Brain Cancer Surpasses Leukemia as #1 Pediatric Cancer Killer

September 19th, 2016


Author: Andrew Black


New data from the CDC shows the mortality rates for pediatric cancers is in decline. A study published by the CDC found that during 1999–2014, the cancer death rate for patients aged 1–19 years in the United States dropped 20%. What is also changing are the type of patients dying. In 1999, leukemia was the leading killer of childhood cancer. That has been replaced by brain cancer. Numerous other trends were also observed in the study.

Brain Cancer Surpasses Leukemia as Leading Cancer Causing Death in Children In both 1999 and 2014, more than one ­half of all cancer deaths among children and adolescents 1­-19 years old were attributable to either leukemia or brain cancer. 3 out of 10 cancer deaths among children and adolescents aged 1–19 years in 1999 were due to leukemia (29.7%), and 1 in 4 were due to brain cancer (23.7%). By 2014, these percentages reversed and brain cancer was the most common site, accounting for 29.9% of total cancer deaths.

Stem Cells May Speed Up Screening of Drugs for Rare Brain Cancers

August 9th, 2016

Researchers in Neuropathology and the Johns Hopkins Kimmel Cancer Center say they have developed a system that uses transformed human stem cells to speed up screening of existing drugs that might work against rare brain and other cancers.

A report on their proof-of-concept work, published in the Aug. 1 issue of Clinical Cancer Research, describes experiments that transform human stem cells into an aggressive and rare form of pediatric brain cancer called medulloblastoma. Those cancer cells’ genetic profiles can then be rapidly compared with hundreds of common, lab-grown human cancer cells already tested against existing drugs.

By creating a cell model of medulloblastoma from human cells rather than working with mouse cells, the researchers say they can be more confident that patients’ response to the drugs identified in the screenings may be more comparable to humans, according to Eric Raabe, M.D., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. He worked together with Charles Eberhart, MD PhD and pathobiology graduate student Allison Hanaford to create the model.

Standard treatment for pediatric medulloblastoma, which strikes 500 children per year in the United States, combines radiation and chemotherapy, but a subtype known as Group 3 — which makes up 28 percent of the cases — tends to cause the most relapses in patients, and the survival rate is only 30 to 40 percent, says Raabe. “Overall, 70 to 80 percent of medulloblastoma patients treated with conventional radiation and drug therapy survive and are considered cured,” he adds, “but many patients with the Group 3 subtype don’t fare as well.”

In recent years, one strategy scientists use to find new or better treatments is to look to databases of existing drugs that have been matched to the genetic profiles of lab-grown cells for common cancers. However, Raabe says, rare cancers and their subtypes are not well-represented in such databases, and creating such lab-grown cell lines directly from patients’ tumors is difficult. Moreover, he adds, such tumor-derived cells sometimes acquire genetic changes that can vary from the original tumor.

For the study, the scientists used lentiviruses as a transport system to insert cancer-related genes common to Group 3 medulloblastomas in human neural stem cells. As the stem cells replicate, the cancer-linked genes transform the stem cells into cancer cells. The tumors then grown from these transformed cell lines “compare very well biologically to actual human medulloblastoma, and their gene expression profile fits with that of human tumor cells,” Raabe notes.

Raabe and his colleagues then used RNA sampled from the new tumors to create a “signature” of gene expression that they could compare to similar signatures in three large databases of cell lines that have been screened and matched with existing drugs. “We wanted to find whether the cells we created matched any of these existing signatures,” Raabe explains, “because if they did, then we would have some idea of what kinds of drugs are more or most likely to kill these cells. We didn’t have to do the laborious screening to test 100,000 compounds against our own cells.”

Using this method, the scientists zeroed in on a group of compounds called CDK inhibitors that may be promising treatments for Group3 medulloblastoma, Raabe says.

One of those drugs, palbociclib, is already approved by the U.S. Food and Drug Administration for treating a type of advanced breast cancer, Raabe says. When he and his colleagues added palbociclib to their transformed cell lines, they found that the drug decreased cell line growth by more than 50 percent and more than tripled cell death compared to untreated cells. The drug also extended the survival of mice implanted with tumors grown from established Group 3 human medulloblastoma cell lines by nearly 50 percent, from 25 to 37 days.

Raabe says that palbociclib and other such drugs, called cyclin-dependent kinase inhibitors, are being tested in phase I clinical trials in children with various brain tumors. “There is interest in testing these agents in more advanced studies specifically for recurrent medulloblastoma, potentially in combination with other new agents,” he says.

Although it took several years to develop this model of Group 3 medulloblastoma and show its similarity to primary tumors, Raabe says, “This system may be one way to find drugs for rare cancers for which there are only a few human cell lines or to model very rare subtypes of adult and pediatric cancers.”

