anemia.

I first learned of Dr. Goldwasser’s death in an obituary I read this morning, and subsequently I found several other pieces about him on the web. These include obits from the University of Chicago, The Chicago Tribune, The New York Times, and journalist Merrill Goozner, who wrote about Dr. Goldwasser’s work in a 2004 book on drug development. Also, a  remembrance by Dr. John Henning Schumann, a Chicago colleague and friend. Taken together, they sketch a committed, multi-faceted man motivated by a scientific challenge and a desire to help advance medical care.

For me, two nuggets from the write-ups standout. First is the vignette of of Dr. Goldwasser meeting a Japanese researcher in the lobby of Chicago’s Palmer House Hotel in 1975 to accept a modestly-sized box that inside held the dried concentrate of 2,550 liters of urine collected from patients with aplastic anemia. Over the next couple of years, Dr. Goldwasser and his associates purified from this gift a few milligrams of human erythropoietin, the first isolation of the human protein and a key step on the path toward cloning the gene and large-scale production.

Second is the poignant story of how both the University of Chicago and Dr. Goldwasser failed to patent erythropoietin, allowing Amgen to become the owner of this very valuable franchise. The University’s omission sounds like an oversight, but for Dr. Goldwasser it was a conscious decision to sidestep the fortune he could have claimed.

“Gene never profited from his discovery, the way that scientists and inventors now clamor to patent everything in sight,” wrote his friend Dr. Schumann. “He believed that his discovery should be shared with the public; after all, the government had funded his research career–he figured the taxpayers ought to get the benefit of his discovery.”

It was an act that recalls a more innocent era in biomedical research. Filing for patents “was not generally done at the time,” said his University of Chicago colleague, Dr. Gary Toback, who added, “He was someone who took enormous delight in doing science.” Soon after Dr. Goldwasser’s death his son said: “He was first and foremost a scientist and he was gratified that he was able to make such a great contribution.” For a person like that, the thrill of having his 20+ year quest fulfilled and seeing the subsequent impact erythropoietin had on clinical practice must have been payback enough.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Making Genotype a Routine Part of Drug Prescribing

Perhaps the boldest move to date to apply genotype information to drug prescribing, and to do it in a timely way to optimize the treatment a patient receives, launched in September at Vanderbilt University Medical Center in Nashville.

Vanderbilt physicians began routinely asking patients scheduled for coronary catheterization if they’d agree to have a small cell specimen genotyped using a commercially available chip that screens for 184 genetic polymorphisms that help determine the way a person metabolizes various prescription drugs. They decided to start with patients undergoing coronary cath, because many of these patients wind up getting a coronary stent and then require prolonged treatment with antiplatelet drugs, usually including clopidogrel. Some patients have a polymorphism in the gene for a protein involved in clopidogrel activation that impairs efficacy. Those patients either get a boosted clopidogrel dose or the pricier alternative, prasugrel. By mid November, 300 patients had undergone genotyping, with 10 poor metabolizers identified who received an alternate regimen.

image courtesy of Flickr user JaypeeOnline

Next up for expanding the program are patients scheduled for hip or knee replacement, because after surgery they’ll all go on an anti-coagulant drug, traditionally warfarin. Genotyping can help guide warfarin dosing during the first few days of treatment. (Since October, though, many patients began receiving dabigatran instead, an anti-coagulant that sidesteps the genotyping issue.)  Future patients to add to the genotyping list include those who are on or may soon start tamoxifen, azathioprine, 6-mercaptopurine, abacavir, codeine, or “virtually every antidepressant and most antipsychotics,” said Dr. Dan M. Roden, assistant vice-chancellor for personalized medicine at Vanderbilt and a driver and shaper of the program.

Although during rollout the program targets patients with a specific, imminent need for a certain drug, the broader concept is to have genetic information about variations in drug metabolism embedded in each patient’s medical record, so that it can automatically come into play whenever the patient gets prescribed a drug. “In the long perspective, it’s every 50-year-old,” because over the rest of ther lives they all stand a decent chance to receive some drug that carries a pharmacogenetic backstory, said Dr. Roden when I spoke with him last month in Chicago at the annual Scientific Sessions of the American Heart Association. Vanderbilt put “a huge amount of money into this,” he added, and it’s hoping to eventually persuade payers to foot the bill. So far Vanderbilt has supplied all the funding, because it believes this will improve outcomes and is also a great marketing tool.

A key element of Vanderbilt’s launch, which it says is the world’s first such program, was the careful wording of the alert that physicians get when their electronic pad identifies a patient with clopidogrel-activation deficiency. The pop-up’s text followed “a year of negotiations between lawyers, pharmacologists, pharmacists, and interventional cardiologists,” Dr. Roden said.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Going Postal

 What’s delivered by the U.S. Postal Service, but can’t fit into a letter or package?

