Working With the Brain's Wall

A blood-brain barrier meeting features a way to reduce cancer drug toxicity in kids, plus the latest on brain imaging controversies.

The latest word on a common medical imaging agent made infamous in a pending lawsuit by actor Chuck Norris, an experimental iron-based imaging agent that gives eye-popping detail of blood vessels in the brain, and a new tumor treatment helper that can prevent hearing loss in kids treated for cancer. These were three of the topics covered in the March 15-16 Blood-Brain Barrier Consortium Meeting in Portland.

In its 24th year, the BBB meeting brought together about 130 scientists and clinicians. Their common interest converged on understanding the BBB better to help treat disease and protect health. The specialized annual gathering was intimate by standards of neurology and neuroscience, where the two of the largest general meetings every year attract 15,000-25,000 doctors and researchers.

It sounds like a single wall, but “blood brain barrier” actually refers to many physical and functional ways of shielding the brain and spinal cord from most substances circulating in the blood, pointed out Norman Saunders, a neuroscientist from University of Melbourne, Australia. Saunders studies the developing brain and presented evidence that a blood-brain barrier forms as soon as blood vessels form in the brain, less than two months after conception.

In adults, the BBB includes several types of cells and tissue surrounding the cerebral blood vessels, he said. Inside the physical lining of endothelial cells, for example, molecular transport systems also stay busy pumping out unwanted bits that leak in, while also selectively admitting necessary nutrients. Another secured barrier site is the lining of the four cavities deep in the brain. Called ventricles, the cavities are filled with cerebrospinal fluid, which circulates in the brain and spinal cord. Many BBB mechanisms remain poorly understood.

The BBB also shields brain tumors from therapeutic drugs. The meeting opened with results from experiments to breach the blood brain barrier to deliver cancer therapy. Researchers from Oregon Health & Science University  and the National Institutes of Health in Bethesda, Maryland, reported on several methods—osmotic opening, ultrasound, and radiation. Later, other speakers discussed how to protect the brain tissue when the BBB is damaged by disease or traumatic brain injury. Slide presentations showcased results of studies and outlined clinical trial proposals to address the next set of questions.

The two-day gathering marked a watershed moment in the career of meeting founder and organizer Edward Neuwelt, a neurosurgeon at Oregon Health & Science University who specializes in brain tumors. For nearly 30 years, Neuwelt has been developing ways to sneak therapeutic agents past the BBB to treat brain tumors that otherwise cannot be reached by chemotherapy.

Two different experimental agents Neuwelt has been systematically studying are nearing the final stages of review for designated clinical use by the U.S. Food & Drug Administration (FDA). One is a drug to protect against hearing loss in people treated with platinum-based chemotherapy agents. The other is an iron-based contrast agent that illuminates blood vessels and other details in MRI brain images. Both agents are marketed for other uses. The meeting had a session on each.

Chemoprotection for the Ears

The hearing protection story has origins in an unexpected side effect in a clinical trial more than 20 years ago. Carboplatin, a platinum-based drug, delivered in a clinical trial in combination with another agent to open the BBB briefly, was causing high-frequency hearing loss. Neuwelt’s team hadn’t noticed that in the preclinical studies.

In the trial, one affected patient, a college professor, recovered from the remaining brain metastasis of her ovarian cancer. While she was receiving the experimental treatment, her husband, a scientist, found a post on an Internet chat room about how sodium thiosulfate (STS), a medicine for cyanide poisoning, could prevent drug-induced hearing loss. On the second round of medication, he entreated Neuwelt to give it to his wife, who had already lost some high-frequency hearing.

Unfortunately, the hearing loss is irreversible, due to the death of the outer hair cells in the cochlea that transfer sound waves to neurons. Instead, Neuwelt scrambled an ad hoc team to study STS further. “It’s a story of a crazy neurosurgeon going into otolaryngology,” he told The Lund Report after the meeting. The preclinical tests were so promising that OHSU applied for a patent and licensed the compound use to a company now called Fennec Pharmaceuticals in North Carolina.

Two recent phase 3 studies have been conducted in children treated for solid tumors of many types with another platinum based drug, cisplatin. A study based in the U.S. found STS reduces the likelihood of cisplatin-induced hearing loss, with the greatest benefit in children younger than age 5. The results were published January 2017 in the journal Lancet Oncology.

A second phase 3 pediatric study, based in Europe, reported slightly better positive preliminary results in October 2017 at a cancer meeting. About half as many children lost their hearing if they were given STS as part of their treatment, compared to those who were treated without the experimental agent, Neuwelt told The Lund Report. Importantly, STS showed no signs of interfering with tumor treatment.  Final results will be published in the near future. On March 21, the FDA announced an expedited “Fast Track” review, for STS (marketed as Pedmark, by Fennec Pharmaceuticals).

Iron Imaging

In another long-term project, Neuwelt has won orphan drug designation for an experimental iron-based agent that can illuminate blood vessels in striking detail. The detail is particularly helpful in brain tumors being treated with new immunotherapy drugs and for imaging vessels for disease and surgical planning.

“We can get better spatial resolution,” he told The Lund Report. “We can detect inflammation. The pictures are unbelievable.”