Other scientists who contributed to the research include Allison Hanaford, Antoinette Price and Charles Eberhart at Johns Hopkins; Tenley C Archer, Jong Wook Kim, Tobias Ehrenberger, Paul A. Clemons, Vlado Daník, Brinton Seashore-Ludlow, Vasanthi Viswanathan, Michelle L Stewart, Matthew G. Rees, Alykhan Shamji, Stuart Schreiber, Ernest Fraenkel, Scott L. Pomeroy, Jill P. Mesirov, and Pablo Tamayo of the Broad Institute at MIT and Harvard; Ulf D. Kahlert and Jarek Maciaczyk of Heinrich-Heine University Hospital Duesseldorf, Germany; and Guido Nikkhah of University Hospital Stuttgart, Germany.

Funding for the study was provided by the St. Baldrick’s Foundation, Hyundai Hope on Wheels, Giant Food’s Pediatric Cancer Research Fund, the Spencer Grace Foundation, the Deming Family, the Children’s Brain Tumor Foundation, the National Cancer Institute (P30 CA006973, R01NS055089, U01CA176152), the National Institutes of Health (R01 CA154480, R01 109467, R01GM074024) and the Comprehensive Cancer Center Freiburg.

Genetically Engineered Mice Suggest New Model for How Alzheimer’s Disease Causes Dementia

July 5th, 2016

Using a novel, newly developed mouse model that mimics the development of Alzheimer’s disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological “insults” must occur in the brain to cause the dementia that is the hallmark of the disease. A description of their experiments is published online in the journal Nature Communications.

For decades, Alzheimer’s disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue.

In Alzheimer’s disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory, notes Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine.

What hasn’t been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells, says lead and corresponding study author Tong Li, Ph.D., an assistant professor of pathology at Johns Hopkins. Prior studies of early-onset Alzheimer’s disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But the new research from Li, Wong and colleagues suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, their studies show, it may set off a chain of chemical signaling events that lead to the “conversion” of tau to a clumping state and subsequent development of symptoms.

“For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that’s actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes,” Wong says. “What appears to be needed is a second insult — the conversion of tau — as well.”

In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, Li says, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau.

To address that problem, the Johns Hopkins researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans, Li says.

The researchers found during brain dissections of the animals that the presence of beta-amyloid plaque alone was not sufficient to cause the biochemical conversion of tau, the repeat domain of tau — the part of tau protein that is responsible for the conversion of normal tau to an abnormal state — alone was insufficient for the conversion of tau, beta-amyloid plaques must be present in the brain for the conversion of tau and the tau fragments could “seed” the plaque-dependent pathological conversion of tau.

One implication of the new research, Wong says, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven’t worked. “The timing may be off,” he says. “If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss and ensuing consequence of the disease.”

The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer’s disease, the researchers say. Their mouse model could be used to test new therapies.

An estimated 5.4 million Americans are living with Alzheimer’s disease, according to 2016 statistics from the Alzheimer’s Association. There is no cure, but there are some medications that may help stabilize cognition for a limited time or help with related depression, anxiety or hallucinations.

Co-authors were Kerstin E. Braunstein, Juhong Zhang, Ashley Lau, Leslie Sibener and Christopher Deeble of Johns Hopkins.

The work was supported by the Ellison Medical Foundation, the Brain Science Institute at Johns Hopkins, the Johns Hopkins University Neuropathology Pelda Fund and the Johns Hopkins Alzheimer’s Disease Research Center.

Dr. Barbara Crain Receives Award From AANP

June 22nd, 2016

Michael N. Hart, MD presented Dr. Crain with an award for her many Crain award 2016 AANP smmeritorious contributions on behalf of members of the American Association of Neuropathologists at their 92nd annual meeting. Drs. Crain and Troncoso are show after she received the award.

New WHO Classification of CNS Tumors

May 21st, 2016

An update of the WHO brain tumor classification has been released by IARC press. Drs. Burger, Eberhart and Rodriguez are all authors of multiple chapters. Key changes include molecular definitions of multiple tumor types such as Glioblastoma – IDH mutant and Diffuse midline glioma – H3K27M mutant.

WHO book

Dr. Fausto Rodriguez Appointed Director of Clinical Neuropathology Service

May 13th, 2016

Congratulations to Dr. Fausto Rodriguez, who has succeeded Dr. Peter Burger as Director of the Neuropathology Clinical Service.

