Best Post of February 2012: Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

The next in our "Best of the Month" series is from February 24, 2012. To read the comments engendered by Dr. Eberhart's question, go to the original post.

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:

Hi Brian,

I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.

"Chasing The Dragon": A Cause of Toxic Spongiform Leukoencephalopathy

My favorite case from the 2012 AANP Diagnostic Slide Session in Chicago last month featured an autopsy slide from the brain of a 25-year-old man with a history of polysubstance abuse found unresponsive at a New Year's Eve party. Toxicology screening was positive for methadone, lorazepam, and cocaine. The patient died after three weeks in the intensive care unit. Attendees were provided glass slides in advance of the session demonstrating the following findings:

Low Power: Marked white matter pallor

High Power: White matter virtually replaced by lipidized macrophages

Presenter Joshua Menke, MD of The Mayo Clinic (Rochester, MN) revealed that white matter damage was diffuse, including infratentorial structures. The subcortical U-fibers were relatively spared and myelin was disproportionately affected as compared to axons, as demonstrated in these photomicrographs from Dr. Menke's presentation:

LFB stain on left and neurofilament stain on right

Discussants included Drs. Tessa Hedley-Whyte, Craig Horbinski, Mark Cohen, and others. Before the diagnosis was revealed, Dr. Horbinski stated that he thought Delayed Hypoxic Leukoencephalopathy might be the best fit for this case. Dr. Cohen pointed out that Delayed Hypoxic Leukoencephalopathy tends spare the infratentorial regions, while the white matter damage is more diffusely distributed in toxic leukoencephalopathy. This case was ultimately revealed to be that of Toxic Spongiform Leukoencephalopathy.

Toxic leukoencephalopathy can be caused by a range of insults including radiation, chemotherapy, and drugs of abuse. Among the drugs of abuse that have been shown to cause toxic leukoencephalopathy are toluene, ethanol, cocaine, 3,4-methylenedioxy-methamphetamine, intravenous heroin, inhaled heroin pyrolysate, and psilocybin (Ref: Filley & Kleinschmidt-DeMasters NEJM 2001). Toxic spongiform leukoencephalopathy is a clinicopathologic entity first associated with the inhalation of pyrolysate heroin vapors, a practice which had its origins in Hong Kong in the 1950's and which came to be known colloquially as "chasing the dragon". Users typically "chase the dragon" by placing heroin on a creased piece of tin foil over a flame. As the drug sublimates, the user inhales the fumes. The pathophysiology of this form of leukoencephalopathy has not been clearly elucidated, but is thought to be related to a direct toxic effect of heroin on oligodendrocytes.

The Intrepid Dr. Mike Lawlor reports on job opportunities discussed at recent AANP meeting

Here's a report from Michael Lawlor, MD, PhD summarizing the job opening updates that came out of last weekend's AANP annual meeting in Chicago. I have updated the job listings on this site to reflect Dr. Lawlor's up-to-date information: 

Hi Everyone,

Dr. Mike Lawlor

As a component of the AANP Trainee Luncheon, we attempted to contact all of the institutions with job postings on the Neuropathology Blog site, and invited them to talk about their positions at the luncheon.  There have been an exceptional number of jobs filled over the past 6 months, so our roster of potential presenters changed considerably over time.  Based on my conversations with people, here is an update on several of the jobs currently posted on the site.

1.       Brigham and Women’s Hospital: Their search for applicants is currently closed.

2.       Case Western Reserve University:  Mark Cohen spoke about this position for a few minutes, which sounds like an excellent opportunity for a research-oriented neuropathologist that wants to spend a minority of their time on clinical work.  I would highly recommend contacting Mark to discuss this position, if you’re in the market for a job.

3.       Mayo Clinic, Stanford University, and UCSF:  These positions remain open, but these institutions are each looking for an experienced neuropathologist who would immediately be able to take on a considerable clinical load.

6.      University of Chicago:  This position remains open, and I think that the link fell off the blog site for a short time (or I missed it).  It looks like it’s back up now, and Peter Pytel confirmed that they’re still looking for people.

7.       University of Manitoba: This position remains open, and Marc del Bigio was able to provide me with some information on it.  This information can all be found on the link to this position, so I won’t repeat it.

8.       University of Wisconsin - Madison:  There had previously been two postings on the blog site, which turned out to be two different “flavors” of descriptions for the same job.  There is one job open at UW-Madison and they have interviewed several promising candidates, but the job currently remains open.

9.       University of Calgary- This job had previously been posted here on the website, but it looks like it has disappeared over the past few months.  The job actually remains open, though, and Jim Wright and Jeff Joseph sent me a lot of information on it.  It looks like the job could involve a combination of clinical, teaching, and research opportunities.  Researchers could either develop their own program or fit into their collaborative neuroscience community, and preference will be given to applicants with interests in neurodegenerative diseases, neuromuscular diseases, inflammatory diseases, or developmental brain disorders.  Jeff Joseph also sent a beautiful picture taken from his backyard to show off some of the scenery of Calgary, and it definitely looks like a breathtaking area.  For more information, feel free to contact Jeff Joseph (jtjoseph@ucalgary.ca) or Jim Wright (jim.wright@cls.ab.ca).

Two additional notes that might be useful to people:

1.        One speaker from the pharmaceutical community mentioned that a lot of biotech/pharmaceutical industry jobs for pathologists are actually posted on veterinary pathology websites.  If you’re interested in pursuing such a position, you may want  to widen your search to these sites.

2.       I talked briefly about the NIH Loan Repayment Program, which provides student loan repayment for projects on which the investigator spends >50% effort on the project.  These are one or two year grants, and the submission process is very reasonable.  For anyone that has student loans, I’d encourage you to check these awards out at their website and contact them for more details.  This is a wonderful program and the people involved in it are extremely supportive and responsive.

Good luck to everyone!

-Mike Lawlor

Thank you, Mike. And if anyone in the neuropathology community has further updates on the job listings (additions, deletions, etc.), please let me know and I'll make the necessary changes.

AANP 2012: Dr. Michael Norenberg talks about the multifunctionality of astrocytes



Dr. Norenberg on "Why the Brain Fails when the Astrocyte Ails"

The University of Miami's Michael Norenberg is currently talking about the functions and physiology of astrocytes. The forgotten function of astrocytes is that they are involved in the synaptic communication between neurons and are an active participant in modulating the neuron-neuron interaction. Dr. S. Ramon y Cajal speculated on this active participation of the astrocyte in the synapse with regard to sleep many decades ago. So, although not a new concept, the concept of expanded functionality of astrocytes has gained scientific support in recent years.

Neuropathologists party hard at this evening's AANP annual reception

L to R: Drs. Heather Sumner and T. David Bourne

Drs. Mark Cohen, T. David Bourne, and Mahtab Tehrani

L to R: Drs. Edward Stopa, William Taylor, and Qian Wu

AANP's "Special Course" is Underway

I am currently in attendance at the American Association of Neuropathologists Annual Meeting special course entitled Acquired Neuropathology in a Changing World. A crowd of more than 300 attendees are present. Dr. Leroy Sharer recently finished his presentation, entitled "AIDS Neuropathology - A 30 Year Perspective", which provided a unique insight into the evolution of our understanding of HIV in the CNS.

Dr. Sharer sharing his persepctive on AIDS neuropathology this morning

Meanwhile, the accomodations at The Palmer House Hotel here in Chicago are magnificent.

Detail from ceiling of the lobby at Chicago's landmark Palmer House Hotel

Yasser Lopez: A Modern-Day Phineas Gage

Above is an x-ray released yesterday by Jackson Memorial Hospital in Miami, Florida depicting a spear entering the head, traveling through the brain, and piercing the opposite skull surface of 16-year-old Yasser Lopez. The boy is on the road to recovery after being accidentally shot in the head while loading a speargun with a friend earlier this month

"It was about one inch above his right eye straight through," said trauma surgeon Dr. George Garcia. "You could feel the tip under the skin on the posterior part of the skull."

"The most important thing is to resist that temptation to pull the thing out," neurosurgeon Dr. Ross Bullock said. Bullock and his trauma neurosurgeon team determined the tip of the spear inside Lopez's head was actually a screw tip. "It was possible for us to figure out a strategy during the operation to be able to unscrew the tip of the spear, instead of having to get this whole spear dragged out through his brain," Bullock said.