The untold hope that a bone marrow match can bring to patients with leukemia, lymphoma and other life-threatening blood diseases.

Since holding its first drive in Baltimore in 1997, the Postal Service has become the largest contributor to the National Marrow Donor Program’s Be The Match Registry, adding more than 40,000 potential donors to the nonprofit registry.

Postal workers comprise the second largest civilian workforce in the country, and perhaps more importantly, one of its most diverse. Offering free tissue type-testing to its employees, their spouses and dependents is one way of harnessing that diversity and leveling the playing field for patients with blood diseases.

About 70% of patients do not have a donor in their family, and only 7% of potential donors on the national registry are African American, according to the NMDP.

In hopes of improving awareness, the NMDP has tapped larger-than-life basketball star Shaquille O’Neal , while its fundraising arm gave the Postal Service its first-ever “Rod Carew Award for Leadership” in recognition of saving more lives – 80 – than any other business organization in the country.

Not bad for a group of workers that have been the butt of jokes for years and frequently endure our ire this time of year.

Anyone interested in becoming a potential bone marrow or cord blood donor can contact the registry at:

Patrice Wendling (on Twitter @pwendl)

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Video of the Week: Personalizing Cancer Medicine

New tools for molecular and genetic testing of cancer tumors could individualize cancer care and revolutionize cancer research, but only if more people start using them, according to Dr. Joseph R. Nevins of Duke University.

Dr. Nevin talked with our reporter, Sherry Boschert, about how molecular and genetic tools have the potential to speed cancer research and greatly improve cancer treatment, at a translational cancer medicine meeting sponsored by the American Association for Cancer Research.

We have the tools that can be applied to these clinical studies that in many instances will give us the capability to identify those patients who will benefit from from a drug and so start moving toward trials that select subgroups of patients for the study based on those molecular characteristics and greatly improve the chance of success of the clinical study.

To see more great videos and to read about the latest medical news, check out Internal Medicine News.

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A Library, and So Much More

National Library of Medicine photo by Miriam E. Tucker

Over the four days I spent at the National Library of Medicine with five other health journalists, I didn’t see a single book until the last day.  And even then, it was only during an optional tour of the building’s underground “stacks.” But of course, the NLM is no ordinary library.

During a fellowship sponsored by the Association of Health Care Journalists, the six of us spent most of our time in front of computer screens, learning about the library’s vast array of resources for the healthcare community, scientists, librarians, students, the media, and the general public.

The NLM, which turns 175 years old next year, houses more than 16 million records from more than 5,000 journals. More than 35 million unique individuals visit the site each year, posing more than 1 billion searches to the online literature search engine Pubmed/Medline.

But, as we learned, NLM is much more than medical literature. We received hands-on training in the use of amazingly comprehensive databases on genetics and toxicology that are designed for use by the research and clinical communities as well as the general public, along with a cool new site – still in beta – that helps consumers identify pills.

In a session on NLM’s database, the site’s director Dr. Deborah Zarin spoke at length about the impact of the Food and Drug Amendments Act of 2007, which mandated trial registration and complete data reporting to of all post-phase 1 interventional studies involving drugs, devices, and biologics approved by the Food and Drug Administration. director Dr. Deborah Zarin photo by Miriam E. Tucker

The new transparency means that companies and other research entities can no longer cherry-pick their data to reflect the most favorable outcomes or simply choose not to report a study with negative findings. Had this law been in effect 10 years ago, the debacles involving suppression of trial data on COX-2 inhibitors and the diabetes drug Avandia might never have occurred. Or at least, the arguments would have been more easily settled.

“That’s how science should be. It would [have been] easier to debate if it [had been] all there in the public record,” Dr. Zarin said.

We spent two sessions learning how to mine data from, a resource I use nearly every day but, as I learned, I hardly knew at all. Everything we were taught—by enthusiastic and engaging medical librarian Kathi Canese—is available in online tutorials. Users must create an account for many of the customized search features but it’s free, as is all of NLM’s content. (Our taxes pay for it.)

Historical books collection housed underground at NLM / photo by Miriam E. Tucker

The fellowship was coordinated and led by NLM senior staffer Robert Logan, Ph.D., a former journalism professor. He told me, “This place really is the home of medical informatics around the world. This is also the home of computational biology…We love books, but nevertheless the folks here have realized that leadership as a great library is much more than that.”

-Miriam E. Tucker (@MiriamETucker on Twitter)


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