Patient plays saxophone while surgeons remove brain tumor

Music is not only a major part of Dan Fabbio’s life, as a music teacher it is his livelihood. So when doctors discovered a tumor located in the part of his brain responsible for music function, he began a long journey that involved a team of physicians, scientists, and a music professor and culminated with him awake and playing a saxophone as surgeons operated on his brain.

Fabbio’s case is the subject of a study published in the journal Current Biology that sheds new light on how music is processed in the brain. In the spring of 2015, Fabbio was serving as substitute music teacher in a school in New Hartford, New York. He was in a small office at the school working on the capstone project for his Master’s degree in music education when he began to suddenly “see and hear things that I knew were not real.”He became dizzy and nauseous and the episode prompted a visit to hospital in nearby Utica later that day. After undergoing a CAT scan, the doctors sat Fabbio down and told him they found a mass in his brain.

I was 25 at the time and I don’t think there is any age when it is OK to hear that,” recalled Fabbio. “I had never had any health problems before and the first thing my mind went to was cancer.”The good news was that the tumor appeared to be benign – in fact, it had probably been slowly growing since childhood – and was in an area of the brain that was relatively easy for surgeons to access. The bad news was that it was located in a region that is known to be important for music function.Fabbio was referred to UR Medicine’s Del Monte Institute for Neuroscience and neurosurgeon Web Pilcher, M.D., Ph.D.

When I met Dan for the first time, he expressed how concerned he was about losing his musical ability, because this frankly was the most important thing to him in his life, not only his livelihood, but his profession and his interest in life,” said Pilcher.

A Precise Map of Brain Function

Pilcher, who is the Ernest and Thelma Del Monte Distinguished Professor of Neuromedicine and Chair of Department of Neurosurgery, had struck up a partnership with Brad Mahon, Ph.D., an associate professor in the University of Rochester Department of Brain and Cognitive Sciences. The two have developed a Translational Brain Mapping program for patients who had to undergo surgery to remove tumors and control seizures.

Removing a tumor from the brain can have significant consequences depending upon its location,” said Pilcher. “Both the tumor itself and the operation to remove it can damage tissue and disrupt communication between different parts of the brain. It is, therefore, critical to understand as much as you can about each individual patient before you bring them into the operating room so we can perform the procedure without causing damage to parts of the brain that are important to that person’s life and function.”

The brain mapping program Pilcher and Mahon developed is tailored to circumstances of the individual. Patients with brain tumors are now routinely referred to Mahon before undergoing their surgery. Mahon and his team subject each individual to a battery of tests, including brain scans that identify important functions – such as motor control and language processing – that may be located in proximity to the tumor and potentially impacted by the surgery.

Everybody’s brain is organized in more or less the same way,” said Mahon. “But the particular location at a fine grain level of a given function can vary sometimes up to a couple centimeters from one person to another. And so it’s really important to carry out this kind of detailed investigation for each individual patient.”

While testing language and motor skills was relatively straightforward, evaluating musical ability, especially in a trained musician, was a different undertaking altogether. Perhaps nowhere in the world was Fabbio’s case a better fit. Not only had Pilcher performed hundreds of these surgeries and had partnered with Mahon to develop a sophisticated brain mapping program that would be key to the procedure’s success – but the famed Eastman School of Music, a part of the University of Rochester, could be called upon to help plan Fabbio’s surgery.

Mahon reached out to Elizabeth Marvin, Ph.D., a professor of Music Theory in the University of Rochester’s Eastman School of Music. Marvin also holds a position in the Department of Brain and Cognitive Sciences and studies music cognition – the ability of our brains to remember and process music.

The two developed a series of cognitive musical tests that Fabbio could perform while the researchers were scanning his brain. During functional MRI (fMRI) scanning, Fabbio would listen to and then hum back a series of short melodies. He also performed language tasks that required him to identify objects and repeat sentences. The fMRI detects changes in oxygen levels, so the parts of the brain that were activated during the tests helped pinpoint the areas important for music and language processing.