Dr. Shuying Sun joins Neuropathology Division

May 6th, 2016

Memo from Dr. Ralph Hruban:

Please join me in welcoming Shuying Sun, Ph.D. from the Ludwig Institute for Cancer Research at the University of California at San Diego. Shuying will join our faculty in the Division of Neuropathology on July 1st, 2016. Shuying received her B.S. degree from Shandong University in China, and her Ph.D. from Stony Brook University, where she worked in the laboratory of Dr. Adrian Krainer at the Cold Spring Harbor Laboratory, and trained in basic molecular mechanisms of post-transcriptional RNA processing. Shuying has been a Postdoctoral Fellow in Don Cleveland’s laboratory since 2010.

A K99/R00 grant recipient, and author of papers in PNAS, Nature Genetics, Nature Communications, Shuying’s research here at Hopkins will focus on disease mechanisms of neurodegenerative disorders and advanced novel RNA-targeting therapy using her knowledge of RNA Biology and technology. In particular, Shuying will focus on a C9orf72 hexanucleotide repeat expansion seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Welcome Shuying!

Ralph Hruban, M.D.
Baxley Professor and Director of Pathology

Friday Interesting Case Conference

April 22nd, 2016

A range of interesting cases including CNS tumors, ocular pathology, neurodegenerative disease, forensic CNS pathology and developmental abnormalities are reviewed each week at 10 AM in Ross 555. All with an interest in neurological and ophthalmic disease are welcome to attend.




Dr. Nikolaos Ziogas Wins First Place; Post-Doctoral Fellow Poster Awards at National Capital Area TBI Research Symposium 2016

April 18th, 2016

Nikolaos Ziogas M.D., LIBRA – post doctoral fellow at the Koliatsos Laboratory, was the winner of the “Post-Doctoral Fellow Poster Awards” at the annual National Capital Area Traumatic Brain Injury Symposium held at National Institutes of Health, Bethesda, DC for his work on the “Characterization of corticospinal tract pathology in mice exposed to impact acceleration injury”. For this work a novel neuroscience technique that makes the brain transparent, CLARITY, has been used to 3D reconstruct the corticospinal tract after traumatic brain injury, the specialized axonal tract responsible for fine movements.

Hidden damage revealed in veterans’ brains

September 3rd, 2015

The discovery of a ”honeycomb pattern” in the brains of combat veterans’ who survived IED blasts may provide clues to the neurological impact of warfare, according to researchers at Johns Hopkins University. Jillian Kitchener of Reuters reports.

Professor Vassili Koliatsos and his team at Johns Hopkins School of Medicine, believe they may have found the signature of “shell shock” in the brains of war veterans. Shell shock has afflicted soldiers since WWI…but it is a phenomenon that is still poorly understood. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “Is it neurological, psychological or both?” Professor Koliatsos believes scientists may soon be able to answer that question. His team has found what they call a unique honeycomb pattern of broken and swollen nerve fibers in brains of Iraq and Afghanistan combat veterans exposed to IED blasts but who later died of other causes. They compared these brains to 24 other people who died of causes such as car accidents, drug overdoses and heart attacks. The honeycomb pattern, Koalitis says, was caused by the FORCE of the blast. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “In this particular case, the force is coming against your chest so the blood gets squeezed. And as the blood gets squeezed, there’s a lot of bad apple blood into the brain. And because there’s a pulse of over-pressure wave that happens (like this), the brain also swells (like this). And when the brain swells, it pushes against some of the fixed elements inside the skull.” The damage, he says, is concentrated in the frontal lobe of the brain. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “And that’s very important because this is the site, the center, of the executive functions of the brain. Functions that allow you to put your life together, organize, plan ahead, understand abstract. And you can imagine this can make your life difficult.” U.S. veteran Aragorn Thor Wold says he has seen how a brain injury can take over a soldier’s entire life. Wold was a Navy Corpsman who served with the marines in combat medicine for nine years. He says it’s hard for medics to diagnose a moderate traumatic brain injury – or TBI – at the scene because troops are busy fighting. (SOUNDBITE) (English) U.S. VETERAN ARAGORN THOR WOLD, SAYING: “How can we differentiate TBI from PTSD. Is it an organic brain injury. Is it an anxiety disorder, illness side, you know. There’s a lot of those questions floating around. So I won’t say the holy grail but a huge deal would be a biomarker.” And while a biomarker has yet to be found, Koliatsos says his study shows there may be a neurological element to psychological suffering. (SOUNDBITE) (English) PROFESSOR OF PATHOLOGY AND NEUROLOGY AT JOHNS HOPKINS SCHOOL OF MEDICINE, VASSILI KOLIATSOS, SAYING: “If there is an executive disfunction, and disfunction of the front of the brain, you may think of different medications.” He says he would also like to see improved body gear that would give greater protection to the chest… and minimize the impact of explosive blasts upon the brain.

Here is the video link: