Voices on Pediatric DIPG Biopsy- Nicholas Foreman MD ChB

The Ethics of Biopsy in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ASCO 2012 Educational Session Presentation

"If the the definition of insanity is doing the same useless thing with the same outcome, this is it."

....Dr Nick Foreman speaking on the negative results on dozens of trials in DIPGs with no biologic knowledge of the tumor

Dr Nick Foreman,  director of the pediatric neuro-oncology program at Denver Children's, presented the second lecture at the 2012 ASCO educational meeting  "Pontine Gliomas in Children:To Biopsy or Not to Biopsy".    Dr Foreman along with his colleague, neurosurgeon Dr Michael Handler, actively and aggressively challenged medicine's standard practice of not preforming biopsies in 10% of children with brain tumors when that tumor (DIPG) has been almost always fatal and no trial has shown any benefit for the tumor.  They argued that it was really unethical to continue to subject these patients to phase 1 trials to obtain toxicity and dosage data when one could not show any benefit from the dozens of trials previously.   These two physicians worked to have the American Society of Neurosurgery reverse the standard practice of not preforming biopsies for DIPG children.   

This 16 1/2 minute presentation is a personal account of the resistance encountered when developing DIPG research that stemmed from work done in 2004 in biopsies of pediatric supratentorial GBMs.  The 2004 work lead to a 2007 IRB proposal in which 10 children with DIPGs were to be biopsied (with parental consent) without treatment based on those biopsies.  This was pretty much exactly what France had already done and published results with no mortality and transient morbidity.  However, the local IRB could not make a decision resulting in an FDA hearing on the topic.  The results of the FDA panel was mixed so the initial proposal of 10 children being biopsied was rejected in favor of the current upfront biopsy trial that is underway.

Now that we have the biopsy trial open in the US  and 2011 Consensus Conference on Pediatric Neurosurgery specifically stated a standard regarding biopsy of typical pediatric DIPGs within clinical trials, we may now be past much of the controversy of the past decade.   Still, I think it is important to know the traumatic, tragic history of how this stagnated DIPG research.  

Dr. Foreman ends pondering a question on whether we "missed the boat" for DIPG children by failing to openly recognize that in experienced hands DIPG biopsy is not more dangerous than in other areas of the brain.    

If the majority understood that the 1993 paper recommending "routine biopsies be relegated to history" was referring to MRI's accuracy of diagnosis and not on DIPGs surgical risk/safety, could we have moved faster in the current age of cancer molecular biology to have known about such abnormalities as the histone mutation much earlier.  Perhaps we could have been further along on a cure.

References:

Nicholas Foreman, Pediatric Neuro-Oncologist

http://www.coloradocancerblogs.org/conversation-dr-nicholas-foreman/

Interpretation of magnetic resonance images in diffuse intrinsic pontine glioma: a survey of pediatric neurosurgeons

http://www.ncbi.nlm.nih.gov/pubmed/21721895

Slides of Dr Foreman's presentation in 2009 to the FDA

http://www.fda.gov/downloads/AdvisoryCommittees/.../UCM150193.pdf

Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brainstem gliomas:  a report from the Children's Cancer Group

http://www.ncbi.nlm.nih.gov/pubmed/8133987

Voices on Pediatric DIPG Biopsy - Stephanie Puget MD PhD

Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?

ASCO 2012 Educational Session Presentation

One of the most controversial subjects in pediatric DIPGs over the last decade has been the biopsy issue.  This has been the topic of discussion in private, editorials and even an FDA open hearing.   At the 2012 ASCO meeting in Chicago there was an educational meeting chaired by Mark Kieran MD PhD entitled "Pontine Gliomas in Children:To Biopsy or Not to Biopsy".   To me the greatest thing about this session is that it was taped and made available on the internet.   This allows for those who were not in Chicago last year for ASCO to have a better understanding directly from some of the key international figures regarding this extremely important matter.

Stephanie Puget MD PhD, a French neurosurgeon, started the session with a 20 minutes presentation on "Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?"  Dr Puget is a central figure in the landmark French DIPG clinical trial with upfront biopsy.   Since the 2007 publication it seems that Dr Puget has had speaking engagements on both sides of the Atlantic to discuss DIPG biopsy.  This was the first time though that I was able to actually hear her speak.

Dr. Puget started her talk with five questions.
1) Is biopsy needed for a DIPG diagnosis?
2) If not, why do biopsy for DIPG?
3) Can DIPG biopsy be safely preformed?
4) Can DIPG biopsy be preformed by everyone?
5) What can be done with the biopsy specimens?

The short answers-
1) No, it is made by MRI in conjunction with clinical symptoms.
2) Analysis of the tumors may lead to relevant biomakers and hopefully better treatment.
3) Yes.
4) No.
5) Allows for molecular studies (including whole genome sequencing and mutational analysis) and cell lines (of which they had 5 stem cell lines a the time).

During the presentation she reviewed the results of the French Biopsy experience.   From 2002 to 2012, 92 biopsies were preformed with no mortality and only 5 patients experience morbidity.  Four of these patients had transient problems including cranial nerve palsies or weakness.  One child had a permanent hemiparesis but also was found to have disease progression.  She said "it could be considered as safe as a stereotactic biopsy in the supra-tentorial space in a well-trained neurosurgical team".

She also addressed a few technical considerations: frame versus frameless surgery, choosing a route and choosing a biopsy site.  Please note at approximately 14:30 minutes there are real videos of biopsy in children.  At 18:30 minutes the size of the biopsy samples is shown as well as pre and post procedure MRIs.

For those interested in the pediatric DIPG biopsy issue, this is a very informative 20 minute presentation from someone who as been on the frontline.  

Reference:
Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?
Stephanie Puget MD PhD
http://meetinglibrary.asco.org/content/66763

DIPG in Istanbul

Recently a publication came out in the journal Child's Nervous System retrospectively reviewing patient characteristics and outcomes in children treated  for DIPG over a 13 year period (February 1999 to May 2012) at Cerrahpassa Medical Faculty and Oncology Institute in Instanbul, Turkey.

In this review there were 26 girls and 24 boys with a median age of 7.  The median duration of symptoms - including cranial nerve palsies, motor  disability and/or cerebellar dysfunction- was 30 days.  The diagnosis was made by a multidisciplinary tumor board which included a a pediatric oncologist, radiation oncologist, neurosurgeon, and radiologist in the multidisciplinary tumor board.

Radiation was part of all the children's therapy although only twelve received radiation alone.  The other children also received some form of chemotherapy with radiation. In 17 patients a radiosensitizer (either vincristine or cisplatin) during radiation and followed by CCNU and vincristine after radiation.   After temozolomide became available this agent was used both during and after radiation for the remaining 21 children.

These three groups were analyzed regarding outcomes:  group 1-radiation alone; group 2-vincristine/ciplastin; group 3- temozolomide.   In this study,  children in either chemotherapy group  did better than those that had radiation alone.    Ten of the children in group 2 were alive at 2 years and 3 at 3 years.  Three children in group 3 were also alive at 3 years.   

Interestingly 3 children in the temozolomide group had biopsies and were found to have pilocytic astroctyomas!

Fo me it is hard to know exactly what caused these two chemotherapy groups had better survival.   It would seem that the 3 children with pilocytic astrocytomas were included in the analysis.   The authors also said that there were improvements in radiation techniques over time which could have been a factor.  Thus children who had radiation alone were the earliest patients in the review.  Also it seems over type palliative care, PEG tubes and shunts became more common in that institution which may have played a role in the statistics.

Positive results of temozolomide with DIPG have not been replicated in other countries.   Still, this article has significance to me to show the increase interest in DIPG around the world as well as the improved treatment for children with cancer.   It was also good to see the conclusion that "the complex biology of DIPG renders an unselected single-agent approach less likely to be effective. Instead, a multi-targeted approach seems to be required to improve the prognosis".   Hopefully we will see increasingly available multi-targeted options for children with DIPG.

Reference:
Pediatric diffuse intrinsic pontine glioma patients from a single center
Childs Nerv Syst. 2013 Apr;29(4):583-8. doi: 10.1007/s00381-012-1986-3. Epub 2012 Dec 8.
http://www.ncbi.nlm.nih.gov/pubmed/23224361

Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma (France)
http://www.ncbi.nlm.nih.gov/pubmed/21858607

Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group
http://www.ncbi.nlm.nih.gov/pubmed/21345842

Prospective evaluation of radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma (India)
http://www.ncbi.nlm.nih.gov/pubmed/19647954

Building a Post Mortem Tissue Donation Program- Part 2

It was back in the summer of 2005 that I first became aware of any institution making a concerted effort to obtain DIPG samples for research purposes.    On a visit to Memphis, I found out that researchers there were going to attempting to put a comprehensive IRB proposal  (and place in clinicaltrials.gov) together to formalize a process for post-mortem DIPG donation.  At that time, France had just started the biopsy trial and to me this was an American attempt to push DIPG research also.  To me it was an exciting time- the first time I had heard of anyone really trying in an organized way to look at DIPG genomics in the US.

Since it was something that was not done, there were concerns on how to approach families- and if they would even donate.  To try to answer some of these issues, specific sections of the research would examine parental feeling towards autopsy through a decisional regret survey and a 7 question survey.   Questions included items such as reasons for participating in the study, what was good and bad about participating and do you have suggestions. In February an article came out electronically ahead of print in the Journal of Pediatrics detailing the parent experience.

Thirty three parents of 32 children answered the the survey (82% participation).  Of these 18 received care at St Jude and 14 at other institutions.   Those that received care at other institutions were in contact with St Jude directly- some specifically because of awareness of the autopsy program.   Parents completed the in a mean time of 11 months.

None of the parents expressed regret in participation.  The parents indicated that they consented to autopsy to help other families in the future and to help other parents know that they are not alone.

Parents also said that:
* it was better if the primary physician asked- specifically someone who "they had a relationship with and who showed concern." 
*there is "no right time" to initiate this discussion.  Parents do recognize that this is tough for the docs as well.  Most said that they would have preferred an earlier discussion.  Some said that an earlier discussion was less comforting.   Timing of the discussion will  likely take an individual approach.  (And from a personal point of view- a mother and a father might be at different places when considering this discussion.)
* there was a need to have clear information about procedures.   Knowing specifics helped decrease anxiety.  Some of these specifics included exactly what would be done during autopsy and how the child would look afterwards.

One of the specific issues addressed early was funding of transportation and autopsy.   Since many of children treated at St Jude die at home and not close to the facility, the logistics of funding had to be considered before this research could even be started.  It was at this point that a DIPG family was looking to make a difference.   Tyler's Treehouse agreed to fund non-covered expenses associated with post-mortem donation in order to make this research happen.

Tyler's Treehouse is named for a 5 year old boy- the 3rd of 4 sons.  Tyler was diagnosed on January 30, 2006 having symptoms only for 1 week.   The family went to St Jude but Tyler's tumor was too advanced to even start treatment.   He died a week later on February 8, 2006.

Without a foundation support like Tyler's Treehouse this type of program may not have been able to get started.   Thank you to the Scott's for their actions in their time of grief.

The logistics of making a DIPG Post Mortem Donation Program are not easy- but it is possible.  And from such programs we are beginning to understand DIPG.  Research is possible from autopsy specimens.   The effort has made a difference.