In a typical MRI, a brain tumor responding to a new immunotherapy drug looks nearly identical to a recurrent glioblastoma. “How can we know this is an inflammatory response and not tumor progression?” OHSU radiologist Ramon Barajas asked. The fine detail of a higher resolution image with ferumoxytol may help surgeons avoid a biopsy, according to preliminary

The agent, ferumoxytol (Feraheme, AMAG Pharmaceuticals), is marketed as intravenous iron replacement medicine for people with kidney disease, but Neuwelt is seeking extended FDA approval for imaging. FDA approval would encourage insurance companies to pay for the procedure. At about $600, the agent, is about 2-3 times as expensive as the more common gadolinium contrast agent.

“From a surgeon’s perspective,” OHSU neurosurgeon Seunggu Jude Han said, “the strength of ferumoxytol is a better picture of the biological processes.” Han is conducting a comparative phase 2 study of glioblastoma, comparing a two different ways of using ferumoxytol to guide tumor resection.

As graduate student, Cymon Kersch had reported earlier from her genetic studies, tumors have distinctive structures, with different activities and gene patterns in the different areas, such as in the more cancerous areas around blood vessels.

With an estimated 800 ferumoxytol-enhanced MRI brain images, Neuwelt said his group in Oregon has more experience with the agent than anyone else in the world. “We’re not trying to put gadolinium out of business,” he told The Lund Report. “Overall, we think it’s a good substitute for people with renal problems.”

Gadolinium Controversy

Gadolinium is the most common contrast agent, used in an estimated 40 million MRI scans per year worldwide, or 400 million total in the last 30 years. Except for people with kidney disease, gadolinium agents have been regarded as very safe.

Four years ago, a Japanese team ignited controversy. They found bright spots in the brains of people who had received repeated gadolinium-enhanced MRIs, and provocatively suggested that gadolinium deposits were being mistaken for disease activity in a certain kind of MRI scan.

Other studies since then have confirmed small amounts of gadolinium are retained in certain brain tissues in amounts roughly proportional to gadolinium exposure. One research team published a survey of people with self-reported symptoms and called it “gadolinium deposit disease.” In November, Gena and Chuck Norris filed a lawsuit against several gadolinium manufacturers, alleging she was “poisoned” and sustained gadolinium deposit disease after a “routine MRI.”

“These agents have saved billions of lives,” said Robert McDonald, a radiologist at the Mayo Clinic in Rochester, Minn. “We hear about the deposition issue and it terrifies us,” he said. “Europe has a different reaction than the U.S., not entirely based on science. Even the worse offender in deposition is still a pretty good agent.”

Nonetheless, McDonald said, “To be scientists and clinicians, we have to be open to the possibility that this is a real but rare phenomenon. But listing it as a disease and naming it—that’s not science.” So far, there is no evidence of brain injury from gadolinium exposure, but McDonald and others are looking.

In studies, McDonald has documented that gadolinium is retained in brains of people without brain or kidney disease, not just in people with brain tumors or other brain diseases that might have created a leaky blood brain barrier.

Last summer, the EMA suspended or restricted use of some gadolinium agents known as “linear,” based on the shape of the molecular carrier. This was based on the belief that another category, called “macrocyclic,” are safer. That is not what McDonald and his team found in a rat study of both categories of agents.

“Gadolinium deposition is real,” McDonald summed up. “It appears to be associated with both linear and macrocyclic agents. This ship will sink with everyone on board.”

It takes a large study to track down rare effects in people. Two years ago, a large hospital database study exonerated gadolinium as a risk factor in Parkinson’s disease. McDonald tapped into the Mayo Study on Aging, the longest continuously funded study of human health, to look for symptoms in people exposed to gadolinium.

“Ultimately, we found gadolinium had no effect on any of these typical neurological outcomes: Memory, language, attention, visual, Parkinson’s, and mental status,” said McDonald. “We’re focusing on the brain, but in reality, the kidney has thousands of times higher gadolinium retention than the brain,” he said. He presented the preliminary results at the November 2017 meeting of the Radiological Society of North America.

Jennifer McDonald , his colleague and wife, wanted to know what happened to kids. She presented results that showing that pediatric patients are also susceptible to gadolinium retention. “The clinical significance is incompletely understood,” she said. “We haven’t found a phenotype.”

Several speakers argued that doctors need to exercise restraint on gadolinium imaging by using appropriate doses within evidence-based radiology guidelines. “One of the main questions is how should the agents be used to minimize risk,” observed Mark Woods, a radiology imaging chemist at Portland State University and OHSU. “It’s wise not to use gadolinium when you don’t have to use it. But if it’s clinically necessary, then it’s clinically necessary.” Woods also advised doctors and radiologists to check out what agents their institutions are buying.

“The perception has been that you don’t omit gadolinium because you might miss something, and you don’t want to miss anything because you could get sued,” Robert McDonald said. “The biggest challenge is that radiologists have typically become the ‘yes’ people. [Evidence] criteria are not followed.”

Research is continuing. “We know very little about this, McDonald said. “If we keep research focused on the patient, we’ll always do the right thing.”



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