Research Articles

Mouse studies show minimally invasive route can accurately administer drugs to brain

Mouse studies show minimally invasive route can accurately administer drugs to brain
Mouse studies show minimally invasive route can accurately administer drugs to brain

In experiments in mice, Johns Hopkins researchers say they have developed a technique that facilitates the precise placement of cancer drugs at their intended targets in the brain. This approach pairs a technique that guides a catheter through the brain's arteries with positron emission technology (PET) scans to precisely place cancer drugs at their intended targets in the brain. If future studies show this image-guided drug delivery method is safe and effective in humans, the researchers say it could improve outcomes for historically difficult-to-treat and often lethal brain cancers, such as glioblastoma.

The study published May 1 in The Journal of Nuclear Medicine.

"Brain disorders are often much harder to treat than disorders elsewhere in the body, not only because of the hard flat skullbones that encase the brain complicating surgical access, but also because of the blood-brain barrier, the brain's sophisticated defense system, denying access to toxins and the majority of drugs," says Miroslaw Janowski, M.D., Ph.D., associate professor of radiology and radiological science at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Institute for Cell Engineering. "Cancer drugs are often administered as pills or intravenous injections, which are easy and comfortable for patients, but only a tiny portion of these drugs reach the brain tumor. Most of it accumulates in other organs, often leading to serious side effects. The intra-arterial approach solves this problem by allowing us to deliver highly concentrated treatments directly and selectively to the tumor," says Piotr Walczak, M.D., Ph.D., associate professor of radiology and radiological science at the Johns Hopkins University School of Medicine and a co-investigator on this project.

In their experiments, the research team tested whether a technique commonly used to treat strokes where a catheter is guided from an artery in the leg, through the body and into the brain, could be used to improve precision and efficacy of drug delivery.

The researchers chose to first test this intra-arterial technique with bevacizumab, an antibody protein used to treat a variety of human cancers. Similar antibodies are used also in the rapidly blooming field of immunotherapy.

Due to their large size, antibodies cannot easily cross the blood-brain barrier. To circumvent that problem, the researchers used a drug called mannitol, which is commonly used to lower pressure in the brain. Mannitol is a sugar found naturally in fruits and vegetables, and when delivered to arteries in the brain, it causes the cells making up the blood-brain barrier to contract, leaving spaces in between where large molecules can pass through.

The researchers studied this drug delivery method, comparing intra-arterial versus intravenous injection with and without opening of the blood-brain barrier. The group paired these methods with dynamic PET imaging that allowed them to watch the location of the drug during and after the infusion.

PET scans are widely used to diagnose and treat patients suffering from various diseases, such as cancer and Alzheimer's disease. These scans are performed by injecting generally safe and relatively short-acting radioactive tracers into the body through a vein to track a variety of metabolic activities, including oxygen flow or the breakdown of sugar molecules.

Janowski's team used one of these tracers, Zirconium 89, to label the bevacizumab antibody.

In the first experiment, the researchers anesthetized four healthy mice and guided a catheter to the brain. The researchers administered mannitol through the catheter to open the blood-brain barrier and approximately 8.5 megabecquerels, a standard measure for radioactive tracers, of bevacizumab labeled with the tracer. The researchers then imaged the brains of the mice on a PET scanner designed for small animals for 30 minutes after the drug was administered, and took more images one hour and one day after treatment.

Another four mice received a similar treatment, but without opening the blood-brain barrier. Again, the animals were imaged for 30 minutes after the drug was administered, and more images were taken one hour and one day after treatment.

The last group of four mice received the same amount of bevacizumab intravenously. This group of mice was imaged on the small animal PET scanner 15 minutes before the mannitol was administered, and 30 minutes, one hour and one day after treatment.

The results show that intra-arterial drug delivery with the blood-brain barrier opened was the most effective method, with 23.58 percent of the dose per cubic centimeter reaching the brain and remaining there until the last observation at 24 hours after treatment.

Intra-arterial drug delivery without opening the blood-brain barrier resulted in 9.66 percent of the dose per cubic centimeter reaching the targeted area of the brain in the first six minutes of treatment, decreasing to 9.16 percent at 24 hours, "which is still quite impressive, but significantly lower, emphasizing the importance of the blood-brain barrier opening," says Wojtek Lesniak, Ph.D., director of the radiometabolite laboratory in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine and first author on the study.

The mice receiving intravenous bevacizumab showed no brain uptake beyond background levels found across the body, regardless of the blood-brain barrier status.

"Although a little more technically demanding than the standard intravenous approach, the degree of enhancement of antibody uptake within the brain using the intra-arterial approach could revolutionize antibody-based immunotherapy for neurooncology," says Martin Pomper, M.D., Ph.D., the Henry N. Wagner, Jr. Professor of Radiology and Radiological Science in the Johns Hopkins radiology department and a co-investigator on the study.

The Johns Hopkins team cautions that more research is needed to establish the safety of this procedure, but Janowski says that using the arterial route to deliver drugs directly into the brain could offer the benefit of limiting exposure of the whole body to toxic anti-cancer agents.

In the future, the researchers plan to move toward clinical trials of this technique in humans.

According to the American Brain Tumor Association, brain tumors affect more than 700,000 Americans. Of the 120 different types of brain tumors, glioblastoma is among the most malignant, with a median survival of 11-15 months. Treatments for glioblastoma vary based on individual patients' needs and characteristics of the tumor. Treatment options often include surgical removal of the tumor, drugs to inhibit the growth of new blood vessels to feed the tumor, radiation and chemotherapy.

Other researchers involved in this study include Chengyan Chu, Anna Jablonska and Yong Du, of the Johns Hopkins University School of Medicine.

