Bonnie Carroll's Life Bites

Tumors ‘Light Up’ With New, Unique Imaging System Using Scorpion Venom Protein and a Laser

Cedars-Sinai Animal Study May Lead to Human Trial of Experimental, Compact Intraoperative Device to Aid Removal of Malignant Brain Tumors

The experimental system consists of a special camera designed and developed at Cedars-Sinai and a new, targeted imaging agent based on a synthetic version of a small protein – a peptide – found in the venom of the deathstalker scorpion. The imaging agent, Tumor Paint BLZ-100, a product of Blaze Bioscience Inc., homes to brain tumor cells. When stimulated by a laser in the near-infrared part of the spectrum, it emits a glow that is invisible to the eye but can be captured by the camera.

Results of animal studies, published as the feature article in the February issue of Neurosurgical Focus, provide the basis for the launch of human clinical trials. The system would be used during surgery to determine if it enables neurosurgeons to remove more tumor and spare more healthy tissue.

Malignant brain tumors called gliomas are among the most lethal tumors, with patients typically surviving about 15 months after diagnosis. “We know that survival statistics increase if we can remove all of a tumor, but it is impossible to visualize with the naked eye where tumor stops and brain tissue starts, and current imaging systems don’t provide a definitive view,” said Keith Black, MD, chair and professor of the Department of Neurosurgery, the article’s senior author.

“Gliomas have tentacles that invade normal tissue and present big challenges for neurosurgeons: Taking out too much normal brain tissue can have catastrophic consequences, but stopping short of total removal gives remaining cancer cells a head start on growing back. That’s why we have worked to develop imaging systems that will provide a clear distinction – during surgery – between diseased tissue and normal brain,” said Black, director of the Maxine Dunitz Neurosurgical Institute, director of the Johnnie L. Cochran, Jr. Brain Tumor Center and the Ruth and Lawrence Harvey Chair in Neuroscience.

In studies in laboratory mice with implanted human brain tumors, the new device clearly delineated tumor tissue from normal brain tissue. Also, with near-infrared light’s ability to penetrate deep into the tissue, the system identified tumors that had migrated away from the main tumor and would have evaded detection.

Pramod Butte, MBBS, PhD, research scientist and assistant professor in the Department of Neurosurgery, the article’s first author, said the tumor-imaging process consists of two parts: deploying a fluorescent “dye” that sticks only to cancer cells, and using a laser and a special camera to make an invisible image visible.

To get the dye to the tumor, it is linked to a peptide called chlorotoxin, which, contrary to its name, is not toxic. It completely ignores normal tissue but seeks out and binds to a variety of malignant tumor cells. It first was derived from the venom of the yellow Israeli scorpion, also called the deathstalker. Article co-author Adam Mamelak, MD, professor of neurosurgery and director of functional neurosurgery, has studied the synthetic version of chlorotoxin and its tumor-targeting properties for more than a decade.

In this study, chlorotoxin was bonded to a molecule, indocyanine green, a near-infrared dye, a version of which already is approved by the Food and Drug Administration. The chlorotoxin-indocyanine green combination – Tumor Paint BLZ-100 – emits a glow when stimulated by near-infrared light.

“Injected intravenously, the chlorotoxin seeks out the brain tumor, carrying with it indocyanine green, which has been used in a variety of medical imaging applications. When we shine a near-infrared laser on the tissue, the tumor glows. But the glow emitted by the tumor is invisible to the human eye,” said Butte, whose MBBS is India’s equivalent of an MD. The camera device, designed in Butte’s lab, solves this problem by capturing two images and combining them on a high-definition monitor.

“Other experimental systems we have seen – which use different tumor-targeting methods – are larger and bulkier because they consist of two cameras,” Butte said. “Our single-camera device takes both near-infrared and white light images simultaneously. This is achieved by alternately strobing the laser and normal white lights at very high speeds. The eye just sees normal light, but the camera is capturing white light once, near-infrared light next, over and over. We then superimpose the two HD images. The image from the laser shows the tumor, and the image produced from white light shows the visible ‘landscape’ so we can see where the tumor is in context to what we actually can see.”

The prototype is compact, but the authors said they are working to make the next generations even smaller, lighter and portable so the device will require very little space in operating room, allowing the neurosurgeon to focus on the operating microscope and give little attention on the imaging system. “We hope that eventually the camera can be transported in a small bag, but we are not sacrificing image quality for portability,” Butte said. “In fact, most systems that use two cameras lose a lot of light. But because of the special filters we use and the way we arrange them, we lose very little light. And from what we have seen and tested, our device provides about 10 times greater sensitivity and contrast than others.”

In an editorial accompanying the journal article, David W. Roberts, MD, from the Section of Neurosurgery at the Geisel School of Medicine at Dartmouth College, said the Cedars-Sinai “paper presents a newer direction in which fluorescence-guided surgery may well be headed.” He noted that the researchers overcame one of the limitations of near-infrared technology – that it is outside of the visible portion of the spectrum. “In this regard, Butte and colleagues have contributed to the field with their implementation of an optical system that is sensitive and efficient. They have characterized well its performance in phantom and animal models, demonstrating proof-of-concept and feasibility.”

