Epidemic of diabetes in New York
High numbers of New York’s poorest residents are seeking treatment for medical complications arising from diabetes, according to data compiled and released by the United Hospital Fund. As with other chronic illnesses, it is more prevalent downstate. Medicaid recipients in downstate counties have higher rates of preventable hospitalizations for long-term diabetes-related complications than many of their upstate counterparts. In 2012, New York City had 222 preventable hospitalizations of this kind for every 100,000 Medicaid patients, compared with the statewide rate of 196.Projects to improve diabetes management abound in the Delivery System Reform Incentive Payment (DSRIP) application, with good reason: The disease’s prevalence has been growing. The portion of adults in New York state with diabetes nearly doubled in the last decade, from 4.6% in 1998 to 8.5% in 2009. On average, health care costs for people with diabetes cost 4.5 times more per year than for those without the disease, according to the state Department of Health. Diabetes-related complications were the 12th most common diagnosis for residents of New York City overall and seventh most common in the Bronx.
Rates of diabetes often correlate to high rates of poverty. In Brooklyn’s East New York and New Lots neighborhoods, with median household incomes around $34,000, more than 20% of adults have been diagnosed with diabetes at some point in their lives, according to the city’s Department of Health and Mental Hygiene.
Half of clinical trial outcomes never published
Healthcare providers and patients enrolled in clinical trials have a major stake in a proposal by the National Institutes of Health that would significantly expand the amount of clinical trial data posted on the publicly available government website, www.ClinicalTrials.gov.
Since 2007, all public or private sponsors of clinical trials that test the clinical effectiveness of Food and Drug Administration-approved products have to register those trials when they begin. They also must publish their final results on the government’s website, but not until three years after their conclusion.
The law has been a major boon to drug or device formulary committees at hospitals and large physician practices, which are in the business of comparing the relative effectiveness of competing products. More than half the 15,000 trials in the database have never appeared in a medical journal, according to a special report from top officials at the National Library of Medicine, which appeared this week in the New England Journal of Medicine.
NIH’s proposed rule (PDF) will extend the requirement to clinical trials for products that were never approved by the FDA. It also ups the ante on the data reporting by requiring more specifics on a trial’s goals when it is initially registered and on the outcomes and adverse events after it is completed.
The proposed rule doesn’t tamper with the inordinately long three-year time frame for reporting results, however, which were put in place to protect the proprietary concerns of drug and device manufacturers. They aren’t keen to see negative information leek to competitors or stock market analysts and traders. European regulators, by comparison, give trial sponsors only a year before public posting is required.
In defending the new proposal, NIH officials say its primary purpose is to help other researchers avoid going down fruitless pathways. But this isn’t just a research question or a stock market question.
Human subjects voluntarily participate in clinical trials to further the cause of medical science (and hopefully benefit by being in the arm of a trial with positive outcomes). They deserve to have knowledge of the final results spread among the general public.
NPs Take on Bigger Jobs
Beginning this week, nurse practitioners in New York with 3,600 hours—about two years—of experience will no longer need to maintain written practice agreements with physicians. The Nurse Practitioners Modernization Act, effective Jan. 1, attempts to provide greater access to providers amid a shortage of primary care physicians. “There are still shortages in primary care areas, and this is a way to help get more nurse practitioners into primary care in particular and make it easier for them to set up practices and create additional access points,” said Dr. Matthew Weissman, chief medical officer at Manhattan-based Community Healthcare Network, which is creating a one-year residency to train NPs. New York requires NPs to be registered nurses and have a graduate degree in nursing, or national certification. Other physicians, including Dr. Sandeep Jauhaur in a New York Times op-ed, argue the new law “underestimate[s] the clinical importance of physicians’ expertise.”
Westchester Medical eyes regional health system deal
The Valhalla, N.Y.-based safety-net hospital formalizes relations with longtime collaborator Bon Secours Charity Health System.
Westchester Medical Center in Valhalla is in talks to explore a joint venture with Bon Secours Charity Health System, a Catholic health care system with operations in the Hudson Valley, New Jersey and Pennsylvania.
The two institutions are already collaborating on several projects in their application for funds under the state’s Medicaid reform program.
Michael Israel, Westchester Medical Center’s president and chief executive, said the joint venture would “further [strengthen] local programs and offerings in the community.”
The deal, in which WMC would become the majority co-member of Bon Secours Charity Health System, would give the safety-net hospital based in Valhalla some staying power at a time when other regional health systems are snapping up Hudson Valley institutions.
Hudson Valley Hospital in Cortlandt Manor recently affiliated with New York-Presbyterian, and Phelps Memorial Hospital in Sleepy Hollow has joined the North Shore-LIJ Health System.
While Westchester Medical Center has strong financials, Moody’s Investors Service recently changed its outlook on the health system to “negative,” citing the risks posed by the medical center’s takeover of bankrupt St. Francis Hospital in Poughkeepsie.
Bon Secours Health System runs three community hospitals and several nursing homes and assisted-living facilities across downstate New York. Its state operations make up about 15% of the system’s revenue; last year, Bon Secours’ New York division lost $8.9 million.
Study shows how lung cancer cells ‘come unstuck’ and spread
Scientists have discovered that a routine cell maintenance process goes wrong in lung cancer cells, causing them to break the protein ties that secure them to their neighbors. The result is the cells can break loose and spread.
Researchers from the Cancer Research UK Manchester Institute, at the University of Manchester in the UK, report their findings in the journal Cell Reports.
The ties that keep the cells lashed together are controlled by a protein called TIAM1.
When cells are working normally, their routine maintenance processes detect and remove faulty and worn out cell parts so they can be broken down and recycled.
But when the maintenance process goes wrong, it goes too far and chops up too many of the TIAM1 ties.
Lead researcher Dr. Angeliki Malliri explains the significance of what they found when they looked at the cells under a microscope:
“This important research shows for the first time how lung cancer cells sever ties with their neighbours and start to spread around the body, by hijacking the cells’ recycling process and sending it into overdrive. Targeting this flaw could help stop lung cancer from spreading.”
HUWE1 protein stimulates lung cancer cell invasion by changing stability of TIAM1 protein
In their study, Dr. Malliri and colleagues found the reason too many TIAM1 ties are scrapped is because of an over-abundance of a protein called HUWE1, which controls the disposal of TIAM1.
HUWE1 has already been linked to tumor formation, but this is the first study to suggest it may also have a role in cell “junction disassembly, migration and invasion.”
Working with cancer cells, the researchers showed that reducing HUWE1, or changing the site on the TIAM1 protein that it binds to, “prevents TIAM1 degradation, antagonizing scattering and invasion.”