This research was funded by the National Institute of Neurological Disorders and Stroke (R01NS091100, R21NS106436), The Maryland Stem Cell Research Fund (3942) and the National Institute of Biomedical Imaging and Bioengineering (EB024495).

Story Source:

Materials provided by Johns Hopkins MedicineNote: Content may be edited for style and length.


Journal Reference:

  1. Wojciech G. Lesniak, Chengyan Chu, Anna Jablonska, Yong Du, Martin G. Pomper, Piotr Walczak, Miroslaw Janowski. A Distinct Advantage to Intraarterial Delivery of 89Zr-Bevacizumab in PET Imaging of Mice With and Without Osmotic Opening of the Blood–Brain BarrierJournal of Nuclear Medicine, 2019; 60 (5): 617 DOI: 10.2967/jnumed.118.218792

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Drug Delivery Approach Shows Promise for Treating Deadly Brain Tumor in Children

Drug Delivery Approach Shows Promise for Treating Deadly Brain Tumor in Children
Drug Delivery Approach Shows Promise for Treating Deadly Brain Tumor in Children

By Jim Stallard, June 15, 2018 - Memorial Sloan Ketting Cancer Center

Brain tumors are notoriously hard to treat with drugs. Treatments such as chemotherapy have trouble getting through the aptly named blood-brain barrier. This membrane is very selective about allowing substances to pass from the bloodstream into the brain. Most drugs given by IV never make it to tumors in high enough concentrations to be effective. As a result, progress in treating some tumors has been agonizingly slow or even nonexistent.

Results from a phase I clinical trial led by researchers at Memorial Sloan Kettering and Weill Cornell Medicine now suggest that treatment of some of the most difficult brain tumors may have taken a major step forward. The study tested a new drug delivery technique called convection enhanced delivery (CED). The findings indicate that CED appears safe and effective at distributing a drug throughout a fatal pediatric brain tumor called diffuse intrinsic pontine glioma (DIPG). The encouraging results are published in the journal The Lancet Oncology.

"This is the most exciting thing I've done in my career by far." -Mark M. Souweidane pediatric neurosurgeon

DIPG tumors begin in the brain stem. This area at the base of the brain regulates many critical body functions, such as breathing, heart rate, and swallowing. DIPG is very difficult to treat because of its location and because the tumor cells can infiltrate normal brain tissue. Surgery is out of the question. The only traditional option has been radiation treatment, which has a minimal effect. Children with DIPG tend to live just a year or less.

The new study provides hope that drugs can be delivered more efficiently to DIPG tumors — and possibly other tumors located deep in the brain.

“This is somewhat groundbreaking because no one has taken CED into the brain stem with any type of systematic clinical trial,” says Mark Souweidane, a pediatric neurosurgeon at MSK and Weill Cornell who led the study. “All we had before were a few anecdotal cases. This trial shows we can use this very powerful drug-delivery platform repeatedly and safely.”

Slowly Pushing from Cell to Cell

The CED approach for DIPG involves slowly infusing the drug through tubes inserted deep into the brain stem. The delivery time lasts up to 12 hours. This extended flow allows the drug to gently push through the fluid compartment between cells in the tumor due to tiny differences in pressure. The drug saturates more of the tumor than has been possible through other delivery techniques.

So far, CED has been tested more on adult brain tumors, such as glioblastoma, another aggressive cancer. Dr. Souweidane thinks the drug delivery technique is better suited for DIPG because these tumors are smaller and restricted to a tighter area.

The research underpinning the use of CED for DIPG was an exhaustive effort conducted at Weill Cornell, where Dr. Souweidane is Director of Pediatric Neurological Surgery and Co-Director of the Children’s Brain Tumor Project. The clinical trial, which began in May 2012, took place at MSK.

In the trial, 28 children with DIPG who had already received radiation therapy to the tumor were given a drug called 124I-8H9 using CED. This drug consists of an antibody linked to a radioactive substance. The antibody binds to a protein on the surface of brain tumor cells, and the radiation emitted kills the cancerous cells. MSK physician-scientist Nai-Kong Cheung created 124I-8H9. The drug has already proven effective in treating metastatic neuroblastoma to the brain.

At seven different dose levels, the delivery method appeared safe in children with DIPG. Researchers determined that 124I-8H9 was well distributed through the tumors by tracking the radioactive substance using PET/CT scans and MRI. Most impressively, the investigators were able to prove that drug concentrations in the tumor were more than a thousandfold higher than anywhere else in the body — a remarkable improvement over what is typical. These results validated using CED for children with DIPG.

The trial did not examine whether this drug delivery approach caused the children to survive longer. It did establish that CED merits further development as a treatment for children with DIPG.

Remaining Challenges

Dr. Souweidane says that data gathered from this trial will guide the next steps toward refining the technique. How much of the drug made it into the tumor, how long it stayed there, the best ways to image and measure results, and other vital information will be assessed to come up with the best therapeutic strategy.

There are still many challenges to overcome. Researchers need to know how much of the tumor must be permeated for the drug to be effective. It also needs to be firmly established that children with DIPG truly benefit from this delivery approach. But proving the feasibility of the technique was a major hurdle.

“This has been revolutionary in my mind,” Dr. Souweidane says. “Our pharmacologists look at the results and say, ‘Where has this been for as long as we’ve been trying to treat these brain tumors?’”

A Long Journey

The success of the trial represents a milestone in a long journey for Dr. Souweidane. He has been studying DIPG and CED’s therapeutic potential for more than two decades. Preclinical work at Weill Cornell enabled Dr. Souweidane to test CED’s safety, efficacy, and proper dosage in rodents, using the findings to refine the technique. The lack of progress in treating the disease, especially compared with other childhood cancers, has taken a heavy emotional toll.

In 2016, Dr. Souweidane’s mission to cure DIPG was highlighted by photographer Brandon Stanton for the popular photo blog Humans of New York as part of a pediatric cancer series Mr. Stanton was shooting at MSK. The stories inspired a huge number of people to take action: Overnight, Dr. Souweidane’s laboratory received $1.2 million in donations to help him find a cure for the devastating disease.

These funds were not used for the clinical trial, which was already well under way. But they are now being applied to accelerate the next steps of the process to make it better.

Dr. Souweidane says this will involve a soon-to-be-opened trial through the Pediatric Brain Tumor Consortium, a collaboration among 11 academic centers and children’s hospitals in the United States. The trial could begin as early as late 2018.

“This is the most exciting thing I’ve done in my career by far,” he says. “I’ve been in this for 30 years, and you just watch these kids die with no alternative. It’s constant, constant turmoil and tragedy. It’s amazing to think you’re on the verge of something big.”

This research was supported by NIH grant P30CA008748, the Dana Foundation, The Cure Starts Now, Solving Kids’ Cancer, the Lyla Nsouli Foundation, Cookies for Kids’ Cancer, the Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering.

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New Research Shows Promise for Pediatric Brain Tumor Treatment

New Research Shows Promise for Pediatric Brain Tumor Treatment
Alisha Savage, a pediatric brain tumor patient, traveled with her family from Ireland to be treated at Dana-Farber/ Boston Children’s.
New Research Shows Promise for Pediatric Brain Tumor Treatment

Published: May 19, 2017, Updated: May 31, 2017 - This article originally appeared on the Dana-Farber Insight blog.

Brain tumors are the leading cause of cancer-related deaths in children under age 10 and the second leading cause of cancer deaths in people under 20. Brain cancer is one of the most difficult cancers to treat, but researchers at Dana Farber/Boston Children’s Cancer and Blood Disorders Center are working towards increasing survival rates dramatically in the years ahead.

Although survival rates for children with some types of brain tumors have risen over the past 30 years, current research aims to increase those rates dramatically in the years ahead. Scientists are focusing on the basic genetic and genomic errors that spawn tumors, and at the elements of the tumor “microenvironment” — the web of tissues and substances that surround tumors — to better understand the origins of brain cancers and how they may be combated in the future.

Some recent advances include:

  • Researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions have found that medulloblastomas — fast-growing tumors that arise primarily in the cerebellum — can be divided into four main subtypes based on the genetic errors in their cells. The researchers have helped develop a diagnostic test for these subtypes and are leading clinical trials of drugs that target several of them.
  • To improve the ability of some chemotherapy drugs to reach brain tumors, investigators have coated some of these drugs with tiny layers of fat, which may help them cross the blood-brain barrier, the mesh of capillaries that protects the brain from foreign substances. Another approach under study is to attach chemotherapy agents to molecules that normally cross the blood-brain barrier.
  • Researchers have recently generated a first-of-its kind mouse model for pediatric low-grade gliomas, cancers that arise in cells that support and surround nerve cells in the brain. The new model, in which tumor cells carry the same genetic alteration found in human tumors, will enable scientists to better predict how effective new drugs will be in patients.
  • Researchers at Dana-Farber/Boston Children’s and McGill University have found several molecular alterations that drive a rare, fatal pediatric brain tumor known as high-grade astrocytoma. Such tumors are extremely difficult to treat with radiation and surgery. At least two of the newly found gene alterations, or mutations, found in one form of high-grade astrocytoma might be susceptible to blocking by existing drugs.
  • Another group of scientists at Dana-Farber/Boston Children’s identified a mutated gene that causes tenacious brain tumors known as papillary craniopharyngiomas. Though benign, such tumors can have severe lifelong effects. In children, the tumors often carry a mutation in the gene CTNNB1, the researchers found, which spurs an onslaught of growth in tumor cells. Although no CTNNB1-blocking drugs have yet reached the clinic, several groups are working on developing them. The discovered mutated gene — BRAF — is responsible for craniopharyngiomas in adults. The finding was especially encouraging because drugs exist that inhibit this gene’s effects.
  • Scientists have long known that cancer cells with a high oxygen content are particularly vulnerable to radiation therapy. Investigators are exploring whether drugs that increase the oxygen supply in tumors can enhance the effectiveness of radiation therapy in pediatric brain cancer patients.
  • Dana-Farber/Boston Children’s researchers have found that pediatric low-grade gliomas often harbor an unusual genetic mutation that may help to classify, diagnose, and guide the treatment of the tumors. An analysis of several dozen tumor specimens revealed that a gene called MYBL1was rearranged or missing a part of its genetic message in nearly 30 percent of them.

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Pediatric Cancer Incidences in Nebraska

Pediatric Cancer Incidences in Nebraska
Pediatric Cancer Incidences in Nebraska

Published Online January 4, 2018 - www.sciencedirect.com

Temporal and geospatial trends of pediatric cancer incidence in Nebraska over a 24-year period

Highlights

• Evaluated the incidence and geospatial trends of pediatric cancer in Nebraska over 24 years.

• Identified areas of increased incidence that could lead to access to care issues.

• Utilized Geographic Information System mapping tools to reduce the geographic burden for families in rural communities.

Abstract

Background

Data from the Surveillance, Epidemiology, and End Results (SEER) revealed that the incidence of pediatric cancer in Nebraska exceeded the national average during 2009–2013. Further investigation could help understand these patterns.

Methods

This retrospective cohort study investigated pediatric cancer (0–19 years old) age adjusted incidence rates (AAR) in Nebraska using the Nebraska Cancer Registry. SEER AARs were also calculated as a proxy for pediatric cancer incidence in the United States (1990–2013) and compared to the Nebraska data. Geographic Information System (GIS) mapping was also used to display the spatial distribution of cancer in Nebraska at the county level. Finally, location–allocation analysis (LAA) was performed to identify a site for the placement of a medical center to best accommodate rural pediatric cancer cases.

Results

The AAR of pediatric cancers was 173.3 per 1,000,000 in Nebraska compared to 167.1 per 1,000,000 in SEER. The AAR for lymphoma was significantly higher in Nebraska (28.1 vs. 24.6 per 1,000,000; p = 0.009). For the 15–19 age group, the AAR for the 3 most common pediatric cancers were higher in Nebraska (p < 0.05). Twenty-three counties located >2 h driving distance to care facilities showed at least a 10% higher incidence than the overall state AAR. GIS mapping identified a second potential treatment site that would alleviate this geographic burden.

Conclusions

Regional differences within Nebraska present a challenge for rural populations. Novel use of GIS mapping to highlight regional differences and identify solutions for access to care issues could be used by similar states.

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Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors

Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors
Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors

Published: November 7, 2014, Updated: February 2, 2018

Study Description
Brief Summary:

The main purpose of phase I studies in general is to determine the best dose ("maximum tolerated dose") of a drug, and to find out the most common side effects. The main purpose of the phase I component of this study specifically is to determine the best dose of the experimental drug MEK162 and to find out whether the drug is safe in children and adolescents with tumors that have grown or come back despite standard therapy.

Another purpose of this study is to measure the concentration of drug in the blood to help understand how much drug gets into the body and how quickly the drug is removed from the body. Another purpose of this study is to determine whether MEK162 turns off the Ras/Raf/MAP pathway as expected by measuring this pathway in blood cells. Finally, in this study, the investigators hope to start finding out whether or not MEK162 causes different types of tumors in children to shrink or stop growing.

The main purpose of the phase II component of the study is to determine whether MEK162 causes specific types of tumors in children and adolescents to shrink or stop growing. These specific types of tumors include low-grade gliomas, tumors in patients with a genetic condition called neurofibromatosis type 1, and other tumors thought to be caused by abnormal activation of the Ras/Raf/MEK molecular pathway.

Another purpose of this study is for researchers to learn whether specific abnormalities in the DNA of tumors can help predict whether tumors will respond to MEK162.

Detailed Description:

PROTOCOL SUMMARY:

Phase 1: Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after standard up-front therapy receiving MEK162 will define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and toxicity profile.

Phase 2: Patients with recurrent or progressive tumors signaling through the ras/raf pathway after standard up-front therapy will be treated in three strata to define the activity of MEK162.

Stratum 1: Pediatric patients with recurrent or progressive low-grade glioma (LGG) characterized by a BRAF truncated fusion (KIAA1549 and similar translocations).

Stratum 2: Pediatric patients with neurofibromatosis type 1 (NF1) and recurrent or progressive LGG.

Stratum 3: Pediatric patients with recurrent or progressive tumors thought to involve the ras/raf/MAP pathway but not included in strata 1 or 2. This includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a patient with NF1, and any other tumor with a known activating BRAF, NRAS or KRAS mutation.

Target validation phase: Patient enrolled on the phase 2 component (any stratum) for whom tumor biopsy or resection is clinically indicated. Patients will receive MEK162 for 7 to 21 days prior to their surgery. Samples will be analyzed for concentration of drug and target inhibition.

Length of therapy:

Protocol treatment will last approximately 48 weeks from the start of MEK162 in the absence of significant toxicity. Treatment will be administered based on the dose escalation schema for phase 1. Patients in the phase 2 component of the trial will also receive a planned 48 weeks of therapy. Those undergoing planned tumor resection based on clinical criteria will be eligible to receive 7-21 days of treatment with MEK162 prior to the surgical procedure.

Imaging to assess response will be obtained at the end of cycle 1 (+/- 1 week), at the end of cycle 3 (+/- 2 weeks) and after every three cycles thereafter (+/- 2 weeks). A cycle will consist of 28 days (+/- 3 days) and MEK162 will be given continuously. Patients deriving benefit may continue therapy beyond study completion but all protocol specific evaluations (other than survival or progression) will conclude after one year. All patients will be followed with progression as the end point.

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PET/CT Helps Predict Therapy Effectiveness in Pediatric Brain Tumors

PET/CT Helps Predict Therapy Effectiveness in Pediatric Brain Tumors
PET/CT Helps Predict Therapy Effectiveness in Pediatric Brain Tumors

Published May 2, 2017 - Neuroscience News

Summary: Researchers use PET neuroimaging technology to help determin which children with DIPG brain cancer will benefit best from Avastin.

Source: Society of Nuclear Medicine.

Brain cancers are difficult to treat, and it can be hard to predict whether a therapy will be effective. When the patient is a child, it’s even more important to predict the potential effectiveness of a drug before beginning treatment. In this first ever molecular drug-imaging study in children, researchers in The Netherlands used whole-body positron emission tomography/computed tomography (PET/CT) scans to determine whether bevacizumab (Avastin) treatment of diffuse intrinsic pontine glioma (DIPG) in children is likely to be effective. The study is featured in the May 2017 issue of The Journal of Nuclear Medicine.

“Children with DIPG have a very poor prognosis, with less than 10 percent of the patients surviving two years from diagnosis,” explains Guus A. van Dongen, PhD, of VU University, Medical Center, Amsterdam, The Netherlands. “These tumors are resistant to all kinds of therapies. Chemotherapy, as well as new targeted therapies, may not reach the tumor due to the location within the brainstem.”

For the study, researchers investigated whether bevacizumab can reach the tumor in children with DIPG by measuring the tumor uptake of zirconium-89 (Zr-89)-labeled bevacizumab with PET. In addition, they evaluated the safety of the procedure and determined the optimal timing of imaging.

Two weeks after completing radiotherapy, seven patients (age range: 6-17) were given whole-body PET/CT scans performed at 1, 72 and 144 hours post-injection. The optimal moment of scanning was found to be 144 hours post-injection. The patients also underwent contrast (gadolinium)-enhanced MRI.