Authors: Pramod V. Butte, MBBS, PhD; Adam Mamelak, MD; Julia Parrish-Novak, PhD; Doniel Drazin, MD; Faris Shweikeh, BS; Pallavi R. Gangalum, PhD, Alexandra Chesnokova, MD; Julia Y. Ljubimova, MD, PhD; Keith Black, MD.

Disclosure: The authors thank Stacy Hansen and Disha Sahetya from Blaze Bioscience, Inc., Seattle, for providing the BLZ-100 samples. The study was internally funded by the Department of Neurosurgery at Cedars-Sinai Medical Center. Dr. Mamelak has ownership in Teal Light Surgical. Dr. Parrish-Novak (one of the authors) is an employee of Blaze Bioscience, Inc.

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Living with diabetes is not easy with the potential to cause problems which people without diabetes take in their stride. Take travel and diabetes for instance. At the moment there are around 17 million leisure and 6 million business travelers living with diabetes. Presently only a handful of resources offer travel guidance for them and while some offer good advice, many limit their scope to storage and transportation of supplies, immunizations and diet advice making them too generalized to answer specific questions such as what to do about insulin and long-haul travel.
Impact of Travel
It has been estimated that around 1 in 10 of travelers on short as well as long-haul journeys experienced problems, most commonly hypoglycemia during the journey or in the first 24 hours after arriving at their destination. One other common problem that insulin-treated individuals face when flying across time zones is confusion about how to adjust their insulin times and dosage amounts to avoid being “out of sync” with local time on arrival.
The Journey with Diabetes
For people living with diabetes any journey is actually a series steps with potential roadblocks in place to disrupt their journey.

At Sansum Diabetes Research Institute we have started to create new technologies to help with travel and diabetes (see www.VoyageMD.com). With the growing use of tablet and mobile devices there are opportunities to create valuable technologies that are easy to use, helpful and will reduce the hassle associated with travel.

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Dear EarthTalk: What’s behind the rise in public transit in the U.S. in the last few years, and how does our transit use compare with that of other developed countries? -- Angie Whitby, New Bern, NC

Transit ridership is indeed at its highest level in the

U.S.

in 57 years. According to data collected by the American Public Transportation Association (APTA), Americans took 10.7 billion trips on public transportation in 2013—the highest number since the 1950s when many fewer of us owned our own cars.

And this increase “isn’t just a one-year blip,” says APTA. Since 1995—when Congress passed the landmark ISTEA legislation and other surface transportation bills that greatly increased funding for public transit—U.S. ridership has risen 37.2 percent, topping both population growth (up 20.3 percent) and vehicle miles traveled (up 22.7 percent). “There's a fundamental shift going on,” says APTA’s president Michael Melaniphy. “More and more people are deciding that public transportation is a good option."

A number of factors are contributing to Americans’ embrace of transit in recent years. For one, the flow of federal dollars to transportation alternatives since 1995 has meant more options than ever are available to those leaving their cars behind: Melaniphy reports that in the last two years, upwards of 70 percent of transit tax initiatives have passed, providing lots more funding for beefing up transit projects coast-to-coast. Another factor is the economic recovery. “When more people are employed, public transportation ridership increases, since nearly 60 percent of the trips taken on public transportation are for work commutes,” says Melaniphy. “People in record numbers are demanding more public transit services and communities are benefiting with strong economic growth.”

Despite these gains, the

U.S.

still lags way behind other developed nations. In a recent issue of The Atlantic, Ralph Buehler cites 2010 statistics showing that, while Americans drive for 85 percent of their daily trips, Europeans opt for cars only 50-65 percent of the time. “Longer trip distances only partially explain the difference,” reports Buehler, adding that 30 percent of daily trips are shorter than a mile on both continents. “But of those under-one-mile trips, Americans drove almost 70 percent of the time, while Europeans made 70 percent of their short trips by bicycle, foot or public transportation.”

The

U.S.

ranked last in the National Geographic Society’s Greendex survey of transit use across 17 developed nations. Only five percent of Americans surveyed reported using public transit on a daily basis and only seven percent reported using it at least once a week. Internationally, 25 percent of respondents reported daily public transportation use, with 41 percent using it at least once a week. According to Greendex, Canadians are more than twice as likely to report weekly or more transit usage than Americans, while Germans are almost five times more likely to use transit at least weekly.

Russia

topped the list with 52 percent of respondents using public transit daily and 23 percent using it at least once a week.

Given America’s suburban sprawl—and the car-based infrastructure that has built up to support it—it’s hard to believe the

U.S.

will ever catch up with other developed countries in transit usage. But that won’t stop millions of forward-thinking Americans from trying.

EarthTalk® is written and edited by Roddy Scheer and Doug Moss and is a registered trademark of E - The Environmental Magazine (www.emagazine.com). Send questions to: earthtalk@emagazine.com.