Using this information the research team produced a highly detailed three-dimensional map of Fabbio’s brain – with both the location of the tumor and music function – that would be used to help guide the surgeons in the OR.

Saxophone Serenades Surgeons

The ability to process and repeat a tune was an important measure, but the team also wanted to know if they were successful in preserving Fabbio’s ability to perform music. So they decided to bring his saxophone into the OR and, if possible, have him play it during the procedure.

The challenge was that Fabbio would be lying on his side, so it would be difficult to play the instrument. Also, the pressure caused by the deep breathes required to play long notes on the saxophone could cause the brain, which would be exposed during the procedure, to essentially protrude from his skull. Fabbio and Marvin ultimately selected a piece – a version of a Korean folk song – that could be modified to be played with shorter and shallower breaths.

The whole episode struck me as quite staggering that a music theorist could stand in an operating room and somehow be a consultant to brain surgeons,” said Marvin. “In fact, it turned out to be one of the most amazing days of my life because if felt like all of my training was suddenly changing someone’s life and allowing this young man to retain his musical abilities.”

During the procedure, Pilcher and the surgical team used the map of Fabbio’s brain that had been developed by Mahon to plan the surgery. They also went through a process of painstakingly reconfirming what the brain scans showed them. This was accomplished by delivering a mild electrical stimulus that temporarily disrupts a small area of the brain. While this was occurring, Fabbio was awake and repeating the humming and language tasks he performed prior to the surgery. Marvin was present in the OR and scored his performance to let the surgeons know whether or not they had targeted an area that disrupted music processing and, therefore, should be avoided during the procedure.

Once the tumor had been removed the surgeons gave the go ahead to bring over the saxophone and let Fabbio play. “It made you want to cry,” said Marvin. “He played it flawlessly and when he finished the entire operating room erupted in applause.”

Fabbio has since completely recovered and returned to teaching music within a few months of his surgery.

Harnessing Science to Improve Brain Surgery

While the brain mapping program’s primary purpose is to help improve surgical outcomes, the information that the researchers gather before, during, and after the surgery is also helping advance understanding of complexities of the brain’s structures and function.

We study about 40 or 50 patients a year and what this allows us to do is ask what are the factors that we can identify in these patients before their surgery or early on after their surgery that distinguish which patients go on to have a good outcome versus which patients may have lingering cognitive impairments,” said Mahon.

The data from Fabbio’s case, which is the basis of a study in the journal Current Biology, has helped more precisely define the relation between the different parts of the brain that are responsible for music and language processing.

As I think back about Dan’s case and about the incredible outcome and what we were able to achieve, it reminds me of how far we have come,” said Pilcher. “Ten years ago, we mapped the brain using very simple tools – electrical stimulation and image guidance. But now, we have all the tools of cognitive science. We have brought the cognitive science laboratory into the operating room and now almost as a matter of course with every single patient.”


New immunotherapy for malignant brain tumors

It is relatively easy to treat cancer in the early stages. However, it is far more difficult to successfully treat advanced cancer. Treatment of brain tumors is particularly challenging because regulatory T-cells accumulate in brain tumors and suppress an immune attack.

In several steps using a new strategy and a novel drug, Burkhard Becher’s team from the Institute of Experimental Immunology at the University of Zurich has now succeeded in doing exactly this in the case of glioblastoma, one of the most dangerous brain tumors. First step, they stimulated the body’s own immune system in such a way that it recognised and then killed the brain tumor cells even in advanced stages of the disease.

The initial objective of their new study was to break through the tumor’s protective shield. “We wanted to establish whether we can actually elicit an immune response to a tumor growing within the brain”, explains Burkhard Becher. To this end, the team used the immune messenger substance, Interleukin-12. When Interleukin-12 is produced in the tumor, immune cells are stimulated locally in such a manner that the tumor is attacked and rejected. Once this procedure had worked well in the early stages of the tumor, the researchers waited in the next stage until the tumor was very large and the life expectancy of the untreated test animals was less than three weeks. “We only began treatment when it was, in fact, already too late”, says the first author of the study Johannes vom Berg. The success rate was low, Berg adds. “We then injected biopharmaceutical Interleukin-12 into the large brain tumor. This did induce an immune response but only led to tumor rejection in one-quarter of the animals.”