“Top row: Zr-89-bevacizumab PET (144 hrs p.i.) fused with T1-Gd weighted MRI per patient; middle row: T1-Gd weighted MRI; lower row: T2-weighted/FLAIR MR-images. Five tumors show variable uptake of Zr-89-bevacizumab (white arrows), with both PET negative and positive areas within each tumor. Two primary tumors are completely PET negative (Fig. 1C and 1E), while the T2 weighted images show tumor infiltration in the whole pons of both patients. In the middle row, the red arrows represent the areas of contrast enhancement within the tumor. In four out of five primary tumors, the PET-positive area corresponds with the contrast-enhancing area on MRI of the tumors (Fig. 1A, 1B, 1F and 1G). In Fig. 1C, the tumor shows an MRI contrast-enhancing area, while there is no Zr-89-bevacizumab uptake. Fig. 1D shows a PET positive tumor, while no Gd-enhancement is observed on MRI. NeuroscienceNews.com image is credited to Sophie Veldhuijzen van Zanten and Marc Jansen, VU University Medical Center, Amsterdam, The Netherlands.he results showed that indeed there is considerable heterogeneity in uptake of Zr-89-labeled bevacizumab among patients and within tumors,” Van Dongen points out. “This non-invasive in vivo quantification of drug distribution and tumor uptake may help to predict therapeutic potential, as well as toxicity, and could help develop strategies for improving drug delivery to tumors.”

Van Dongen adds, “Children with brain tumors and other solid cancers are particularly likely to benefit from molecular drug imaging, as drugs without therapeutic effect–based on a lack of drug-uptake in the tumor–may cause life-long side effects. Molecular drug imaging will open avenues for administering the right drug to the right patient at the most appropriate stage of the disease.”

Society of Nuclear Medicine “PET/CT Helps Predict Therapy Effectiveness in Pediatric Brain Tumors.” NeuroscienceNews. NeuroscienceNews, 2 May 2017.
<http://neurosciencenews.com/brain-scan-pediatric-cancer-6568/>.

Abstract

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging.

Methods: Patients received 89Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89Zr-bevacizumab was quantified as SUVs.

Results: Seven DIPG patients (4 boys; 6–17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0–6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter- and intratumoral heterogeneity of uptake, and 89Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor–to–blood-pool SUV ratios increased with time after injection (P = 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq).

Conclusion: 89Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.

“Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma” by Marc H. Jansen, Sophie E.M. Veldhuijzen van Zanten, Dannis G. van Vuurden, Marc C. Huisman, Danielle J. Vugts, Otto S. Hoekstra, Guus A. van Dongen, and Gert-Jan L. Kaspers in Journal of Nuclear Medicine. Published online May 1 2017 doi:10.2967/jnumed.116.180216

 

The Promise (and Limits) of Pediatric Proton Radiation

The Promise (and Limits) of Pediatric Proton Radiation
The Promise (and Limits) of Pediatric Proton Radiation

By Lisa Esposito - Published 6/24/2016

WHEN YOU LEARN YOUR child has brain cancer or another aggressive tumor, you're intensely focused on the immediate present. Which course of treatment – what combination of surgery, chemotherapy or radiation – will best help your child survive? But with most kids living long pasttheir cancer diagnosis, it's also important to consider how treatments they undergo now may affect them later, even as adults.

One choice some parents may face is whether to seek a newer type of radiation called proton beam therapy, instead of conventional X-ray radiation, to potentially reduce harmful side effects in their developing child. Proton beam therapy is considered a big advance in cancer therapy by some experts. Others, however, hesitate to get caught up in the early hype without more long-term evidence. Even so, people are traveling far and wide so their children can receive proton therapy from the handful of centers where it's offered.

Four leading radiation oncologists explained to U.S. News what parents should understand about proton therapy and its possible benefits:

Proton beam therapy is a form of radiation that may reduce late side effects compared with conventional X-ray radiation. The pinpoint beam and lack of exit dose – which is unneeded radiation as the conventional X-ray beam passes beyond the tumor and through the body on its way out the other side – spares healthy, normal tissue in developing areas such as the brain, heart and lungs.

Childhood brain cancer is considered one of the most evidence-based uses for proton therapy. It may prevent late effects such as hearing loss or reduced ability to do well in school. However, at least for now, proton therapy does not offer a higher possibility of cure than traditional X-ray radiation.

The brain is the most common area for kids to develop cancerous tumors that require radiation treatment, says Dr. Torunn Yock, director of pediatric radiation oncology at Massachusetts General Hospital and an associate professor at Harvard Medical School.

"Because the pediatric brain is still growing and developing, if you irradiate the brain during this process, it won't continue to grow and develop as it normally would," she says. "And this over time leads to slowing of development, which shows up as drops in neurocognitive testing."

The younger the child, the more potential exists for stunted development, Yock says. "A 2-year-old is very different from a 15-year-old in terms of brain development, so the adverse consequences are much greater in the 2-year-old."

Clearly, there's an advantage to not irradiating healthy brain tissue, she says. For instance, avoiding the brain's vision and auditory centers may save children from loss or impairment of sight or hearing.

Proton beam therapy allows doctors to give the same dose as with traditional radiation, while reducing the dose – and complications – to normal, healthy tissue, says Dr. Sameer Keole, medical director of the proton beam therapy program at Mayo Clinic in Arizona. It also allows the use of a higher dose than traditional X-ray radiation (also called photon radiation) to treat resistant tumors, while still protecting surrounding tissue.

With traditional radiation to the brain, the radiation scatters. "That collateral radiation exposes large amounts of brain to low doses of radiation," says Dr. Thomas Merchant, chair of radiation oncology at St. Jude Children's Research Hospital in Memphis, Tennessee. Even lower doses of radiation can be harmful, he adds. 