References:
DNA Analysis of Tumor Tissue Samples from Patients with Diffuse Brain Stem Glioma (NBTP02)
http://clinicaltrials.gov/ct2/show/NCT00899834?term=St+Jude+brainstem+glioma&rank=2

Bereaved Parents' Intention and Suggestions about Research Autopsies in Children with Lethal Brain Tumors
J Pediatr. 2013 Feb 19. pii: S0022-3476(13)00039-5. doi: 10.1016/j.jpeds.2013.01.015. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23433673

Somatic Histone H3 alterations in pediatric diffuse intrinsic pontine glioma and non-brainstem gliobastomas
http://www.ncbi.nlm.nih.gov/pubmed/22286216

Building a Post-Mortem DIPG Tissue Research Progam

Perhaps the biggest rate limiting step in DIPG research has been the lack of tissue.   Without tissue, what is there really to study in the basic science realm?   However,  DIPGs pose significant hurdles in getting tissue as biopsies have not been traditionally preformed and post-mortem donations have infrequently been requested.

Over the years there have been many barriers to post-mortem donations.  Some lacked knowledge- the medical system just didn't know that any research was actively being done.   Some didn't believe that usable samples could be obtained for research.   Some didn't know how to logistically make this happen especially if the child died at home and the research was being done somewhere else in the country.  Some didn't know how or when to approach the parents on this delicate topic.

There have been a few places that have worked to collect post-mortem DIPG samples for research.   One of the most impressive total package programs is Children's National Medical Center.   These researchers have taken on each obstacle and overcome them.

For me the first hurdle is if there is any DIPG research being done at that institution.   It doesn't do us any good to have a sample donated and then it sits in the freezer.   At Children's National Medical Center there was an interested researcher, Javad Nazarian, who already had a funded grant from the Childhood Brain Tumor Foundation to study DIPGs.    This meant there was some money and someone to do the research but there are still huge problems- how does anyone know you need the samples and how do you obtain them.

A researcher-clinician partnership was lead to a multi-disciplinary team.   This team included a pediatric neurosurgeon (Suresh Magee) and two pediatric neuro-oncologists (Roger Packer and Brain Rood) as well as Javad Nazarian.

To address the awareness issue, three things were done.  First, the researchers developed an IRB protocol and took the innovative step to have it placed in clinicaltrials.gov.  In this way,  interested physicians and parents might more easily find out about the research and have the contact information. Secondly, they developed a brochure detailing the information which parents could take away and review at a later time.  By the way,  it also had a 24 hour contact pager to help facilitate logistics.  Thirdly, they included their information on the Kid V Cancer site on research needing tissue.

The logistical problems of having a child die at home and then donating a post-mortem sample are complex; but, they are overcomeable.   It is easier to overcome them with some advanced planning.  Transportation is one of the recurrent hurdles as often times if the child will have to be transported to the hospital first then this is not covered by insurance.   There have been foundations that have stepped up to fund these expenses so that this research will not be stopped.  In this case, the Musella Foundation has supported that aspect of the program.

And now to maximize research,  Children's National Medical Center is part of a DIPG tissue sharing consortium called the Mid-Atlantic DIPG Consortium (MADC).  The other two institutions are Johns Hopkins and the National Institute of Health- Pediatric Oncology Branch.  This collaboration must be highly successful as several DIPG abstracts have come out for a series of spring meetings including AACR, USCAP and the SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference.

If asked, some families will donate their child's tumor.   It will not be all, but many will and it is made so much more possible with a program in place to address the issues.  Kid's V Cancer is a good place to find out more about autopsy donation- both for families (FAQs and others experiences) as well as physicians  (how to ask and autopsy donation checklist).

Thank you Children's National Medical Center for putting this program in place to advance DIPG research.

References:
Molecular Analysis of Samples from Patients with Diffuse Intrinsic Pontine Glioma and Brainstem Glioma
Brochure: http://www.virtualtrials.com/pdf/dipg.pdf

Clinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT01106794

Selected DIPG articles/abstracts from Javad Nazarian and group:
Protein profiling of formalin fixed paraffin embedded tissue: Identification of potential biomarkers for pediatric brain stem glioma
http://www.ncbi.nlm.nih.gov/pubmed/21136889

Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of spinal fluid
http://www.ncbi.nlm.nih.gov/pubmed/22492959

Targeting the Notch and mTor pathways in diffuse intrinsic pontine glioma
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3086&sKey=6fa486c2-2701-4a76-8431-b22144df78e4&cKey=c3e199ac-82f7-486d-9d65-bb1c13525e3b&mKey=%7b9B2D28E7-24A0-466F-A3C9-07C21F6E9BC9%7d

NG2 Upregulation in Pediatric Diffuse Intrinsic Pontine Glioma and Its Role in Tumorigenecity in Vivo
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740466

Maddie's Mark

Just five days.... that is all they got between leaving the hospital after first hearing DIPG until their girl was gone.

Just five years....to live a lifetime.

Maddie had the memory of an elephant.  She had a winning smile.  She was "fiercely independent".  She was a kindergartener.   She was the big sister to two younger sisters.   She loved arts and crafts.   She also had DIPG.

The little girl diagnosed last year on February 3rd in Albany was supposed to go on a Wish Trip to Disney.   She never made it there.   She did get to go to Kindergarten and make her First Communion.   Those final "best days ever" were spent at a dream house in Lake Placid surrounded by family.  When they arrived home, it was too much of a struggle to go back and forth to the hospital so the oncologist came to them.  She died on February 8th.

At one point when she was struggling her dad asked her how she was doing.  Her said reply, "I can't do the things I want to do."  Those were her last words to him- a truly heartbreaking part many have on the DIPG journey.

The community had raised funds to help with expenses but after Maddie died money was left over.   The Mustos family decided to start a foundation- Maddie's Mark Foundation.   The purpose of this foundation was to allow kids in New York  to do things they wanted to do and have a "best day ever".

Here are some examples of Best Days Ever":

• Naomi , a 6 year old with Ewing's sarcoma, was able to go to a Phillies game- in VIP style.
• Devon, a boy with an eye tumor, was able to go camping at Old Forge and Enchanged Water Safari.
• Myles, a 9 year old boy with pontine gliomas,  "best day ever" included a reptile adventure party with a "pile of friends" which included his favorite pizza and cupcakes and a video camera.   They also provided him with a recliner to be more comfortable.   He died a week later in his comfy chair surrounded by family.
• Devon, also with DIPG,wanted a day having fun with friends and family.  Maddie's Mark set up a dinner .  Superhero Devon pins were made for this special day.