Bullock said Lopez can speak normally. "He can, for example, he says he's not having pain. He's worried about the fact he can't use his left-side properly."

Lopez's story brings to mind that of Phineas P. Gage, whose left frontal lobe was obliterated by a railroad spike that exploded upward when he was tamping it down in 1848.

Phineas P. Gage (1823-1860)

As for the day he got shot, Lopez knows nothing. Doctors expect him to make a near-full recovery.

Read more here: http://www.miamiherald.com/2012/06/18/2856543/doctors-miami-dade-teen-shot.html#storylink=cpy

Best Post of January 2012: The area postrema is not the only area where the BBB is lacking

The next in our "Best of the Month" series comes from January 9, 2012:

I'll paraphrase a question posed by one of my 2nd-year students at Southern Illinois University School of Medicine:

I understand that the Area Postrema was a site where there was increased penetrability of the blood brain barrier. I am not sure, but thought I had come across additional sites of increased penetrability last year in my reading. Are there other sites where there is increased permeability of the BBB?

 

In pondering an answer to this question, I immediately thought of the illustrious Dr. John Donahue, consummate neurologist, neuropathologist, and neuroanatomist.  I posed the question to him and got the following response:

Dr. John Donahue, Brown University, Providence, RI

"Not increased permability of the BBB.  NO BBB!  Area postrema is one of the circumventricular organs, areas in the brain that lack a BBB.  Being the vomiting center, it is imperative that it lacks a BBB so that it can sample the systemic circulation.  Being in the medulla, it is the only circumventricular organ that is adjacent to the fourth ventricle; all of the others are adjacent to the third.  It is the only paired circumventricular organ; all of the others are single and midline.  The other circumventricular organs are subfornical organ, organum vasculosum of the lamina terminalis, median eminence, posterior pituitary gland, subcommissural organ, and pineal gland."

 

There you have it!

2,000 players unite in suing NFL over head injuries

CNN reports today that a unified lawsuit on behalf of more than 2,000 National Football League players has been filed against the league in federal court, alleging that the NFL failed to acknowledge and address neurological risks associated with the sport and then deliberately failed to tell players about the risks they faced. The complaint unites the more than 80 pending lawsuits filed against the NFL.

Lawyers representing the players cited "dementia, depression, reduced cognitive ability, sleeplessness, early-onset Alzheimer's, and a debilitating and latent disease known as chronic traumatic encephalopathy" as some of the specific injuries caused by head trauma in the NFL.

Thanks to Dr. Jeff Bennett for alerting me to this story.

Best Post of December 2011: Naegleria-tainted neti pots possibly killed two people

Naegleria fowleria (photo courtesy of Dr. Mark Cohen)

The next in our Best of the Month series is from December 16, 2011:
Now that it's winter and our noses and sinuses are being dried out by our heating systems, many of us turn to neti pots (also known as 'nose bidets'). The illustrious J. Clay Goodman, MD, neuropathologist at Baylor, just sent me an article from The Houston Chronicle warning people to use distilled, bottled, or boiled water. Officials in Louisiana are investigating whether a 51-year-old woman and a 20-year-old man both contracted the brain-eating amoeba Naegleria fowleri after using tap water in their neti pots. The disease, while rare, is most commonly contracted after inhaling water from a lake, pond or river. If investigators confirm the two victims died after using tap water from a neti pot it will be the first time the disease has been contracted from tap water.

Update on May 29, 2012: A comment was left in the original post suggesting that the water used in the two deaths may have resulted from the use of well water, not tap water. I was unable to confirm that contention in an internet search on the topic. All the news sources I consulted state that the water was indeed tap water.

National Baseball Park Tour Raises Awareness of PSP

The Shea's at AT&T Park in San Francisco

CurePSP is an organization dedicated to raising public awareness of progressive supranuclear palsy (PSP). A member of the board of CurePSP, Justin Shea, is currently taking his parents on a tour of baseball parks throughout the nation in an effort to raise public awareness and funds for PSP. Justin, whose father was diagnosed with PSP in March of 2009, is documenting the family's journey with a blog. Justin writes: "[S]ince my Dad's diagnosis, we have been able to raise both awareness and considerable funds to help researchers find a cure... Collectively, we have raised over $30,000. We have decided to continue these efforts throughout the country by visiting every MLB park."