In November 2015, the new St. Jude Red Frog Events Proton Therapy Center – the world's only proton-therapy center dedicated solely to the treatment of children – began treating kids with aggressive cancers, including brain tumors and Hodgkin lymphoma.

"There are certain brain tumors in children where we have to treat the entire brain and spine," Merchant says. "If we give proton therapy, we don't have exit radiation into the chest and abdomen that you have when you treat someone with conventional radiation." That may reduce long-term side effects in the heart and lungs.

With the newest form of proton therapy, called pencil-beam scanning – which conforms or shapes the highest-dose radiation to the targeted tumor – it's possible to reduce the "margin" area around the tumor exposed to radiation, Merchant says. That method, which is used by St. Jude, may eventually have the potential to reduce the risk of secondary cancers.

Dr. Anita Mahajan, a professor and chief of pediatric radiation oncology at the University of Texas MD Anderson Cancer Center, says when she describes proton therapy to parents, she emphasizes that proton therapy is radiation.

The biggest difference, she explains, is that the subatomic particle, the proton, stops where the oncologists need it to. "It has to get in, but we can stop it from coming out."

That ability to avoid other organs is important. "For instance, if we're treating a young child for pelvic rhabdomyosarcoma [a muscle and connective tissue cancer], one of the things we might be able to do is avoid the growth plates in the femurs," Mahajan says. "That might give you less problem with growth asymmetry of the legs as they get older."

Future fertility is a factor in cancer treatment planning. In cases involving radiation around the pelvic area, it's sometimes possible to avoid the ovaries in a young girl or the testes in a boy.

'Spaceship Hamster Wheel'

A proton is a positively charged atomic particle. In proton therapy, a powerful machine called a particle accelerator speeds protons up to reach a high energy level. The technology is massive – three stories high and weighting upward of 100 tons – requiring special housing within a treatment facility to contain the equipment and deliver the proton beams. A rotating device called a gantry releases protons to the tumor from different angles. You can take a quick virtual tour of proton beam therapy at the Mayo Clinic in Arizona.

In the treatment room, patients are positioned on a table or in a specialized chair. CT or MRI scans are taken before each treatment to ensure accurate positioning. Some children need sedation to sleep through the treatment, while others who can remain still may stay awake.

Patients may need immobilization devices to keep them in the proper, precise position for every proton-beam treatment. With brain cancer, patients usually wear a custom-fitted mask to maintain their position.

Parents can accompany children to the treatment room and see them settle in before treatment begins, Mahajan says. A child life specialist is part of the team to help children and families cope with the entire patient experience.

While the treatment itself is painless, side effects can include skin problems like swelling, dryness, blistering or peeling – similar to traditional radiation. Fatigue, nausea and vomiting are side effects as well and are also due to other treatments patients receive, like chemotherapy.

Meg McQuillan of Riverside, Connecticut, recalls her son's introduction to proton beam therapy three years ago, when he was treated at Mass General for a type of brain tumor called medulloblastoma. He and fellow patients named the device the "spaceship hamster wheel."

Young people take the treatment process in stride, Keole says. "Kids are tough," he says. "Sometimes they're a lot tougher than adults. By and large, they have a great attitude."

Cost and Access

There are 23 operating proton beam centers in the U.S., according to the National Association for Proton Therapy, unevenly distributed throughout the country. Only a portion exist in the context of a pediatric-focused cancer program. Between 500 and 600 pediatric patients get proton radiation therapy each year, according to Yock's rough estimate.

With a typical treatment course lasting six weeks, families face the disruption of traveling to a children's hospital with a proton therapy center, finding lodging and making arrangements for other children at home.

Proton therapy costs roughly twice as much as traditional X-ray radiation. The average cost for a full course of proton radiation treatment is estimated at $40,000.

Creating a new proton center is a huge investment. "If you look at simply the upfront costs, it will be three to four times more expensive than photons," Yock says. "It is absolutely intensive in terms of people and equipment needed and the quality assurance and the engineers and the physicists. It's a huge team that's required to run it safely, with good quality control."

Yock co-authored a study published in December 2015 in the journal Cancer, which compared the cost-effectiveness of proton radiation therapy versus traditional radiation among kids with medulloblastoma. The study, which used models to measure long-term side effects and related costs in treatment, work-force participation and quality of life, found that proton therapy was cost-effective.

As Mahajan says, "If we can prevent some neurocognitive deficits, endocrine issues, growth issues, skeletal deformities, those are going to help that child be more productive in society and need fewer medical interventions down the road."

Insurance usually covers the cost of proton therapy when a cancer is considered curable, Yock says: "Ninety-eight percent of the time, we are successful with arguing to get a pediatric patient treatment," she says.

"We don't take the recommendation to give radiation lightly," Merchant says. Patients are carefully evaluated to determine the course of treatment. "It's so important for the parents, as well as the child, to know what they're getting into," he adds. "One thing we do is compare treatment plans using proton, or conventional or photon radiation, and choose the best plan. And in most cases, the proton plan looks better."

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Going Beyond Genetics Yields Clues to Challenging Childhood Brain Cancer

Going Beyond Genetics Yields Clues to Challenging Childhood Brain Cancer
Going Beyond Genetics Yields Clues to Challenging Childhood Brain Cancer

By Nicole Fawcett - November 23, 2016 

Changes in epigenetics suggest a predictive marker for childhood ependymomas and similarities with DIPG tumors. 

Now, new research suggests changes at the epigenetic level — specifically alterations in proteins that affect gene expression, rather than genetic mutations — could be driving childhood ependymomas.