They also showed that depleting TIAM1 in HUWE1-depleted cells restores migration and invasion.
The team concludes that their results show that “HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability.”
Studies like this will help find treatments that stop cancer spread
Nell Barrie, senior science information manager at Cancer Research UK, says:
“Early-stage research like this is essential to find treatments which could one day block cancer spread – which would be a game changer.”
Like other cancers, the earlier that lung cancer can be diagnosed, the higher the chances of treatment being successful and the lower the chance that the cancer has spread. Cancers that have spread – or metastases – are the major cause of death from cancer.
Lung cancer is the leading cause of cancer deaths. In 2012, lung cancer accounted for 1.59 million of 8.2 million cancer deaths worldwide.
According to the National Cancer Institute, there were over 224,200 cases of lung cancer diagnosed in the US in 2014 and over 159,200 deaths. In the UK, where the research was done, there are over 43,000 new cases every year and over 35,000 deaths.
The most important thing people can do to lower their risk of lung cancer is to quit smoking and avoid secondhand smoke.
A link discovered between ferrets and humans which could lead to improved therapies for a range of diseases
Research that provides a new understanding as to why ferrets are similar to humans is set to have major implications for the development of novel drugs and treatment strategies.
Published in the prestigious journal Nature Communications, the research is a collaboration between Professor Michael Jennings and other researchers from the Institute for Glycomics, Griffith University and collaborators at the University of Queensland and the University of Adelaide.
The team has shown for the first time that ferrets share a mutation that was previously thought to be unique to humans, among the mammals. This helps to explain why the molecular characteristics of ferrets so uniquely mimic human susceptibility, severity and transmission of influenza A virus strains.
Professor Michael Jennings, Deputy Director of the Institute for Glycomics, says these findings open up a completely novel approach to tackling human diseases from influenza through to cancer.
“For over 80 years we’ve known that ferrets are uniquely susceptible to human influenza A virus, but the precise reason was unknown,” Professor Jennings said.
“We have shown that ferrets have a mutation in a gene required to make a crucial sugar called sialic acid. Most animals can make two types of sialic acid. Ferrets, like humans can make only one. Different flu strains have preferences for the type of sialic acid they bind to cause infection. Because ferrets can only make the human form of this sugar, they are naturally “humanized” for the receptors recognised by human strains of the flu virus.”
New review of prostate cancer research published
The American Journal of Hematology/Oncology, has published a provocative article exploring the role of follicle-stimulating hormone (FSH) in the development, progression and potential treatment of prostate cancer.
The article references seminal published endocrinology research and proposes the possibility that there could be a connection to prostate cancer that has new therapeutic implications. Dr. Andrew Schally, PhD, MDhc, DSc,hc, discovered and described gonadotropin-releasing hormone (GnRH) and its complex control of the gonadal endocrine system through its regulation of FSH and luteinizing hormone (LH), and its effects on androgens, estrogens and the ovulatory cycle. He was awarded a Nobel Prize in Physiology and Medicine in 1977 for his work in this area. Dr. Schally shared the prize that year with Roger Guillemin and Rosalyn Sussman Yalow.
Lead author E. David Crawford, MD, is the distinguished Professor of Surgery, Urology, and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus. Recognized as one of the best cancer doctors in America by Men’s Health, Dr. Crawford is an active clinician, researcher and teacher. He and his team of co-authors, along with Dr. Schally, present an article in the December issue describing the relationships between FSH, vascular endothelial growth factor (VEGF) and other modulators of prostatic cancer. Dr. Schally is the Distinguished Medical Research Scientist of the Veterans Administration, Head of the Endocrine, Polypeptide and Cancer Institute at the Veterans Affairs Medical Center in Miami and Distinguished Professor in the Department of Pathology and Professor in the Division of Hematology/Oncology at the University of Miami Miller School of Medicine.
“Dr. Crawford and his team of distinguished colleagues leverage Dr. Schally’s research and lend insight to the role of follicle-stimulating hormone in prostate cancer, a potentially pivotal pathway that may open new avenues for prostate cancer therapy,” said Debu Tripathy, MD, editor-in-chief of The American Journal of Hematology/Oncology and professor of medicine and chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. “We are privileged to publish their work and the advances it may bring to the understanding and ultimate treatment of prostate cancer.”
The December article reviews the dysregulation of the FSH system and a growing body of evidence that supports the role of the FSH system in the development and progression of prostate cancer. The authors explain that FSH receptors are overexpressed in prostate cancer and tumor-associated blood vessels, and pathophysiological alterations in key modulators can result in increased FSH signaling with consequent impact on downstream processes, such as angiogenesis. The article also reviews research from Dr. Schally’s team at the University of Miami along with Dr. Crawford, who have developed and tested GnRH antagonists, which like GnRH agonists (such as leuprolide) suppress androgen production, but, unlike them, also cause long term suppression of FSH. Moreover, the authors discuss that the long term suppression of FSH by GnRH antagonists may provide a basis for the development of other targeted therapies modulating the FSH axis.
Prostate cancer is the most common noncutaneous related cancer in men, and the American Cancer Society estimated over 230,000 new cases of prostate cancer and nearly 30,000 deaths in the United Sates in 2014.
Research for the article was partially funded by Ferring Pharmaceuticals Inc.
Cannabis-based medicine to be tested as child epilepsy therapy
Children with severe epilepsy could be helped by a new treatment derived from the cannabis plant.
Doctors in the UK have been given the go-ahead to test the medicine, which does not contain the ingredient that produces the high associated with recreational cannabis use.
The treatment – called Epidiolex – is based on one of the non-psychoactive components of the cannabis plant, called CBD.
Early studies in the US have shown that treatment with CBD may reduce the frequency and severity of seizures in children with severe forms of epilepsy. The new trial marks the first time the treatment has been tested in the UK.
Patients are being enrolled for a randomised controlled trial of the treatment at The University of Edinburgh’s Muir Maxwell Epilepsy Centre, based at the Royal Hospital for Sick Children in Edinburgh, and Great Ormond Street Hospital.
The Royal Hospital for Sick Children in Glasgow and Alder Hey Children’s Hospital in Liverpool are also driving the study. There are further centres in the US, France and Poland.
Their initial focus will be on children with Dravet Syndrome, a rare but serious type of epilepsy that is difficult to treat. Some children will receive the treatment while others will receive a placebo.
In a further phase, researchers will also study the effect on children with Lennox-Gastaut Syndrome.
Only children whose seizures cannot be controlled with existing medications will be invited to take part in the trial.
Dravet Syndrome usually takes hold in the first year of life. It causes seizures that are often prolonged, lasting longer than five minutes. They then develop other seizure types. This has a significant impact on the child’s development and can be fatal in some cases.