Another thing Maddie's Mark does is make stuffed animal elephants- fitting for a girl who had a memory like an elephant.  Proceeds go to support the foundations.

This is another wonderful foundation started by a family wounded and grieving from DIPG.

Reference:
Maddie's Mark
http://www.maddiesmark.org/

Maddie's whole purpose 'was to care'
http://www.timesunion.com/local/article/Maddie-s-whole-purpose-was-to-care-3258157.php

Madeline Musto's memory helping children have 'best days ever'
http://www.watertowndailytimes.com/article/20130217/NEWS03/702179849

Capecitabine Phase 1 Trial Publication

As a dose-escalating phase 1, this trial's main objective was to establish the maximum tolerated dose and toxicity of capecitabine (Xeloda) in a pediatric population (between the ages of 3 and 21).   The drug was given for nine weeks in two daily doses from the start of radiation.   There was then a two week break followed by another 3 cycles of capecitabine in which the drug was given twice daily for two weeks followed by a one week break.

From a parent perspective, a very cool thing about capecitabine is that this flavored, film coated, rapidly disintegrating tablet did not have to be swallowed intact but could be disolved in water.   There have been other studies where the younger patients were excluded because of the inability to swallow pills intact.

The way capecitabine works is that it is a pro-drug and can be broken down to 5-fluorouracil (5-FU) by a cellular enzyme thymidine phosphorylase (TP).  TP is found at significantly higher levels in many cancers.   Only 5-FU has antiproliferative properties.   The hope is that then the active metabolite 5FU will concentrate specifically in the tumor cells.  In addition, radiation induces the enzyme TP.   

5 FU has been around as a antimetabolite chemotherapy on its own since it was patented in the late 1950's.  The way it works is that 5 FU blocks an enzyme (thymidylate synthase inhibitor) which allows the cell to make a protein that is needed for DNA.   Without this, cells can not make new DNA needed for cell division and thus undergo a "thymineless death".

Since TP has been found in increased level in gliomas, it was thought that a combination of capecitabine and radiation could be a way to attack pediatric DIPGs and high grade gliomas.    Of note, capecitabine has been effective for breast cancer brain metastases.

Of the 24 enrolled kids, 15 patients had DIPG.  The dose-limiting toxicity included grade 2 and 3 palmar/plantar erythroderma and grade 2 and elevation of a liver enzyme alanine aminotransferase.

This trial (PBTC-021) was run from at the institutions of the Pediatric Brain Tumor Consortium. Interestingly, the phase 2 (PBTC-30) has also finished patient accural.   .  Although the hope of radiosensitizers in general for DIPG have not lived up to expections, this radiosensitzer seems to have other effects which perhaps might have increased effectiveness.   The phase 2 is expected to complete data collection in June 2013.   Hopefully,  meeting abstracts or publication will follow shortly thereafter.

References:
Phase I trial of capecitabine rapidly disintegrating tablets and con concomitant radiation therapy in children with newly diagnosed brainstem glioma and high-grade gliomas
http://www.ncbi.nlm.nih.gov/pubmed/

Capecitabine therapy of central nervous system metastases from breast cancer
http://www.ncbi.nlm.nih.gov/pubmed/17611719

Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report
http://www.ncbi.nlm.nih.gov/pubmed/16800978

New Trial- Imetelstat for Refractory/Recurrent Pediatric Brain Tumors

A new Pediatric Brain Tumor Consortium phase 2 trial using a telomerase inhibitor, Imetelstat also known as GRN163L,   for recurrent or refractory DIPG (as well as three other recurrent or refractory pediatric brain tumors) just went up on clinicaltrials.gov this week.   This two section component study will be both a phase 2 study as well as a molecular analysis study.   DIPGs will be excluded from the molecular analysis study component of this trial and will not require tissue/histological confirmation.  The protocol will include a two hour IV infusion on day 1 and 8 followed by repeat infusions every 21 days for two years.

What are telomeres?  I think of them like the plastic coating at the end of shoelaces which keeps the laces from fraying out. 

Telomeres are thought to be an important in keeping a cell's DNA intact.    They are located on the end of chromosomes and shorten with cell divisions.   This shortening of telomeres protects the inner DNA as if it wasn't there the DNA could be affected.   One can actually see how these telomere are at the end of chromosomes (image).   When the telomeres in normal cells become too short the cell stops dividing and dies.   However,  there is an enzyme called telomerase which adds some bases to the end of telomeres to keep them from getting too short.  This can be present in normal young cells; but is seems to be more prevalent in cancer cells.  It is thought that telomerase might be one of the things that allows cancer cells to keep dividing and not die out. 

For those that are interested in getting some background on telomeres check out these two article...
*New Telomere Discovery Could Help Explain Why Cancer Cells Never Stop Dividing
*Are Telomeres the Key to Aging and Cancer?

The hope is that if one can block telemorase activity in cancer that these cells will die out.   

For those interested in work that has been done in pediatric brain tumors with telomeres/telomerase, check the work of Uri Tabori (Sick Kids) who published work about telomeres in pediatric low grade gliomas back in 2006 and ependymomas in 2008.  In addition, St Jude made a study available in the end of 2012 using whole-genome sequencing to look at telomere content in pediatric cancer.

The Pediatric Brain Tumor Consortium (PBTC) is a group of US institutions banded together first in 1999 with the goal of improving treatment/outcomes with children with primary brain tumors by "rapidly conducting novel phase 1 and 2 clinical trials of new therapeutic drugs, new biological therapies, treatment delivery technologies and radiation treatment strategies in children" and a second goal of "characterizing reliable markers and predictors of response to new therapies".   At this time there are 11 full members and 4 temporary members of the PBTC.  Currently the PBTC is running 5 open trials of which two are related to DIPG- one is this trial and the other is ABT-888/temozolomide trial for newly diagnosed kids with DIPG.  The primary investigator for this Imetelstat trial is Maryam Fouladi (Cincinnati).  Contact information is available on the references below.