“Clearly there’s more to cancer than just genetic mutations. Not every cancer is going to fit that box of having a genetic driver,” says Sriram Venneti, M.D., Ph.D., an assistant professor of pathology at the University of Michigan Medical School.

Three separate groups, including one at U-M, have performed advanced sequencing on ependymomas — a tumor that occurs at the part of the brain called the posterior fossa, which is the back base of the brain including the cerebellum, pons and brain stem. It can develop in both young children and adults but is much tougher to treat in children.

When sequencing efforts did not yield any recurring genetic alterations, the U-M team looked at epigenetics — in particular, changes in histone and DNA methylation, processes that regulate gene expression. They found about 80 percent of pediatric hindbrain ependymomas had substantially reduced levels of H3K27me3, a critical histone H3 protein modification. These tumor samples consistently tied to worse outcomes in children, suggesting a critical marker for predicting prognosis.

What’s more, the researchers found that simple immunohistochemical staining methods in tumor biopsy samples can show whether the tumor has high or low levels of H3K27me3 that could predict prognosis.

“We could do it very simply, with a very fast and economic process that is easily incorporated in patient care,” Venneti says. The study is published in Science Translational Medicine.

Underscoring the discovery’s significance: Traditional prognostic markers based on tumor grade have proven unreliable for ependymomas. Understanding a patient’s prognosis, then, can help doctors make treatment recommendations — which has long been a particular challenge for affected children.

In children, ependymomas typically occur before age 5. Surgery is a preferred course of action, but it can be difficult in tiny brains where many critical functions are developing. Surgeons often don’t get the entire tumor out, leading to recurrence. Meanwhile, chemotherapy and radiation can cause devastating side effects to children, and the benefits remain unclear.

Researchers are also exploring a potential new therapy that could target H3K27me3 and reverse the lowered levels. This work is still in early phases; more study is needed.

Vulnerabilities in developing brains

Although ependymomas also occur in adults, none of the adult tumor samples in the study had reduced H3K27me3.

On the other hand, Venneti’s team found very similar epigenetic changes, including low H3K27me3 and similar DNA methylation, in another type of pediatric brain tumor — diffuse intrinsic pontine gliomas, or DIPG. These also occur in the posterior fossa of young children. Former U-M football coach Lloyd Carr’s grandson, Chad Carr, died from DIPG in 2015.

“Different mechanisms are involved in these two tumors, but they arrive at the same place,” Venneti says. “This suggests low methylation of H3K27me3 is important to tumors in this region of the brain. These tumors arise from similar epigenetic states.”

Most childhood brain tumors develop in the posterior fossa of the brain — very different from where adult brain tumors occur. Venneti suggests something about the development of that region may make children susceptible to these cancers. Preliminary research implicates neuronal stem cells. Studies looking at the posterior fossa of the developing human brain showed low H3K27me3. Neuronal stem cells are marked by their ability to differentiate into other types of cells. That process does not appear to happen in these brain tumors.

“We still don’t know the mechanism of how this is happening. Brain tumors are the most common type of solid cancer in children, but they’re still poorly understood,” Venneti says. “We hope that studying the epigenetics will give us more information on how the brain develops — and in turn, understanding how the brain develops could help bring answers to understand these deadly cancers.”

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Researchers find five sub-types of the brain cancer glioma

Researchers find five sub-types of the brain cancer glioma
Researchers find five sub-types of the brain cancer glioma

The Institute of Cancer Research - April 24, 2018

There are five distinct molecular sub-types of the brain cancer glioma, according to findings from the largest ever genetic study of its kind of the cancer.

A new study identifies five types of glioma based on mutations that develop early in the disease, and could help understand the biological mechanisms that trigger gliomas.

The study, published in the prestigious neuropathology journal Acta Neuropathologica, gives an unprecedented insight into the likely causes of gliomas and how they develop.

Understanding the causes of glioma

Glioma is an aggressive type of brain cancer with poor survival outcomes. To improve treatment, more needs to be known about the underlying causes of the disease.

Genetic studies of patients with glioma have identified 25 ‘markers’ in patients’ DNA that influence glioma risk.

These markers – single-letter DNA changes known as single nucleotide polymorphisms – are more likely to be found in people with glioma than without. But how these markers of risk affect glioma development is unclear.

Connections between glioma risk and genetic mutations

ICR researchers, with colleagues in France, studied DNA from more than 1,600 people with glioma for three early forming genetic mutations in the disease.

The researchers, funded in the UK by Cancer Research UK and the DJ Fielding Medical Research Trust, identified five types of glioma with distinct molecular profiles, based on the interactions between the markers and the glioma-driving mutations – called 1p/19q, TERT, and IDH.

They highlighted intriguing clues to the causes of the distinct types of glioma, which might in the future point towards new ways to treat the disease.

The researchers went on to search for interactions between the single nucleotide polymorphisms and other genes, using a technique called Hi-C.

Hi-C allows researchers to ‘fish’ for physical interactions between genes that can be far apart within, or even on different, strands of DNA – but that come together as DNA folds and unfolds, sometimes only at certain times in the life-cycle of a cell.

They discovered a potential role in glioma for several other genes – including several involved in the development of brain cells, and others linked to a network of molecular cell signalling called EGFR-AKT.

Insight into how glioma develops

Professor Richard Houlston said: “Glioma is a devastating disease with an extremely poor prognosis. It’s caused by a cacophony of different cell types and mutations, but the underlying causes of glioma are still largely unknown.

“Our study identifies links between risk markers for glioma and sub-types of the disease.

“These mutations are early events in glioma development, and relationships between molecular profiles and genetic markers that influence glioma risk could provide insight into how glioma develops and pathways critical to glioma susceptibility.

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More effective treatment approach to fight pediatric brain cancer

More effective treatment approach to fight pediatric brain cancer
More effective treatment approach to fight pediatric brain cancer

PTI | London November 03, 2018

Personalisation of treatment have helped improved outcomes for patients

Scientists have been able to identify the group of children needing more intensive, aggressive chemotherapy treatment for the most common form of brain cancer.

The chromosome signature they found in medulloblastoma may allow medics to adapt treatment so that each child is targeted individually, improving the 60 per cent survival rate for high-risk patients, said researchers from the Newcastle University in the UK.

The findings, published in The Lancet Oncology journal, also show that many youngsters with medulloblastoma could avoid unnecessary doses of chemotherapy and radiotherapy with less toxic side effects.

While others, who have the most serious form of the disease, may be targeted with more intensive chemotherapy. Currently all patients receive the same treatment.

"Our findings provide a new blueprint for the personalisation of treatment in medulloblastoma so that all children are not given the same intensity of therapy," said Professor Steve Clifford from Newcastle University.

"Our findings provide a new blueprint for the personalisation of treatment in medulloblastoma so that all children are not given the same intensity of therapy," said Professor Steve Clifford from Newcastle University.

"This study shows that low-risk patients may receive kinder treatments aimed at reducing toxicity and side effects, while targeting more intensive treatments to the high-risk patients who need it most," said Clifford.

Medulloblastoma is the most common malignant childhood brain tumour and it is important that we have improved outcomes for patients with this disease, researchers said.

"Through a greater understanding of brain tumours we hope to increase the cure rate but critically, for those children who survive, we want to make sure their quality of life is good after treatment," Clifford said.

Scientists at Newcastle University worked with Northumbria University in the UK to examine the molecular pathology of the cancer.

Experts identified that children with the cancer can be split into two clinical groups—about half of which are low-risk with close to 100 per cent survival, while the other half are high-risk, with 60 per cent survival.

The study analysed data from the PNET4 clinical trial of standard-risk medulloblastoma, which ran from 2001-2006.

The standard-risk patients involved in the cohort were children with no recognised risk factors for the disease and who would be expected to have a survival rate of around 80 per cent after five years.

Working with the University of Bonn in Germany, the team identified recurrent patterns of chromosome gains and losses in medulloblastoma tumours.

The team found a chromosome signature that identifies a group of patients with 100 per cent survival rates, and a high-risk group with just 60 per cent survival. 

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Liquid Biopsies May Bring a Future of Hope For Pediatric Brain Cancer

Liquid Biopsies May Bring a Future of Hope For Pediatric Brain Cancer
Liquid Biopsies May Bring a Future of Hope For Pediatric Brain Cancer

By Katie Kosko - Published November 19, 2018 on www.curetoday.com

Researchers have found a potentially safer and faster way to determine if treatment for a type of childhood brain cancer is working, according to early study findings published in Clinical Cancer Research.

The technique is called a liquid biopsy, which tests blood drawn from a patient for circulating tumor DNA — DNA that comes from cancerous cells and tumors. Liquid biopsies are less invasive, more cost-effective and may be able to show changes occurring in the brain from treatment before they appear on scans, such as an MRI, according to researchers.

“If you have a solid tumor that has a certain characteristic — the number of genes and changes in these genes compared with normal tissue — and we realize now that part of the DNA that is specific to the tumor can be detected in the bloodstream,” co-senior author Sabine Mueller, M.D., Ph.D., a pediatric neuro-oncologist at UCSF Benioff Children's Hospital San Francisco, said in an interview with CURE.

“That’s fascinating when you think about how this can happen for patients with brain tumors because of the blood-brain barrier,” she added. “Normally, we have an intact blood-brain barrier and a lot of medications that we are giving don’t even reach the brain tumor in significant amounts. But we have shown now that we can detect this in the blood.”

The study, which was led by researchers from UCSF Benioff Children's Hospitals and Children's National Health System, examined blood and cerebrospinal fluid — fluid found in the brain and spinal cord — samples from 84 children. Diffuse midline glioma (DMG), an aggressive, high-grade brain tumor, was seen in 48 patients and 36 patients had non-central nervous system disease.

Researchers confirmed through the samples that 42 of the children with DMG had H3K27M, a mutation commonly found in patients with this type of brain tumor (about 80 percent), which helps drive the cancer. The level was comparable to what is found using a standard biopsy, which requires surgery, noted researchers.

“We had nice correlation of the amount of circulating tumor DNA in the blood compared to the imaging,” Mueller said. “The question now is what do you believe? And, what is the gold standard? This remains a challenge, but at least for the patient we can clearly see progression.”
DMGs usually occur in children but can also be diagnosed in adults. Brainstem tumors, which comprise the majority of DMG, account for 11 percent of primary brain tumors in children and adolescents, according to the UCSF Brain Tumor Center.

Biopsies for brain tumors are challenging, explained Mueller. And, therefore, understanding how tumors are changing in response to therapy can be difficult. But examining circulating tumor DNA may be a way to get around it. “There is huge potential for this technology, but it has to get more sensitive and specific. It’s a great first step,” she said.

Mueller reiterated that this research is still in its very early stages and not a clinically approved test. “This is an exciting new area for parents and children with brain tumors that we have been able to show that there is circulating tumor DNA on detectable levels in the blood and cerebrospinal fluid for these patients,” Mueller said. “Now we hope to build on the findings to further expand the technology so that in the future we might be able to take a blood sample from the child and then tell the family that this is the type of tumor that they have.”

In addition, study author Javad Nazarian, Ph.D., said that a vulnerable population could be helped by making this technology clinically relevant. “Liquid biopsy provides the opportunity to use blood or cerebrospinal fluid to monitor a tumor that is otherwise inaccessible for molecular studies,” said Nazarian, associate professor at the Children’s National Health System and George Washington University School of Medicine and Health Sciences. “Our data are exciting and will certainly need to be expanded and validated across more cancer cases.”

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