Epidiolex has been developed by the British biotechnology company GW Pharmaceuticals, which is sponsoring and funding the trial.
Dr Richard Chin, Director of the Muir Maxwell Epilepsy Centre, said: “Many children with serious forms of epilepsy do not respond to the medications that we currently have available. We need new means of treating these conditions so that we can give back some quality of life to these children and their families.”Professor Helen Cross, of Great Ormond Street Hospital and Chief UK clinical investigator of the initial part of the trial, said: “Severe epilepsy can have an incredibly debilitating effect on individuals. These trials will allow us to accurately test the viability of treatment with CBD in a safe and controlled way.”
Ann Maxwell, founder of the paediatric epilepsy charity the Muir Maxwell Trust, said: “I welcome the launch of these trials as it marks an important milestone in our long journey towards understanding the condition and improving the treatment of those suffering this severe form of epilepsy. As the mother of a teenager with this life altering condition, I strongly support the exploration of ground breaking medications that could seek out new ways to improve patients’ life quality.”
Dr Sameer Zuberi, Clinical Lead of the Glasgow Epilepsy Genetics Service and Epilepsy Specialist , Royal Hospital for Sick Children, Glasgow, said: “The 40,000 children with epilepsy in in the UK have many different genetic causes for their seizures. The opportunity to trial new treatments in children with specific gene changes gives families hope for better and more focused therapies.”
Dr Richard Appleton, Clinical Lead, Epilepsy Service and Director, the Roald Dahl EEG Unit, Alder Hey Children’s Hospital, Liverpool, said: “It is crucial that research in children with epilepsy is undertaken far earlier than it has been in the past; so often children are only considered as an ‘afterthought’ in clinical research.”
Scientists locate homing signal in brain, explaining why some people are better navigators
The part of the brain that tells us the direction to travel when we navigate has been identified by UCL scientists, and the strength of its signal predicts how well people can navigate.
It has long been known that some people are better at navigating than others, but until now it has been unclear why. The latest study, funded by the Wellcome Trust and published in Current Biology, shows that the strength and reliability of ‘homing signals’ in the human brain vary among people and can predict navigational ability.
In order to successfully navigate to a destination, you need to know which direction you are currently facing and which direction to travel in. For example, ‘I am facing north and want to head east’. It is already known that mammals have brain cells that signal the direction that they are currently facing, a discovery that formed part of the 2014 Nobel Prize in Physiology or Medicine to UCL Professor John O’Keefe.
The latest research reveals that the part of the brain that signals which direction you are facing, called the entorhinal region, is also used to signal the direction in which you need to travel to reach your destination. This part of the brain tells you not only which direction you are currently facing, but also which direction you should be facing in the future. In other words, the researchers have found where our ‘sense of direction’ comes from in the brain and worked out a way to measure it using functional magnetic resonance imaging (fMRI).
“This type of ‘homing signal’ has been thought to exist for many years, but until now it has remained purely speculation,” explains Dr Hugo Spiers (UCL Experimental Psychology), who led the study. “Studies on London cab drivers have shown that the first thing they do when they work out a route is calculate which direction they need to head in. We now know that the entorhinal cortex is responsible for such calculations and the quality of signals from this region seem to determine how good someone’s navigational skills will be.”
In the study, 16 healthy volunteers were asked to navigate a simple square environment simulated on a computer. Each wall had a picture of a different landscape, and each corner contained a different object. Participants were placed in a corner of the environment, facing a certain direction and asked how to navigate to an object in another corner.
“In this simple test, we were looking to see which areas of the brain were active when participants were considering different directions,” says Dr Spiers. “We were surprised to see that the strength and consistency of brain signals from the entorhinal region noticeably influenced people’s performance in such a basic task. We now need to investigate the effect in more complex navigational tasks, but I would expect the differences in entorhinal activity to have a larger impact on more complex tasks.
Dr Martin Chadwick (UCL Experimental Psychology), lead author of the study, said: “Our results provide evidence to support the idea that your internal ‘compass’ readjusts as you move through the environment. For example, if you turn left then your entorhinal region should process this to shift your facing direction and goal direction accordingly. If you get lost after taking too many turns, this may be because your brain could not keep up and failed to adjust your facing and goal directions.”
The entorhinal region is one of the first parts of the brain affected by Alzheimer’s disease, so the findings may also help to explain why people start to get lost in the early stages of the disease. The researchers hope to develop their simple simulation task so that it might be used to aid early diagnosis and monitor the progression of the disease.
Dr John Isaac, Head of Neuroscience and Mental Health at the Wellcome Trust said: “Neuroscientists have made huge advances in our understanding of how we navigate space, widely recognised after this year’s Nobel Prizes, and this research is yet another step forward. Why some people are better navigators than others is intrinsically interesting, but it also helps us explain the processes that go wrong in people with degenerative brain disorders such as dementia. An estimated 850,000 people are living with dementia in the UK, many of whom suffer deterioration in their navigational skills, leaving them lost and confused.”
The president rewrites the ObamaCare law — again
On Thanksgiving eve, the Obama administration dumped reams of mind-numbing ObamaCare regulations into the Federal Register — including yet more unilateral rewrites of the Affordable Care Act.
Dropping the rules as most Americans were busy preparing for the holiday made a mockery (again) of President Obama’s promise to have “the most transparent administration in history.” The stunt has even worked to keep most of the media from reporting on the rules.
Yet the changes these regulations make in the health care law are substantial.
For one, the president is redefining what health plans are “adequate” for larger employers (100-plus workers) to offer under the Affordable Care Act. He’s also “asking” insurers to pay for new benefits — while warning that, if they don’t, they may be forced to.
Under the Constitution, Obama lacks any authority to make such changes to the health law, or any law. Only Congress has that power. But he’s doing it, and not for the first time.
The president has made two dozen changes to his health law by executive fiat, from delaying the employer mandate to allowing people to keep health plans that don’t meet ObamaCare standards.
In fact, the House of Representatives is suing him (after Obama explicitly challenged it to do so) for making changes without Congress’ OK.
Of course, the president says he’s merely “taking executive actions to help people.”
Yet, as a former constitutional law professor, he surely knows better. And his mother surely warned him about the perils of “the end justifies the means” reasoning — even when the end is helping people.
In any case, last week’s changes, like the president’s previous fixes, create new losers as well as winners — the sort of tradeoffs that legislators are supposed to weigh in our system of government. The basics:
- Obama will require large employers to provide more coverage than the Affordable Care Act specifies. The move disqualifies plans now offered by 1,600 employers to 3 million workers, according to Kaiser Health News. Those employers will have to find a way to cover the higher costs — and some will surely do so by stopping coverage for spouses or part-time workers.