Reference:
A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma, Medulloblastoma/Primitive Neuroectodermal Tumor and Diffuse Intrinsic Pontine Glioma
http://clinicaltrials.gov/ct2/show/NCT01836549?term=dipg&rank=24

Protocol Summary for Parents from PBTC
http://www.pbtc.org/public/PBTC-036_v1_1%20Summary%20for%20patients%20and%20families.pdf

Protocol Summary for Health Care Providers from PBTC
http://www.pbtc.org/public/PBTC-036%20Protocol%20Abstract%20and%20Schema%20for%20health%20prof_v3.pdf

COG Phase 1 Imetelstat Trial in Young Patients (appears to still be recruiting)
http://clinicaltrials.gov/ct2/show/NCT01273090?term=imetelstat&rank=6

Genomic Landscape of treatment-naive DIPG Biopsy Sample

Yesterday I posted about the first International DIPG conference held in 2009 in Barcelona, Spain.  During that conference,  Dr. Jaume Mora moderated a two hour session discussing proposals for common international/interdisciplinary DIPG research agenda items.    Many things seems to be evolving collaboratively in the European DIPG arena.  The action points of the 2012 Barcelona meeting are impressive (click here to see).

In looking at the SNO/PBTF Pediatric Neuro-Oncology Basic Science and Translational  Research Conference abstracts, I noticed a somewhat unusual abstract.   This abstract (to me) highlighted the internationally collaborative nature of DIPG research today.   The authors were from 4 countries- France, England, Spain and Canada (Vancouver)!

This abstract examined the whole genome sequencing of 20 pre-treatment DIPG samples (all high grade gliomas) obtained by stereotactic biopsy in France.

Although the abstract word limits don't allow for in-depth understand of the work, there were some interesting things.  First,  the K27M mutations was seen in all cases.

It would seem that there were some cases where the initial untreated specimen was compared with a post-mortem sample.   Not really unexpected, the autopsy sample has increased number of mutations.  The authors write conclude that DIPG biopsy provides an opportunity to study the genome and identify possible intervention targets.

Something more fascinating to me - and not part of the abstract - is the question of how did these researcher get together to do this research for this abstract.   I believe the children from Spain might be offered the option of going to France for biopsy.   I believe that the children in the UK were offered that in that past as well.   In addition, Chris Jones was tasked as the responsible member for the biopsy biological studies (for SIOP-E DIPG Network).   In his Barcelona 2012 presentation, Chris Jones talked about "What to Do With Tissue".  In this, he did mention transatlantic collaboration.  

The thing that I wonder about though- is British Columbia.   Sick Kids has been a powerhouse of DIPG research out of Canada.   It would seem that Vancouver might be a place to watch as well.

Reference:
The Genomic Landscape of treatment-naive DIPG Biopsy Sample
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738496

DIPG Around the World: Spain and DIPG

For me, the DIPG community started to come together in Barcelona, Spain in February 2009.  Eleven pioneering,international researchers came together in Barcelona, Spain to try to figure out new ways to fight this devastating pediatric cancer.   It is also a time when advocacy foundations started to work together specifically on DIPG.  The Alicia Pueyo Foundation funded this conference and the Musella Foundation in conjunction with Just One More Day made videos available of the presentations.  These videos are still available today (click here).

Many of the names that were at that first conference are mentioned frequently in the DIPG community- Hargrave (UK), Kieran (Boston), Caretti(at that time Netherlands but now in Michelle Monje's lab), Van Vuurden (Netherlands),  Gururangan (Duke) and Broniscer (St. Jude).  

I'm not sure why the other names are not as well known.  It certainly has been a significant and unfortunate oversight that the Spanish researchers and doctors who initiated the cascade of events that we have seen unfold over the last four years are not as well recognized as these other names.   Today I hope to rectify some of that.

So those names back in 2009:
OFELIA CRUZ (Barcelona)  -Diffuse brainstem glioma: a clinical introduction
SEBASTIA PONS (Barcelona)- Brainstem embryology/ brain precursor cells
JOAN SEOANE (Barcelona) - Molecular gliomagenesis: genes and pathways
MANUEL RAMIREZ (Madrid)- Gene therapy strategies
In addition, Dr Jaume Mora moderated a two hour session discussing proposals for a common international/interdisciplinary research agenda!

Spain didn't just get the ball rolling on DIPG, but they have also continued to push forward in various aspects of DIPG research and treatment.   Perhaps the most visible accomplishment was the 2012 Barcelona conference.  Again the European DIPG participants made the presentations available.  In this meeting Spain had five different presentations-
*Biopsy and Autopsy (Mora)
*Intra-arterial Chemotherapy (Sola)
*Oncolytic Adenovirus for DIPG (Alonso)
*Intra-tumoral delivery of Oncolytic Adenovirus (Carcaboso)
*Irinotecan/Cisplatin Clinical Trial (Cruz)

The Irinotecan/Cisplatin trial started spring 2012.   Because of a keyword issue, it might be hard to find as it is listed under brain stem tumor, brainstem glioma and intrinsic brain stem tumor (but not DIPG or pontine glioma).

Clearly Spain has been a major factor in the advancement of DIPG Research.   Thank you for making this happen.

Much of the DIPG work in Spain has been funded by the Alicia Pueyo Foundation.   You can site a listing of their projects on their site.

ABC transporters limit dasatinib efficacy in mice

Ever since the first whole genome DIPG profile paper from Sick Kids in Canada came out in 2010, there has been interest in platelet derived growth factor receptor alpha.  This is because all the samples (9 post-mortem and two pretreated surgical samples) showed PDGRF-alpha expression.  The hope was that PDGFR-alpha could be a target to make a difference in DIPG.   The search was on for an agent to try.

An available PDGFR-alpha antagionist was found, dasantinib.  This Bristol-Myers-Squibb drug is marketed under the name Sprycel for the indication chronic myelogenous leukemia (CML).  When looking in clinicaltrials.gov, there are already 219 trials up for this drug.  It has been already been tried on adults and in children.   The availability and prior use seemed to make this drug easily translatable to trials for DIPG kids.  St. Jude has completed one trials using dasatinib and vandetanib and another open trial using dasatinib and crizotinib.

The thing about dasatinib is that it seems that it can be pumped out a a cell because by ABC (ATP-binding cassette) transporters.   This is a "superfamily" of  proteins that transport things (such as sugars, lipids, toxins and drugs) across the cell membranes.  Three of these ABC transporters are known to cause chemoresistance.  These are MDR, ABDG2 and ABCB1.  Datinib is known to be a substrate for MDR and ABCG2.

An abstract from Oren Becher's lab at Duke is going to be presented at the SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference next month in Fort Lauderdale looking at whether altering these transport proteins can alter dasatinib activity.   They did this by making DIPG mouse models that were deficient in the transporters ABCG2 and MDR.  At the first signs of tumor, these mice were given dasantinib.  The mice were sacrified a day later and the brains examined for specific things (caspase-3 and phospho-histone H3).

There was no difference in phosoph-histone H3 whether the transporter was present or not in the mice. However,  mice without the transporter had a 20 fold increase in caspace C levels as compared to those mice with the transporter.

These researchers concluded that these ABC transporters impact dasatinib's efficacy.  Further study is need to see if transporter-deficient mice can live longer when treated with dasatinib and if a transporter inhibitor (such as elacridar) can increase efficacy hopefully increasing survival.

Reference:
ABC transporters, ABCG2 and MDR, limit the efficacy of dasatinib in a diffuse intrinsic pontine glioma (DIPG) mouse model
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740371

Brain distribution and bioavailability of elacridar after different routes of administration in the mouse
http://www.ncbi.nlm.nih.gov/pubmed/22611067

Oren Becher Lab at Duke
http://pediatrics.duke.edu/faculty/details/0541183

UK Gives CED a Go

Just yesterday a DIPG/CED article came out electronically ahead of print in the journal Acta Neurochirugica-essentially a case report of a 5 year-old-boy with progressive DIPG who received carboplatin by CED- in Bristol, UK!

Since drug delivery into the pons has been considered a major hurdle in the treatment of pediatric DIPG,  there has been increasing world-wide interest in convection-enhanced delivery as a novel treatment for DIPG.  In the US there is the Cornell trial using 124I-8H9, the NIH trial using IL13-PE38QQR and a recent publication out of Columbia using topetecan.   Although not specifically termed a DIPG, Japanese physicians reported in 2011 about the use of nimustine via CED for a pediatric infiltrating brainstem GBM with improvement of symptoms and regression of the lesion. Basic science research has been going on in Spain using CED to deliver oncolytic viruses into DIPG lesions.   The Netherlands seems to be doing basic science CED research using carmustine.

It appears that the UK was on the forefront of the biopsy debate by offering families participation in the early French biopsy study.   Dr. Darren Hargrave reported on this back in 2009 at the first International DIPG conference in Spain.   One can view the lecture (go to 19:30 to start on the UK biopsy involvement).  One the CED front, however, the UK is not a country that has really come up before in the literature or internet.   Thus, this case report was somewhat surprising.

In this technical notes publication,  the authors report the "first use of carboplatin for the treatment of advanced DIPG using a robot-guided catheter implantation technique" performed on a 5 year old boy with progressive DIPG.  The child sounds like he had a typical DIPG course developing ataxia, double vision and swallowing issues over a month.    The initial MRI showed expansive pontine mass extending into the midbrain and right cerebellar peduncle.  He was first treated with radiation and steroids.   Because of progressive deterioration, the child underwent CED therapy nine months after diagnosis.

As this is a technical notes article, the publication goes into detail on the method of CED infusion (and has several MRI images).    Here is a very basic description of the procedure and infusion.   A catheter is placed through a typical transfrontal approach (3cm frontal skin incision).  After fixation the child underwent MR imaging to for drug distribution investigation.   Once this was determined the child recovered from anesthesia and the carboplatin infusion continued.  Initial carboplatin infusion occurred over three consecutive days.   Then there was a 4-day rest period followed by another 2 days of infusion.  The catheter was replaced with a stylet on day 12 to remain as a guide tube if needed for further infusions.  Discharge occurred on day 14 after the procedure.

During infusion, the child had some worsening neurological symptoms; however, a month after infusion he was more alert, was able to decrease his steroid use by more than half but his neurological status was mixed with some things were improved and others were worse.  Two months after infusion the boy had a rapid deterioration and died.

The discussion highlights a number of "technical challenges" with CED especially revolving around getting sufficient drug concentration with in the tumor which include reflux of the infusing drug and poor drug distribution.   Also "off target" side effects have been barriers.   To me these off-target side effects are not unexpected as one is infusing a liquid under pressure into a relative small tight space.  

The authors felt that this case demonstrated the feasibility and safety of CED infusion for pediatric DIPG.   Most importantly they end with something to watch for in the future...." It is our intention to use the experience gained in this case to develop a robust protocol for a phase 1 clinical trial of convection-enhanced delivery of carboplatin for progressive brainstem glioma."

Reference:
Robotic-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma
Acta Neurochir (Wien). 2013 Apr 18. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23595829

Netherlands Radiolabeled Bevacizumab Trial

In the age of molecularly-targeted chemotherapy, diffuse intrinsic pontine gliomas are tough tumors.  DIPGs seem to be molecularly heterogenous tumors- not only between individuals but also within a single tumor.  If one can not obtain tissue then it is impossible to know if a particular tumor even has the target.  And if one does get a biopsy the concern is is really representative?

There is also the concern perhaps the brainstem is more difficult to get agents in- is the blood brain barrier just more tight in that area?

For me the question has been, how do we address these concerns clinically?  It appear that the researchers at VU University Medical Center in the Netherlands are trying to look at these questions by using an immuno-PET approach.

Immuno-PET scanning  uses a radio-labeled monoclonoal antibody.   The idea is that the radio-labeled agent will stick at the place where there is the specific receptor and the tag will let it light up on the scan.   One could think of it as "a comprehensive immunohistochemical stain in vivo".    In this case the monoclonal antibody bevacizumab is labeled with 89Zr.  PET scans will be done at 1, 72 and 144 hours after administration.

Immuno-PET looks like a  novel way to get answers to some of these questions.  My hope is that this study will provide new knowledge on drug distribution with a anti-VEGF in DIPG.   Since pediatric high grade gliomas are also included it will be interesting to compare these two different populations.

This research has been supported by Stichting Semmy.

Reference:
Determining the tumor uptake of labelled bevacizumab in children with high grade or diffuse intrinsic pontine glioma on PET Scans
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3518

Immuno-PET: a navigator in monoclonal antibody development and applications.
Full Text-http://theoncologist.alphamedpress.org/content/12/12/1379.long

Is Biopsy Safe in DIPG? An Institutional Experience

This spring abstract season which means one can comb through the abstracts to find the newest research being presented- sometimes more than a year before publication.   The hope in finding and highlighting relevant meeting abstracts is to significantly shorten that time period in figuring out who is doing what.  

On of the meetings with potential is the 26th Annual American Society of Pediatric Hematology and Oncology (ASPHO) Anual  Meeting being held in Miami from April 24-27.   With all the different pediatric blood and cancer disorders, I don't usually expect much success in looking for brain tumor abstracts let alone DIPG.   This year, though,  I was surprised by abstract 750 (page S67):

Is Biopsy Safe in Diffuse Intrinsic Pontine Glioma?

An Institutional Experience

The surprise didn't end there.   Although the institutions is one of the collaborators for the multi-institutional trial with molecular determination for treatment by upfront biopsy,  it is not one that has been obviously on the forefront of the US biopsy debate- Children's Hospital of Michigan in Detroit.  

These authors report on 22 newly diagnosed children with DIPG between 2002 and 2012.    Stealth guided biopsies were performed in 68% of the cases.   There were no deaths related to biopsy.  Three of the fifteen children undergoing biopsy has transient issues post-operative which resolved within two weeks.   The issues included one child developed a facial nerve palsy, one child has some speech difficulty and extremity weakness and the third has ataxia and swallowing difficulties.

All biopsies showed gliomas (grade 2-4). 

The authors conclude that biopsy at their institution has been relatively safe and the resulting tissue will allow for molecular profiling which may lead to targeted therapy and perhaps in the future prolonged survival or a cure.

So, why is the percentage of biopsy so high at this institution?   These authors report a case of theirs in which a child was found to have a PNET tumor rather than a glioma.   Subsequently, biopsy is considered in the majority of these tumors at diagnosis.

Reference:
Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma
http://clinicaltrials.gov/ct2/show/NCT01182350?term=dipg&rank=5

DIPG Yahoogroup 5th Anniversary

Today marks the 5th anniversary of the DIPG Yahoogroup.  Started by on April 16th, 2008 by one mother who wanted to have a place for DIPG parents to talk with one another and share experiences as well as information.   From that one, there are now 616 members listed with almost 25,000 posts.

So much has changed in those five years.   Back in 2008,  it was common to hear parents say brainstem glioma not realizing how heterogeneous that term really was.   I don't remember any listings of trials on clinicaltrials.gov under DIPG.   Today there are 26 listed making it much easier for parents to locate and sort through these trials.   And back there research was severely limited because there was no tissue to examine; and because of the lack of tissue there were no cell lines or representative animal models.

The research landscape was just beginning to change for DIPG with the French biopsy study having just been published the year before and several institutions working to gather post-mortem samples.  The start of the list coincided with the rapid expansion of DIPG research.

I firmly believe it is because of some of the members of this group that DIPG research was pushed more quickly. Some played their part on spreading the word on tumor donation while others funded workshops, trials and research.   Often interesting items appeared on the list significantly before publication like the MD Anderson reirradation pilot- perhaps pushing the spread of information faster than ever has been seen before.

Here is a listing of some of the important events in DIPG over the past decade:

2002- Sick Kids start autopsy collection of DIPGs
2005- France starts trial with upfront biospy
2006- St Jude stars autopsy collection of DIPGs
2007- France first reports on trial with upfront biopsy
2008- DIPG Yahoogroup opened
2009- First International DIPG Meeting in Barcelona
2009- FDA DIPG biopsy hearing
2009- Dylan donates tumor to Stanford
2009- First CED trial on recurrent DIPG open in US
2010- Toronto DIPG Think Tank
2010- First DIPG Genetic Analysis Publication
2011- Amsterdam DIPG meeting
2011- Stanford reveals first DIPG neurosphere
2011- Vaccine study for newly diagnosed DIPG begins at Stanford
2011- First DIPG/Oncolytic Virus Case
2011- DIPG.org Symposium
2011- DIPG Preclical Consortium formed
2011- DIPG Registry
2011- MD Anderson opens first DIPG Reiiradiation trial
2011- DIPG Concensus Conference at the NIH
2012- DIPG Barcelona Conference
2012- ACCO Book- Understanding the Journey
2012- DIPG Genomics Repository
2012- US multi-institution biopsy trial begins
2012- CED trial for newly diagnosed DIPG opens at Cornell
2013- Academic Colloquium: State of the Art in DIPG (Amsterdam)

I extend deep gratitude to all that participated in the list which has helped get us to where we are today.

Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis

The first hints of data from a Cincinnati/Lurie Children's study using temozolomide, irinotecan and avastin appears to be coming out with a poster presentation at the 3rd biennial Pediatric Basic and Translational Research Conference looking at patterns of progression with an avastin-based therapy for kids with newly diagnosed DIPG or high grade glioma.

The issues of potential increased invasiveness and spread have been popping up for the past few years. We have seen discussions of this in internet-based communities as well as publications in adult GBM patients.   Common terms related to this are "diffuse invasiveness" and "evasive resistance".   The adult literature has some that do not believe that avastin increases remote relapses.  There is very little regarding children relapse patterns with bevacizumab-based therapies.

In this study of 17 patients (14 DIPG and 3 HGG), 12 patients had progressive disease in a median time of 8.2 months.  In nine patients the furst progression was local and  in the remaining three the progression was local, diffuse and distant.   However with further progressive disease a total of six children had diffuse or distant progression.

The authors speculate that these findings might be explained by increasing invasiveness through co-opting native blood vessels or activation of other pro-angiogenic pathways.     

It would be interesting to have direct comparison to non-bevacizamab-based therapies for comparison as other authors have indicated a high risk of leptomeningeal dissemination with DIPG.  Interestingly, in that study 8 of the 16 children had leptomeningeal spread but only the 3 with anti-VEGF (2 with avastin and 1 with vandetanib) had spread to bilateral cerebral hemispheres.  The other 5 had spread to the spinal cord or posterior fossa.

It is likely questions like this is where a registry can be valuable if one is able to look at a large number of imaging studies. 

Reference:
Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=736163

A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas
http://clinicaltrials.gov/ct2/show/NCT00890786?term=dipg&rank=10

Bevacizumab does not increase remote relapse in malignant glioma
http://www.ncbi.nlm.nih.gov/pubmed/21446027

Prospective neuroaxis surveillance reviews a high risk of leptmeningeal dissemination in diffuse intrinsic pontine glioma.
http://www.ncbi.nlm.nih.gov/pubmed/20623246

Foundation Spotlight- A Cure From Caleb Society

Many of the recent posts have been highly scientific.   It the spring season of new abstracts so I guess it isn't to be unexpected.   However, sometimes I feel that I just need to sit back and look at pictures to gain perspective on more than molecular pathways.  Today I did just that.   I looked at pictures of a little boy I got to know only from the internet.

Caleb loved hockey and jokes but his life was completely derailed at age 8 when he was diagnosed with DIPG.  Due to the persistence of his parents got a second round of radiation at progression that gave them another 9 months.  This was something that simply wasn't done before and was only happened due to the valiant fight of this family.

Caleb still inspires fighting for change through the A Cure From Caleb Society which specifically fund s DIPG research.  This past Friday, the foundation hosted a Spring Dance to create awareness and fund research.

The research A Cure From Caleb Society is supporting is that of Cynthia Hawkins, MD PhD of Sick Kids.   Dr. Hawkins has been on the leading edge of many recent advances in DIPG research-from creating an post-mortem tissue collection program at Sick Kids to the first publication of DIPG molecular analysis.  She was also instrumental in the Toronto DIPG Think Tank in 2010 and is a participant in the DIPG Preclinical Consortium.    I am sure there is going to be much more research coming from this lab as in addition to yesterday's abstract there another one that will be presented at the same conference.

And for Caleb- we are not chicken and will continue to work on crossing the road to a cure.

Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas

Sick Kids instituted an brainstem glioma project back in 2003 in hopes of trying to understand diffuse intrinsic pontine glioma.   To do this the researchers reached out to families with an autopsy-based protocol asking for consideration of post-mortem tissue donation.    This decade commitment and collaborative effort against DIPG has lead to another DIPG abstract for the upcoming SNO/CBTF supported 2013 Pediatric Neuro-Oncology Basic and Translational Research Conference.  This one comes from Sick Kids in conjunction with Oren Becher from Duke.

The researchers examined 71diffuse intrinsic pontine tumors:

• 65 were high grade gliomas, 8 were low grade and 3 were PNETs.
• survival was not related to grade.
• leptomeningeal spread was present in one third of cases.
• 68% had K27M-H3.
• these tumors were histologically heterogenous, however increased homogeneity  was found of the histone mutation.
• the histone mutations were also present in low grade tumors that had worse outcomes.

The authors conclude with a call for "incorporation of histological and molecular data"- specifically stating  "histone mutational status at biopsy"- in designing new therapies for DIPG.

There has been a rash of publication regarding K27M mutations recently.   Several of the other abstracts for this meeting feature this histone mutation in DIPG.   I am sure more will be coming in the future.

Reference:
Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=73797

Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

http://www.sciencemag.org/content/early/2013/03/27/science.1232245

St Jude Looks at Long Term DIPG Survivors

At a poster session for the 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference next month,  physicians from St Jude Research Hospital will be presenting a retrospective review of their patients who had prolonged survival despite being given a diagnosis of diffuse intrinsic pontine glioma.

These physicians reviewed the records of DIPG patients at St Jude from October 1, 192 to May 31, 2011.  Of the 191 patients there were 5 long time survivors with a median time from diagnosis being 9.3 years!    It seems 4 out of 5 of these patients had some atypical clinical or imaging features that put them on the side of potentially better outcomes than the average.

All these survivors underwent neurocognitive testing.  Interestingly, and unfortunately like so many other children who undergo brain radiation, cognitive function was impacted in 4 of 5 patients- two falling in the range of borderline/mild mental retardation.   These findings will become increasingly important when there is better survival statistics for DIPG.

The researcher point out that prolonged survival does not equal cure.   Two of the patients had progression years after their initial treatment with radiation.

It will be interesting to see what comes of this.  Certainly the DIPG Registy could become very important to bring the information on all long term survivors together at one place.   

Reference:
Clinico-radiologic characteristics and neurocognitive assessment of long-term survivors of diffuse intrinsic pontine glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738281