From 25 to 80 percent: combined treatment leads to success

The researchers were successful when they drew on a new development in skin cancer treatment. They combined intra-tumoral Interleukin-12 treatment with the intravenous administration of a novel immunostimulating drug that suppresses the regulatory T-cells. The rejection of the tumor then worked in 80 percent of the test animals. “I have rarely seen such convincing data in preclinical glioma treatment”, says Michael Weller, neurooncologist and Director of the Clinic for Neurology at the University Hospital Zurich. He added, “That’s why this development should be tested as soon as possible in clinical trials.”

In a joint trial, the team then tested the treatment in a further tumor model which mimics the clinical situation of the brain tumor patient even better. And once again they were successful.

The next step: a clinical trial as soon as possible

The findings of the current research work have been published in the Journal of Experimental Medicine. Their promising results do not mean that the treatment can already be as effective in brain tumor patients. This has to be examined in the next phase for which the team now actively seek commercial partners. Burkhard Becher puts it like this, “We are cautiously optimistic but it’s time that we adopted completely new strategies to really get to grips with this fatal tumor”

vom Berget et al.,(2013). Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell mediated glioma rejection. J. Exp. Med., EPub Ahead of Print, doi: 10.1084/jem.20130678 [Abstract]

Microencapsulation produces uniform drug release vehicle

Consistently uniform, easily manufactured microcapsules containing a brain cancer drug may simplify treatment and provide more tightly controlled therapy, according to Penn State researchers.

“Brain tumors are one of the world’s deadliest diseases,” said Mohammad Reza Abidian, assistant professor of bioengineering, chemical engineering and materials science and engineering. “Typically doctors resect the tumors, do radiation therapy and then chemotherapy.”

The majority of chemotherapy is done intravenously, but, because the drugs are very toxic and are not targeted, they have a lot of side effects. Another problem with intravenous drugs is that they go everywhere in the bloodstream and do not easily cross the blood brain barrier so little gets to the target tumors. To counteract this, high doses are necessary.

Perfect microspheres were produced using 4 percent by weight of the polymer.
Click here for more information.

Current treatment already includes leaving wafers infused with the anti-tumor agent BCNU in the brain after surgery, but when the drugs in these wafers run out, repeating invasive placement is not generally recommended.“We are trying to develop a new method of drug delivery,” said Abidian. “Not intravenous delivery, but localized directly into the tumor site.”

“BCNU has a half life in the body of 15 minutes,” said Abidian. “The drug needs protection because of the short half life. Encapsulation inside biodegradable polymers can solve that problem.”

Encapsulation of BCNU in microspheres has been tried before, but the resulting product did not have uniform size and drug distribution or high drug-encapsulation efficiency. With uniform spheres, manufacturers can design the microcapsules to precisely control the time of drug release by altering polymer composition. The tiny spheres are also injectable through the skull, obviating the need for more surgery.

Microfibers were produced using 10 percent by weight solutions of the polymer.
Click here for more information.

Abidian, working with Pouria Fattahi, graduate student in bioengineering and chemical engineering, and Ali Borhan, professor of chemical engineering, looked at using an electrojetting technique to encapsulate BCNU in poly(lactic-co-glycolic) acid, an FDA-approved biodegradable polymer. In electrojetting, a solution containing the polymer, drug and a solvent are rapidly ejected through a tiny nozzle with the system under a voltage as high as 20 kilovolts but with only microamperage. The solvent in the liquid quickly evaporates leaving behind anything from a perfect sphere to a fiber.

“Electrojetting is a low cost, versatile approach,” said Abidian. “We can produce drug-loaded micro/nano-spheres and fibers with same size, high drug-loading capacity and high drug-encapsulation efficiency.”