- The new rules suddenly treat state high-risk pools as adequate coverage under the Affordable Care Act — a 180 from what the law actually says.
When the ACA became law, these plans for people with chronic illnesses were offered in 35 states. Winners will be those who live in the 10 states that haven’t yet phased out their high-risk plans. Losers: the many thousands in 25 states that already gave up their plans to comply with the ACA’s mandates. - The rules tell insurers to give new enrollees a 30-day grace period during which they can continue to use doctors not in their plan’s network. Winners: people who need time to switch to in-network doctors. Losers: taxpayers — who’ll be obliged to bail out the insurers clobbered with the extra cost.
Speaking of bailouts, Section 1342 of the law promises taxpayer-funded bailouts to insurers that lose money selling plans on ObamaCare exchanges. But the bailouts can’t happen unless Congress appropriates the money, something the GOP-controlled Congress won’t want to do. Yet the new Federal Register notices explicitly double down on the administration’s pledge to make insurers whole if losses are bigger than expected.
By repeatedly contradicting the letter of the Affordable Care Act, these new rules add to a pattern of lawlessness in implementing the health law — even as the administration’s boldest misreading of the law is before the Supreme Court.
Two years after the justices ruled 5-4 to uphold ObamaCare’s individual mandate, the health law is back in front of the high court.
The issue this time, in King v. Burwell, is whether Obama is violating the law by handing out taxpayer-funded subsidies to ObamaCare enrollees in all 50 states. The letter of the law clearly allows subsidies only in the 14 states that established their own exchanges.
If the Supreme Court rules against the administration, enrollees would have to pay the actual cost of ObamaCare premiums — which would mean staggering hikes of 400 percent in many cases.
That could be the end of the president’s health law — or at least force him to actually negotiate with Congress on a complete rewrite tantamount to the Republicans’ “Repeal and replace” refrain.
Will the justices endorse the president’s rewriting of the law on ObamaCare subsidies? If so, they’ll surely be facing even more cases down the line, over all his other unilateral changes to his signature statute.
Researchers find drug that could halt kidney failure
Use of rheumatoid arthritis drug saved transplanted kidney in four patients, achieved remission in fifth
Adrug approved for the treatment of rheumatoid arthritis may also turn out to be the first targeted therapy for one of the most common forms of kidney disease, a condition that almost inevitably leads to kidney failure. A team led by researchers at Harvard-affiliated Massachusetts General Hospital (MGH) is reporting that treatment with abatacept (Orencia)appeared to halt the course of focal segmental glomerulosclerosis (FSGS) in five patients, preventing four from losing transplanted kidneys and achieving disease remission in the fifth. The report was issued online in the New England Journal of Medicine (NEJM).
“We identified abatacept as the first personalized, targeted treatment for kidney disease and specifically for FSGS, a devastating and largely untreatable disease” said Peter Mundel of the Division of Nephrology in the MGH Department of Medicine. “We also identified a biomarker that helps us discern which patients are most likely to benefit from therapy with abatacept.”
Mundel is senior author of the NEJM paper and an associate professor of medicine at Harvard Medical School (HMS).
FSGS is characterized by the formation of scar tissue in the glomeruli, the kidney’s essential filtering units. Some forms of FSGS are inherited and some have no known cause, but the vast majority of cases develop in individuals with hypertension, obesity, or diabetes. Although the underlying mechanism is unclear, FSGS disrupts the function of podocytes, cells within the glomeruli that are crucial to kidney function. While treatment with steroids and some immunosuppressive drugs helps some patients, the drugs’ side effects make long-term use problematic.
Previous research by Mundel’s team found that the expression on podocytes of an immune molecule called B7-1 signaled the breakdown of the kidney’s filtering function, leading to protein leakage into the urine (proteinuria) and ultimately to kidney failure. Currently approved to treat rheumatoid arthritis and being studied for other conditions, abatacept inhibits the activity of B7-1, a molecule that is not expressed in healthy podocytes. After in vitro tests indicated that abatacept blocked the primary pathogenic effect of B7-1 expression in podocytes, the team tested treatment with the drug in five FSGS patients, four with recurrent disease affecting a transplanted kidney and one with treatment-resistant disease who was at high risk for kidney failure.
In all five patients, abatacept treatment induced remission of FSGS-caused proteinuria. Two of those with recurrent disease have remained in remission for three and four years, respectively, after a single dose of abatacept. The other two required a second dose when proteinuria reappeared a few weeks later and have been in remission for 10 and 12 months, respectively. The patient with high-risk, treatment-resistant disease, who is being treated at MGH, went into remission for the first time in more than a year, continues in remission a year later, and has resumed a normal lifestyle. While she still receives monthly doses of abatacept, she no longer needs the high-dose steroids and immunosuppressive drugs she had depended on, some of which actually increase the risk for kidney failure.
Mundel explained that, while a large-scale clinical trial is needed, he and his colleagues are hopeful that abatacept will prove an effective treatment for kidney disease characterized by B7-1 expression on podocytes. “We have a decade of good experience with the use of abatacept for rheumatoid arthritis, so we have every reason to believe that it will be an excellent long-term option for the treatment of all B7-1-positive diseases, including FSGS and perhaps diabetic kidney disease.”
New hope for treating ALS
Patient stem cells help identify common problem, leading to clinical trials
Harvard stem cell scientists have discovered that a recently approved medication for epilepsy might be a meaningful treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, a uniformly fatal neurodegenerative disorder. The researchers are now collaborating with Massachusetts General Hospital (MGH) to design an initial clinical trial testing the safety of the treatment in ALS patients.
The investigators all caution that a great deal of work needs to be done to assure the safety and efficacy of the treatment in ALS patients before physicians should start offering it.
The work, laid out in two related advance online publications in April by Cell Stem Cell and Cell Reports, is the long-term fruit of studies by Harvard Stem Cell Institute (HSCI) principal faculty member Kevin Eggan, who in a 2008 Science paper first raised the possibility of using ALS patient-derived stem cells to better understand the disease and identify therapeutic targets for new drugs.
Now Eggan and HSCI colleague Clifford Woolf have found that the many independent mutations that cause ALS may be linked by their ability to trigger abnormally high activity in motor neurons. Using neurons derived from stem cells made from ALS patient skin cells, the two research teams conducted clinical trials of the anti-epilepsy medication on neurons in laboratory dishes, finding that it reduced the cells’ hyperexcitability.
ALS is a devastating and currently untreatable degradation of motor neurons, the long nerve cells that connect the spinal cord to the muscles of the body. While several potential treatments have looked promising in mice, all proved disappointing in the clinic.
“The big problem in ALS is that there are more than 100 mutations in dozens of genes that all cause the disease, but almost all of the therapeutics that have gone forward in the clinic have done so for just one of those mutations, SOD1, which almost everyone studies in mice,” said Eggan, a professor in Harvard’s Department of Stem Cell and Regenerative Biology.
“And so,” he continued, “the key question that we really wanted to address was: Are clinical efforts failing because the mouse is taking us on a wild goose chase, or is it simply that people haven’t had the opportunity to pretest whether their ideas are true across lots of forms of ALS?”
In the Cell Stem Cell study, Eggan and postdoctoral fellow Evangelos Kiskinisled an effort to make stem cell lines from two women with ALS who have SOD1 mutations in order to compare human biology and mouse biology. Using a technology called RNA sequencing to look at how the mutation changed gene expression in these lines, the researchers then traced the changes to their impact on biological pathways.
“We found that the mutation makes changes in the motor neurons, which aren’t so different from the changes that you see in the mice,” Eggan said. “I think our paper says that while there are definitely some human-specific biology, the mice weren’t totally misleading.”
Eggan’s lab then created more stem cell-derived motor neurons from patients with another form of ALS, as well as people without the disease, to see what changes occurred in ALS cells and if these were present across independent genetic mutations.
The surprising result, described in the Cell Reports study, was that the motor neurons that possessed ALS mutations had a sporadic increase in neuron firing, while the healthy neurons were quiet unless stimulated in some way.
The ALS hyperexcitability was further examined by Woolf’s team, led by Harvard Medical School neurologist Brian Wainger. Working with Eggan and Kiskinis, they found a cyclical relationship between the increased neuron activity and abnormal protein folding. In the two papers, they describe how the overexcitable ALS neurons generate more abnormally folded proteins, further increasing their excitability. The strain of this cycle seems to put the neurons in a vulnerable state, where they are more likely to die.
“The convergence on a single mechanism offered a very attractive place to intervene therapeutically,” said Woolf, a Harvard Medical School professor in neurology and neurobiology and director of the neurology center at Children’s Hospital Boston, who also co-leads HSCI’s Nervous System Diseases Program.
“It looked like there’s a deficit in potassium channels in the ALS motor neurons, and that led us to then test whether drugs that open the potassium channels may reduce this hyperexcitability. And indeed that’s exactly what we found,” he said. “We found that retigabine, which has recently been approved as an anticonvulsive, normalized this activity. So now we can formally go from the dish to the patient and actually explore whether the drug might have any beneficial effect.”
MGH neurologist Merit Cudkowicz, with Wainger, will be running the clinical trials, which will first test for side effects in ALS patients treated with the drug. The researchers caution against calling this work a breakthrough or having doctors prescribe this drug to patients immediately. Clinical trials are necessary to determine whether there are any unusual interactions between the drug and ALS, since having a particular disease can make someone more sensitive to certain types of drugs.
“The whole intact nervous system is more complicated than the cells that we have in the dish at the moment,” Eggan said. “And now the next step is to say whether or not the drug will be helpful in that context, and it’s too early to say for sure.”
The scientists credit emerging technologies and the unique collaboration between a stem cell lab and a neuron physiology lab as an essential part of making this research clinically relevant for ALS patients.
“I think it’s the beginning of a complete change in the way we do medicine for serious diseases like this,” Woolf said. “In a traditional clinical trial, you give the patient the placebo or an active ingredient to see the effects they have, and it’s over. Here we can take the same stem cell lines and have an infinite capacity to do clinical trials in a dish.”
Funders of the research include Target ALS, Project A.L.S., P2ALS, the National Institute of Neurological Disorders and Stroke, the Howard Hughes Medical Institute, the National Institutes of Health Director’s Pioneer Award, Harvard NeuroDiscovery Center, the ALS Association, the American Brain Foundation, ALS Therapy Alliance, the Angel Fund, Pierre L. de Bourgknecht ALS Research Foundation, Al-Athel ALS Research Foundation, ALS Family Charitable Foundation, and the New York Stem Cell Foundation.
A close look at blinking after facial transplantation
Recovery of blinking function is a critical but easily overlooked outcome after facial transplantation, according to a report in the January issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS).In their study, ASPS member surgeon Eduardo DeJesus Rodriguez, MD, DDS, and colleagues highlight the need for careful surgical planning and technique to achieve optimal voluntary and reflex blinking—essential to protect long-term visual outcomes—in facial transplant recipients. Dr. Rodriguez is chair of the Department of Plastic Surgery at NYU Langone Medical Center and director of its Institute for Reconstructive Plastic Surgery.
Blinking Function Restored after Facial Transplantation
The study included detailed assessments of blinking function in a patient who underwent “facial vascularized composite tissue allotransplantation” after a devastating injury to the central and lower face caused by an accidental gunshot. The operation was one of the most extensive facial transplants to date, including “total face, double jaw, and tongue transplantation.” The facial transplant was performed in March, 2012, when Dr. Rodriguez was at the University of Maryland Medical Center in Baltimore.
Vision and blinking function were evaluated before facial transplantation and up to several months afterward. Assessments included slow-motion video analysis of blinking—particularly involuntary or “reflex” blinking, which is essential to protect the eye.
Before transplantation, the patient had 100 percent voluntary blinking function (complete eyelid closure) in both eyes. But reflex blinking was significantly impaired immediately following the surgery, with only 40 percent reflex blinking on the right side. On the left side, the patient had 90 percent reflex blinking function.
Six months following the transplantation, visual acuity and eye movement remained normal on both sides. Meanwhile, involuntary reflex blinking improved substantially: 70 percent in the right eye and 100 percent in the left eye.
Call for Increased Attention to Periorbital Planning and Follow-up
Vision and blinking function again decreased as the patient went through a series of revision surgeries to improve functioning and appearance in the months after transplantation. These issues likely resulted from nerve injury (neuropraxia) caused by tissue handling during surgery. Both vision and blinking recovered over several weeks after these procedures.
Facial transplantation is still a rare procedure, but experience has shown excellent outcomes for carefully selected patients with severe facial injuries. Although blinking is easily overlooked, it is a complex facial function that is critical to protecting vision. At least some facial transplant recipients have experienced severe eyelid-related complications.
The study provides important information on recovery of blinking, especially reflex blinking, after facial transplantation. Dr. Rodriguez and colleagues believe their successful results reflect careful preservation of periorbital tissues from both the recipient and donor, followed by ingrowth of critical facial nerves. They encourage other facial transplant groups to perform similar evaluations of blinking function.
The effort to monitor restoration of blinking ability is an example of refinements to improve the long-term outcomes of facial transplantation, according to this month’s introductory video by Rod J. Rohrich, MD, Editor-in-Chief, on the Plastic and Reconstructive Surgery website. “The fact that we are now researching blinking outcomes for these patients when face transplantation likely seemed more science fiction than science just a decade ago, shows how dedicated plastic and reconstructive surgeons around the globe have been in developing and refining this amazing, life-changing procedure,” Dr Rohrich comments. Watch the accompanying “Hot Topics in Plastic Surgery Video.”
Lyme disease enhances spread of emerging tick infection
Mice that are already infected with the pathogen that causes Lyme disease appear to facilitate the spread of a lesser-known but emerging disease, babesiosis, into new areas.
Research led by the Yale School of Public Health and published Dec. 29 in the journal PLOS ONE used laboratory experiments, mathematical models, and fieldwork data to find that mice infected with the agent that causes Lyme disease (Borrelia burgdorferi) are at increased risk for also transmitting Babesia microti, the pathogen responsible for babesiosis, and could be enhancing the geographic spread of this emerging disease. Both diseases are transmitted to humans through the bite of infected black-legged ticks (Ixodes scapularis).
The finding provides a possible answer as to why human babesiosis is only emerging in areas where Lyme disease is well established, said Maria Diuk-Wasser, senior author of the study, who performed the research in collaboration with Peter Krause’s and Durland Fish’s research groups while she was assistant professor at the Yale School of Public Health. Diuk-Wasser, who maintains an adjunct position and active collaboration with the Yale School of Public Health, is an associate professor at Columbia University. Other study collaborators were at the Yale School of Medicine, Tufts Medical Center, and the Royal Melbourne Institute of Technology.
“Ticks and natural hosts are commonly co-infected in nature, so understanding how these pathogens may influence each other’s abundance and distribution is key for public health,” Diuk-Wasser said. “We found that B. burgdorferi and B. microti co-occur in ticks more frequently than expected, resulting in enhanced human exposure to multiple infections that can cause more severe symptoms and sometimes make diagnosis more difficult.”
Ninety-five percent of all Lyme disease cases are reported from 14 states (primarily on the East Coast and in the Midwest), and there are approximately 30,000 new cases reported each year. Babesiosis is found in similar regions, but 95% of cases are concentrated in the seven “core” Lyme disease states (Connecticut, Massachusetts, New Jersey, New York, Rhode Island, Minnesota, and Wisconsin). About 1,000 new cases of babesiosis are reported annually.
While the two diseases share some of the same symptoms, babesiosis is potentially fatal in immunocompromised patients and can be transmitted through blood transfusions in addition to tick bites, posing an additional public health threat.
Refined mathematical models may allow scientists to better predict areas that are at risk for B. microti expansion and to assess whether methods to reduce B. burgdorferiinfection in ticks and mice may simultaneously reduce B. microti infection, Diuk-Wasser said.
Strategy for diabetes treatment
Newly discovered compound slows natural degradation of insulin in body
With the discovery of a compound that can slow the degradation of insulin in animals, scientists at Harvard have opened the door to a potential new treatment for diabetes.
The new approach, described by David Liu, professor of chemistry and chemical biology, and Alan Saghatelian, associate professor of chemistry and chemical biology, uses the compound to inhibit insulin-degrading enzyme (IDE). Inhibiting IDE in mice, they have shown, elevates insulin levels and promotes insulin signaling in vivo. Eventually, using this compound in patients may help maintain higher insulin levels to improve glucose tolerance and thereby treat diabetes. The discovery of the compound, and tests demonstrating its efficacy in mice, are outlined in a May 21 paper in the journal Nature.
“This work validates a new potential target for the treatment of diabetes,” Liu said. “What we show is that inhibiting IDE in an animal can improve glucose tolerance under conditions that mimic the intake of a meal if you administer this compound beforehand.”
For decades, insulin-based diabetes treatments consisted of three main strategies — inject insulin into diabetics, provide drugs that stimulate insulin secretion, or administer drugs that make the body more sensitive to insulin.
“What’s been missing has been the ability to regulate the degradation of insulin,” Saghatelian said. “The technological leap we’ve made was in identifying a molecule that allows that to happen. This opens up a new avenue to control insulin signaling in vivo.”
To identify the new molecule, Liu, Saghatelian, and their co-workers turned to DNA-templated synthesis, a method of creating molecules that self-assemble according to an attached DNA sequence. The system works by combining DNA “templates,” or short segments of DNA, with the chemical building blocks of molecules, each of which is linked to a complementary piece of DNA. As the DNA segments bind, the building blocks are brought together and react with one another, forming molecules of greater complexity. The composition of the resulting molecules can be identified by sequencing their associated DNA strands.
“We took a library of about 14,000 DNA templates and combined it with several sets of DNA-linked reagents,” Liu said. “The resulting synthesis of about 14,000 small molecules was largely driven by, and programmed by, DNA base pairing. At the end of that process, we had 14,000 strands of DNA, each with a unique compound at its end.”
Researchers then took that library of DNA-linked compounds and incubated it with IDE in the hope that some might bind to the enzyme.
“Our hypothesis was that the molecules that were retained by IDE might modulate IDE’s activity,” Liu said. “In this case, right out of the library, we found quite a potent and selective inhibitor. Perhaps most important, this molecule had a good half-life in animals, so it could be used to answer the 60-year-old question of what happens when you slow down the natural degradation of insulin in the body.”
Identifying a molecule that could inhibit IDE, however, was only the first step.
Researchers were also able to show that the compound remained active in the body, and experiments with mice showed that it was able to help regulate blood-sugar levels.
“To validate that this strategy of slowing the degradation of insulin is actually therapeutically useful, we have to show that this compound can transiently inhibit the target, and show that it has a benefit in animals,” Liu said. “That is what we demonstrate in this study.”
In addition to pointing the way toward a new way to treat diabetes, researchers uncovered information about how IDE works in the body.
“In the process of resolving some seemingly paradoxical results, we discovered that IDE is actually somewhat misnamed,” he said. “It doesn’t just degrade insulin, it degrades at least two other important glucose-regulating peptide hormones, glucagon and amylin.”
While the discovery of the molecule is exciting, Liu emphasized that it may still be some time before the compound finds its way onto pharmacy shelves.
“To develop a drug requires a number of additional tests and developments,” he said. “But this work validates IDE as a new target for the treatment of diabetes, and it provides experimental tools that can be used to develop this compound further into potential therapeutic leads.”
“What this paper has done is given a proof of concept that targeting this protein is the way to go,” Saghatelian said. “To make the leap from this molecule to a drug, there are other factors that need to be optimized. But we’ve hung the carrot out there for the pharmaceutical industry and other labs to start looking at IDE as a potential target for treating diabetes, and to push through the remaining obstacles that are there. We’ve shown it’s worth the effort to look into this more deeply, and hopefully what we’ve done is opened people’s eyes to IDE as a valid therapeutic target.”
Researchers from Stony Brook University, the Albert Einstein College of Medicine, the University of California, Irvine, and the University of Chicago contributed to the research.
A malignant ‘switch’ in breast cancer
Engineers and biologists explain how tissue stiffness can contribute to invasive carcinoma
Ateam of researchers led by David J. Mooney, the Robert P. Pinkas Family Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS), has identified a possible mechanism by which normal cells turn malignant in mammary epithelial tissues, which are frequently involved in breast cancer.
Dense mammary tissue has long been recognized as a strong indicator of risk for breast cancer. This is why regular breast examinations are considered essential to early detection. Until now, however, the significance of that tissue density has been poorly understood.
By isolating mechanical and biological variables one by one in vitro, Mooney and his research team discovered how the physical forces and chemical environment in those dense tissues can drive cells into a dangerously invasive, proliferating mode. The findings were published online in Nature Materials.
“While genetic mutations are at the root of cancer, a number of studies over the last 10 to 20 years have implicated the cellular microenvironment as playing a key role in promoting or suppressing tumor progression,” said lead author Ovijit Chaudhuri, a former postdoctoral fellow in the Mooney Lab at Harvard who recently joined the mechanical engineering faculty at Stanford University.
The new research found that the stiffness of the extracellular matrix and the availability of certain ligands (molecules that bind to cell membranes) can together determine which genes are actually called on — and whether normal epithelial cells begin to exhibit the behaviors characteristic of highly malignant cancer cells.
“Our findings suggest that evaluating the composition of this microenvironment, in addition to mammographic density, could potentially provide a better assessment of breast cancer risk,” Chaudhuri said.
Research in the Mooney Laboratory explores how the physical properties of natural biomaterials and synthetic polymers can affect the way cells sense their environment, react to it, and signal to one another. The extracellular matrix — the complex network of cross-linked proteins and polymers that connects living cells to one another and aids communication between them — offers a challenging subject for study. The usual 2-D culture of cells on petri dishes has proven to be a poor model of 3-D tissues.
“As bioengineers, we can now design 3-D culture systems where environmental parameters such as composition, porosity, and stiffness can be precisely tuned to study the importance of these cues on tumorigenesis,” said coauthor Sandeep Koshy, a Harvard graduate student in the Harvard-MIT program in Health Sciences and Technology, who works in Mooney’s lab at SEAS and at the Wyss Institute for Biologically Inspired Engineering. “We’re seeing that some of these factors have a major impact on cell behavior that is not possible to observe in conventional 2-D cell cultures.”
Prior studies have used varying amounts of a fibrous protein called collagen to adjust the stiffness of the extracellular matrix, but Mooney’s team recognized early on that collagen has more than a simple mechanical effect on cells. It can also trigger certain signaling pathways. Fibrous collagen is not normally found in the basement membrane that surrounds the mammary epithelium, so any collagen signaling could confound the conclusions of those studies.
To eliminate uncontrolled variables, the team designed a new material model that uses alginate gel, instead of collagen, to stiffen the extracellular matrix without binding to any cell receptors. When this model was in its softest mode, normal (benign) mammary epithelial cells behaved normally within it, forming cellular structures, called acini, that capture many key features of the normal mammary epithelium. But when the gel was stiffer, the cells began to increase the expression of cancer-related genes. Activity also increased on a pathway that is known to drive cell proliferation and invasion.
“It is striking that these changes, found in many human cancers, can be induced in normal mammary epithelial cells simply by varying the stiffness or composition of the matrix surrounding them,” said Koshy.
But while stiffness is a key part of the story, it is not all of it. Further experiments indicated that the cells would recover their normal behavior in high-stiffness gels if they were exposed to increasing concentrations of laminin, a protein naturally found in the basement membrane.
When the extracellular matrix is very flexible, or when a high concentration of laminin is readily available, proteins called α6β4 integrins within the cell membrane bind with laminin to form small structures called hemidesmosomes, which anchor the epithelial cells to the basement membrane. But fluorescence microscopy revealed that the cells in a stiff matrix were not forming hemidesmosomes at all, so Mooney’s team hypothesized that a stiffer matrix and a shortage of laminin were leaving the α6β4 integrins with dangling, unbound tails.
The team’s final experiments demonstrated that these unbound integrin tails are indeed up to no good. They participate in the activation of two key biochemical pathways that are necessary to induce malignant cell behaviors in the epithelial tissue.
“If further studies validate that these processes are critical in human breast cancers,” Koshy said, “the possibility exists that agents that favorably modify the biophysical properties of the extracellular matrix, or that target the receptors and signaling molecules associated with how cells sense this matrix, could be used as a new avenue for the prevention or treatment of breast cancers.”
In addition to the implications of this research for cancer biology, the development of the alginate-based extracellular matrix model is also significant.
“Studies of many other biological processes could benefit from the use of this system,” said Mooney, who in addition to his role at SEAS is a core faculty member at the Wyss Institute. “Studies on stem cell biology, wound healing, and development in a variety of tissues and organs could utilize this system.”
Mooney, Chaudhuri, and Koshy were joined in this research by Cristiana Branco da Cunha, a visiting graduate student in the Mooney lab from the Universidade do Porto in Portugal; Harvard postdoctoral fellow Jae-Won Shin; Catia S. Verbeke, who was a graduate student in engineering sciences at SEAS; and Kimberly H. Allison, associate professor of pathology at Stanford University Medical Center.
This research was supported by the National Institute of Biomedical Imaging and Bioengineering and the National Cancer Institute, the Natural Sciences and Engineering Research Council of Canada, the Howard Hughes Medical Institute, and Portugal’s Fundação para a Ciência e a Tecnologia, Fundação Calouste Gulbenkian, and Fundação Luso-Americana para o Desenvolvimento. The work was performed in part at the Center for Nanoscale Systems at Harvard and the Materials Research Science and Engineering Center at Harvard.
Improving the odds of beating opioids
Residential treatment may be an appropriate first-line option for young adults who are dependent on opioid drugs — including prescription painkillers and heroin.
Research indicates that live-in programs may result in higher levels of abstinence than the outpatient treatment that is currently the standard of care.
A study from the Harvard-affiliated Massachusetts General Hospital (MGH) Center for Addiction Services found that a monthlong, 12-step-based residential program with strong linkage to community-based follow-up care enabled almost 30 percent of opioid-dependent participants to remain abstinent a year later. Another recent study found that 83 percent of those who entered an office-based opioid treatment program had dropped out a year later.
“Our results suggest that abstinence-focused, 12-step residential treatment may be able to help young adults recover from opioid addiction through a different pathway than the more typical outpatient approach incorporating buprenorphine/naloxone treatment,” said John Kelly of the Center for Addiction Medicine in the MGH Department of Psychiatry. Kelly is the senior author of the study that was published online in the journal Drug and Alcohol Dependence, as well as the Elizabeth R. Spallin Associate Professor of Psychiatry in Addiction Medicine at Harvard Medical School (HMS).
Corresponding author Zev Schuman-Olivier also noted, “We found that participants who met DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition] criteria for opioid dependence seemed to do better during residential treatment than did opioid misusers — those who reported some illicit opioid use in the past 90 days but did not meet dependence criteria.
“Interestingly, young adults with intermittent opioid misuse are often encouraged to go into residential treatment if they can afford it or it is covered by insurance, while those with opioid dependence often start with office-based buprenorphine/naloxone treatment,” explained Schuman-Olivier, a clinical instructor in psychiatry at HMS. “Our findings indicate that opioid-dependent young adults might benefit from starting out with residential treatment and then linking up with continuing outpatient care after discharge. In contrast, many nondependent opioid misusers may not be ready to benefit fully from the time spent in 12-step residential treatment.”
The authors note that the significant increase in opioid misuse among adults ages 18 to 25 led to a 350 percent increase in the numbers admitted to treatment programs from 1998 to 2008, greater than any other age group. Many individuals with opioid dependence (criteria for which include continued use despite substance-related problems, drug tolerance, and withdrawal symptoms) have benefited from outpatient treatment using a combination of buprenorphine and naloxone as an opioid replacement. But another study — led by Schuman-Olivier and published earlier this year in the Journal of Substance Abuse Treatment — found that outpatient buprenorphine/naloxone treatment was significantly less effective in opioid-dependent young adults than in older adults. Given those discouraging findings, the current study was designed to investigate whether residential treatment would be a viable alternative.
The study enrolled 292 young adults participating in a residential treatment program that followed the 12-step Minnesota Model treatment philosophy, which includes detoxification, a number of evidence-based psychotherapeutic approaches, and engagement with community-based mutual-help groups such as Narcotics Anonymous after discharge. Among the enrollees, 73 had been diagnosed with opioid dependence, 58 with opioid misuse, and the other 66 were being treated for use of other drugs, such as alcohol, cocaine, or marijuana. Among all participants the average stay in the residential facility was 26 days, and 84 percent were discharged with staff approval, indicating successful completion of the inpatient treatment.
A year after leaving residential treatment, 29 percent of the opioid-dependent participants remained abstinent from drugs, compared with 22 percent of the opioid misusers, despite the fact that the dependent participants had more significant opioid-related symptoms and consequences when entering the treatment program. Among all three groups, the opioid misusers had the lowest rates of treatment completion, were least likely to engage in outpatient care, and used more marijuana and alcohol during the follow-up period. The authors hypothesize that the poorer outcomes among opioid-misusing participants may reflect less recognition of the seriousness of their condition, leading to less willingness to comply with treatment and recommendations for continuing care.
“Our study emphasizes the importance of strong linkage between residential treatment and continuing care,” says Schuman-Olivier, who also is with the Outpatient Addiction Services at Cambridge Health Alliance. “Right now there is a huge gap between residential and community services in many health systems. Yes, residential treatment can be costly, but with an opioid-dependence epidemic that has led to frequent overdose deaths, it’s important to think about what works, not just costs. We have evidence that outpatient treatment for opioid dependence is not as effective in young adults as it is in older adults, so we need alternatives to protect this vulnerable population.”
Gene test aids cancer profile
The first round of chemotherapy did little to suppress Ron Bose’s leukemia. The second round, with 10 times the dose, knocked the proliferating blast cells down, but only by half.
That’s when his physician, David Steensma, used a new test developed by a team at the Harvard-affiliated Dana-Farber/Brigham and Women’s Cancer Centerthat provides a tumor’s molecular profile, checking samples for 95 specific genes often mutated in blood cancers.
The results indicated that Bose, 70, of Pawcatuck, Conn., had acute myeloid leukemia that contained a rare mutation that Steensma matched to an experimental drug developed by the Cambridge-based pharmaceutical company Agios. By November, after several months on the drug with few side effects, Bose’s blast cell levels had fallen significantly, to a point where he said he not only feels better, but he’s also a potential candidate for a bone-marrow transplant.
The test, called a Rapid Heme Panel, was developed by a team that was led by Harvard Medical School Professor of Pathology Jon Aster, a physician at Brigham and Women’s Hospital.
The test, Aster said, builds on work done by the Profile research project at the Dana-Farber/Brigham and Women’s Cancer Center. That project, which focuses on solid tumors, scans tumor samples for 305 gene mutations found in all types of cancers.
The Rapid Heme Panel was designed not for research, however, but for patient care. Previous clinical tests often took weeks to return results and were limited to a small number of possible mutations. The new test can return results within days.
“The nice thing about a panel like this is you get a whole bunch of mutations all at once, including ones you may not have thought to send,” Steensma said.
The new test helps in a couple of ways, said Steeensma, an associate professor of medicine at Dana-Farber Cancer Institute. It can identify specific conditions in cases where the diagnosis is ambiguous. It can help physicians determine a patient’s prognosis and course of treatment, and it can quickly identify whether a patient is a candidate for an experimental treatment designed to attack specific genes. In Bose’s case, for example, his leukemia was determined to have the IDH2 mutation, which is targeted by Agios’ AG-221 drug.
The Rapid Heme Panel is the natural outgrowth of information-rich times, Aster and Steensma said. With genetic analysis allowing physicians to identify tumors not just by cancer type — blood, lung, breast, brain — but also by individual genetic makeup. With drug companies searching for treatments targeting specific genetic vulnerabilities, a way is needed to guide physicians and patients through an increasing number of diagnosis and treatment options.
“I think we have a better understanding of the molecular basis of blood cancers, more targeted therapies than other cancers,” Aster said. “The more targeted therapies you have, the more targets you have to identify.”
The Rapid Heme Panel went into use in August and has been operating at close to capacity — 42 samples per week — since, Aster said. Aster said the test’s developers are continuing to evaluate it to ensure the best mix of genes is represented.
“This is really the way of the future,” Steensma said. “We are going to be practicing medicine not based on how cells look under the microscope, but rather on what makes a disease tick.”