The researchers tested solutions of polymer from 1 percent by weight to 10 percent by weight and found that at 1 to 2 percent they obtained flattened microspheres, at 3 to 4 percent they had microspheres, at 4 to 6 percent they had microspheres and microfibers, at 7 to 8 percent they had beaded microfibers and above 8 percent they obtained only fibers. They report their results in the current issue of Advanced Materials.

This is a scanning electron micrograph of BCNU-loaded microspheres (black and white background) with 3D rendered images of brain cancers cells (yellow) and released BCNU (purple).
Click here for more information.

The researchers also investigated the sphericality of the spheres.“Depending on the desired applications, all the shapes are useful except for the beaded fibers,” said Abidian. “While fibers are not good for drug delivery, they are good for tissue engineering applications.”

“We looked at how spherical they were and found they were perfect,” said Abidian. They have a height versus width ratio of 1.05 and they have size uniformity. A perfect sphere would have a ratio of 1.

The researchers also looked into how BCNU releases from the microcapsules. Using mathematics, the researchers established a drug diffusion coefficient for the encapsulation system. This helps in designing how much drug to include in each microcapsule and how long the microcapsules will deliver the required dosage.

The researchers note that BCNU is not the only drug that can be encapsulated in polymer beads for drug delivery. Other drugs can be used but would have their own diffusion coefficients and half lifes.

Fattahi et al., (2013). Microencapsulation: Microencapsulation of chemotherapeutics into monodisperse and tunable biodegradable polymers via electrified liquid jets: Control of size, shape, and drug release.Adv. Mater., 25: 4529 [Abstract]

Novel insight into ‘hot’ experimental cancer treatment

Physicists from the University of York have carried out new research into how the heating effect of an experimental cancer treatment works.

Magnetic hyperthermia is viewed as an attractive approach for the treatment of certain cancers as it has no known side effects compared to more conventional therapies such as chemotherapy. It is particularly suitable for the treatment of prostate cancer and brain tumours. However, until now there has been no clear theoretical understanding of how it actually works.

Treatment by magnetic hyperthermia involves injecting magnetic nanoparticles directly into a tumour then placing the patient in a machine which produces an alternating magnetic field. The nanoparticles oscillate and heat is produced inside the tumour tissue. When the temperature rises above 42ºC cells begin to die. This heating process has been demonstrated to reduce tumour size.

The study, by researchers from the University of York’s Department of Physics and Liquids Research Ltd, of Bangor, North Wales, showed that the amount of heat generated by magnetic nanoparticles can be understood when both the physical and hydrodynamic size distributions for the samples are known to high accuracy.

The results of the study are published in the Journal of Physics D: Applied Physics as a fast track communication.

Lead author Dr Gonzalo Vallejo-Fernandez, from York’s Department of Physics, said: “While clinical trials have shown the potential of magnetic nanoparticles for cancer treatment, the mechanisms by which the heat is generated have not been fully understood. This understanding is critical to produce particles with optimised properties for specific applications at minimal dose.”

Previously the heat generated was impossible to predict as several mechanisms were involved. The new work has identified and quantified the mechanisms so that work can now begin to determine the dosage required for effective treatment.

Dr Vallejo-Fernandez said: “Through our study we have produced the first comprehensive assessment of how the heating effect in magnetic hyperthermia works. We are now in a position where we can do further work to calculate accurately the dose of magnetic nanoparticles and length of treatment required.”

For the study, the researchers used magnetic nanoparticles produced by a new technique by Liquids Research Ltd, which was developed under the EU project MULTIFUN (Multifunctional Nanotechnology for Selective Detection and Treatment of Cancer). The nanoparticles are very uniform in size and well separated, which enabled detailed experiments to be performed which broadly confirmed the accuracy of the calculations.

Dr Vijay Patel, Director of Liquids Research Ltd, said: “The development of this new theory coincided with our work on the new process to fabricate the nanoparticles enabling us to ‘design’ almost ideal particles for this application.”

Vallejo-Fernandez et al., (2013). Mechanisms of hyperthermia in magnetic nanoparticles.  J. Phys. D: Appl. Phys. 46 312001 doi:10.1088/0022-3727/46/31/312001 [Abstract]