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 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

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

Focus on Research- Mitochondria and DIPG (New Australian Abstract)

The 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference jointly sponsored by the Society of Neuro-Oncology and the Children's Brain Tumor Foundation will be held on May 16th and 17th in Fort Lauderdale Florida.   Several of the already available abstracts are several on DIPG.   One of the ones that caught my eye will be a poster presentation from Australian researchers entitled " Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma". 

The interest in cellular metabolism in cancer goes back the early 1900's with  Otto Heinrich Warburg. The Warburg Hypothesis says "the prime cause of cancer is the replacement of the respiratory of oxygen in normal body cells by a fermentation of sugar."  He speculated that tumor development is driven by insults to the mitochondria which affects cellular respiration.  Mitochondria have become a potential target for cancer therapy.   One of the key mitochondrial proteins implicated in cancer has been adenine nucleotide translocase (ANT).

In this abstract, the researchers used DIPG neurospheres to evaluate the effectiveness of an ANT inhibitor PENAO.    This agent appears to have first hit the internet in 2011, when some of the authors unveiled this novel compound at AACR in an abstract " PENAO: A small molecule tumor metabolism inhibitor".  In the AACR abstract PENAO led arrest of proliferation and apoptosis of tumors cells.  It was well tolerated by IV and subcutaneously in mice.

In this study, the use of PENAO on DIPG neurospheres was found to be a "promising therapeutic strategy" to treat DIPG.  In addition, combination with a MRP1 ( multidrug resistance-associated protein ), Reversan,  increased the effect.   Effectiveness of PENAO was also increased by 3-bromopyruvate.

This is interesting research with a different approach to DIPG in utilizing mitochondrial small molecule inhibitors.   Now, the challenge would seem to be in the steps to translate this from bench to bedside.   The great thing now compared to just a few years ago is that several institutions have been able to developed DIPG animal models to be able to preform the necessary translational research.

Reference:
Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740145

Mitochondria and Cancer: Past, Present, and Future
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581248/

Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer
http://www.ncbi.nlm.nih.gov/pubmed/20950584

Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia
http://cancerres.aacrjournals.org/content/65/2/613.full

DIPG- Adults versus Kids

Adult diffuse pontine lesions have a median survival range of 4.9 to 7.3 years!

There seems to be a bimodal type of distribution of diffuse brainstem lesions.  The first peak is generally in the the 4-9 year olds and the second is in the 20-50 year olds.   Like children, diffuse brainstem gliomas are the most frequent type of brainstem tumor in adults.   Unlike children who tend to have high grade lesions with a prognosis on average of about 1 year, young adults with similarly appearing lesions when biopsied are low grade and may have a much greater life expectancy.

 Although adult and pediatric DIPG patients might present with similar symptoms (such as ataxia and cranial nerve palsies), is important to realize that despite potentially similar appearances of the diffuse pontine lesions on MRI this is not the same disease process.   This is made clear in the review (full text link) published last year in The Oncologist.  For those interested the read is not near as difficult as the recent molecular tumor biology publications.   In addition, there are three MRI series of adult patients with diffuse pontine lesions.  One of these survivors' MRIs is shown 10 years out.

 I highly recommend a peak at these MRIs (which is easier to do on pub med if one doesn't want to read the entire publication.)  It is amazing how the MR imaging is so similar to what we see in pediatric patients, yet the course can be so much different.

 No one know yet why the tumors are so different in different ages.

Reference:
Adult Brainstem Glioma
Oncologist. 2012;17(3):388-97. doi: 10.1634/theoncologist.2011-0335. Epub 2012 Mar 1.
Full Free Text
http://theoncologist.alphamedpress.org/content/17/3/388.long

Focus on Research: 3 New DIPG Abstract This Week!

One of the frustrating things about medical research is the delay between when research is presented at a scientific meeting and when it actually gets to publication.   Unfortunately, sometimes the gap is more than a year.   For this reason, I trawl around the meeting abstracts which might have potential.    One such meeting is the American Association of Cancer Research (AACR) concluding it's five-day Annual Meeting tomorrow.    I am thrilled to report there are DIPG presentations at this meeting.

Here are the citations for the three presented abstracts:

1)  Nathalene Truffaux, Ludivine Le Dret, Stephanie Puget, Gilles Vassal, Birgit Geoerger, Jacques Grill.
Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models
 In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013 {Abstract 2763}

2)  Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Packer, Javad Nazarian. 
NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5004}

3)  Marianne Hutt, Wendy Goldstein, Javad Nazarian, Antoinette Price, Kah Jing Lim, Katherine Warren, Howard Chang, Charles Eberhart, Eric Raabe.
Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013.  {Abstract 5049}

The first abstract is from the French researchers that have pioneered the way for biopsies.  The second is from National Children's in DC, Duke and Emory/Georgia Institute of Technology.  The third is from the Mid Atlantic DIPG Consortium (MADC).  The MADC abstract appears to be an extension of the abstract we highlighted here on March 23this year.

As the abstracts are meant for a group of researchers, they are most definitely highly scientific.  Here is one thing to take away-  it is possible to establish cell lines from freshly biopsied DIPG material.   The French group has been able to establish 12 lines in this way!  

Hopkins New Trial for Progressive DIPG

Johns Hopkins has put up a new pilot study for children (age one month to 17 years) with progressive DIPGs using intra-arterial (IA) chemotherapy.   This procedure will involve placing catheters into the arteries and guiding them to the blood vessels that directly feed the tumor.    Melphalan hydrochoride, a chemotherapeutic agent, will be delivered directly into these vessels at two intervals 4 weeks apart.  The hope is to increase the amount of drug to the tumor while decreasing the toxicity to the rest of the body.

An interesting part of this study in the interdepartmental nature of the panel which approves inclusion to the study.   The panel included two neuro-oncologists- Ken Cohen and Eric Rabbe; a neurosurgeon- George Jallo; a radiation oncologist- Stephanie Tezakis; and a interventional neuroradiologist- Monica Pearl.   A truly novel part of this study is that the primary investigator is the interventional neuroradiologist!   It is exciting to see such a diverse team interested in novel ways to combat DIPG.

One of the hurdles for DIPG, and in fact all brain tumors, has been getting adequate drug to the tumor.   There have been some attempts at trying to get chemotherapy directly to the tumor through the arteries in the past.    In 2011, Cornell neurosurgeons published an article using the basilar artery to instill chemotherapy near recurrent pediatric ependymomas.   Prior to that there was a publication on blood-brain barrier disruption chemotherapy specifically for diffuse pontine gliomas.  Given the failures so far with DIPG treatment, it is good to see another institution interested in new ways to treat DIPG.

This pilot study is being funded by Solving Kids' Cancer.   This organization, founded by two fathers of children with neuroblastoma, has a mission "to create more effective and less toxic treatment options for kids with the deadliest childhood cancers.  Solving Kids' Cancer's therapeutic paths include genomics, tumor initiating cells, biotherapeutics, immunotherapeutics, embryonic development mechanisms, tumor cell surface receptor and implicated molecular pathways.

References:
Intra-arterial Chemotherapy for the Treatment of Progressive Diffuse Intrinsic Pontine Gliomas
http://www.hopkinsmedicine.org/interventional_neuroradiology/conditions_procedures/progressive_diffuse_intrinsic_pontine_glioma

Super-selective basilar artery infusion of bevacizumab and cetuximab for multiply recurrent pediatric ependymoma
http://www.ncbi.nlm.nih.gov/pubmed/22192550

Osmotic blood-brain barrier disruption chemotherapy for diffuse pontine gliomas
http://www.ncbi.nlm.nih.gov/pubmed/16314949

Catching the Wave: Biopsy and DIPG

I confess I have never surfed.   Still, I imagine that DIPG research could be compared to surfers paddling out on the ocean waiting for a wave.    For DIPG though, the waters have been incredibly flat for a long time.   Now, the sea is changing.

For years, we have been stuck in a conundrum.  We need tissue to know if a child can get benefit from a therapy but maybe we should not biopsy unless we know that the child will get benefit.  It has been a catch-22 that has been difficult to break.

As the era of tumor molecular biology has blossomed,  France first re-instituted the biopsy option for typically appearing pediatric diffuse intrinsic pontine glioma.  Increasingly there have been ripples all over the world expressing the importance of biopsies in designing treatment for these children in hopes of finally improving the dismal statistics.

Last year, Ryo Nishikawa, a Japanese neurosurgeon and Executive Editor JSNO,  wrote a short opinion letter in Neuro-Oncology.   Despite the issue of intratumoral variation, he pointed out that biospies must be performed to "determine genetic profiles" of brainstem lesions.   He also highlights the neurosurgical advances in stereotactic biopsy which has made it more feasible and less dangerous to biopsy brainstem lesions. He concluded with the statement raising hopes for tailored treatment in pediatric DIPG.

As I read more articles on the DIPG biopsy issues, I also have the feeling of new waves for diffuse intrinsic pontine glioma research and treatment.

Reference:
Diffuse intrinsic pontine gliomas: New Waves
Neuro Oncol. 2012 March; 14(3): 245.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280815/

Brazil and DIPG

How much interest is there in DIPG around the world?

One of the most fascinating parts of this blog is a part that I suspect few have ever seen- the cluster map.    The cluster map tracks the general location of people who are checking the blog.    There are dots on every country, well, except Antartica.  Scrolling down on the right hand side there is a listing of more than 90 countries!  Just the other day I noted Brazil come up twice in a few hours from different parts of the country.   I wondered, "what is Brazil doing in DIPG?"  

Here are a couple of things I found.

Brazil does have a clinical trial on DIPG.  It isn't necessarily easy to find in clinicaltrials.gov as it is listed under the keyword brainstem gliomas (not pontine glioma or DIPG).  Still, from it's official name it clearly is a DIPG trial- Use of Nimotuzamab and Radiotherapy in the Treatment of Pediatric Patients with Diffuse Brainstem Glioma.  The trial was first received on the site in June 2010 and still listed an enrolling patients.  There is a tight age restrictions (age 3-18) and is open at 4 Brazilian and one Cuban hospital.

In addition, Brazil presented an abstract,  Pediatric Brainstem Glioma: Experience of One Brazilian Institution, at the 15th International Symposium of Pediatric Neuro-Oncology (ISPNO) in Toronto, Canada in June 2012.  The authors wished to understand the variety of brainstem gliomas that presented to  the Instituo Nacional de Cancer in Rio de Janerio over a 5 year period (2005-2010).  Of the 48 children diagnosed with brainstem gliomas, 40 were considered diffuse and 39 were in the pons.

In looking at the over survival (OS) among the groups:
1 year OS- midbrain 100%, medulla 75%, and pons 41%
2 year OS-midbrain 100%, medulla 75% , and pons 12.93%
2 year OS by extension- focal 100%, exophytic 67% and diffuse 15%

It is what we have seen before- diffuse, pontine tumors have the worse outcome and need new approaches to improve outcomes.  Still, it is good to see that Brazil is also a place in the world trying to learn more about DIPG and looking for new ways collaboratively to treat kids with DIPGs.

New Trial Pending: Reirradiation for DIPG

Every once in awhile I will just randomly go through clinicaltrials.gov searching to see if anything new has been put up.   I had gone through a few times recently seeing two reirradiation trials listed- one open and one not yet open.   Knowing of the MD Anderson trial I thought it was just a computer glitch.   When I finally opened the page, it was a surprise it wasn't MDA but a trial based in Israel.  

It not that Israel hasn't come up before in the brain tumor community.   It definitely has.  There has been interest in the Newcastle Disease oncolytic virus and the Novocure device on internet groups to which I belong.   However, both have had issues that made it problematic in the DIPG community.   In the former lack of a tissue diagnosis could be a hurdle and the latter has significant issues with pad placement for electrical fields have made the device not possible- at least not yet.   It is just that Israel isn't one of the places that is often mentioned in DIPG work.

It would certainly seem that this pending trial was based on the MD Anderson work published last year (abstract link below).   In that pilot project 4 of 6 children had significant clinical improvement after  receiving re-irradiation at symptom progression.   Three of these children were able to walk again after re-irradiation.   The mean progression free survival was 5 months.  Those children with the longest time interval between radiation courses had the greatest benefit.

This trial is interesting it is allowing for a short interval for radiation at a minimum of 4 months.  Since at one time it was thought that re-irradiation wasn't even possible is is a huge shift in thinking.  

Another interesting thing is the increased specifics on the inclusion criteria-
-diagnosis of DIPG based on short classic history,
-clinical signs (long tract signs, cranial nerve deficits and ataxia), and
-classic MRI features (more than 2/3 of the tumor is located within the pons and tumor encompasses more than 60% of the pons).

I think we are going to increasingly see this type of specific DIPG definition be articulated in trial inclusion criteria.   It is important to be able to better interpret results.

The increasing international inertia to fight DIPG is palpable.  It is good to see another country join in the fight to try to do something to help these children.

Reference:
Israel- Hadassah Medical Organization
Palliative Re-irradiation for Progressive Diffuse Intrinsic Pontine Glioma (DIPG) in Children
http://clinicaltrials.gov/ct2/show/NCT01777633?term=dipg&rank=3

MD Anderson
Diffuse Intrinsic Pontine Glioma (DIPG) Reirradiation (ReRT)
http://clinicaltrials.gov/ct2/show/NCT01469247?term=dipg&rank=13

Palliative reirradiation for progressive diffuse intrinsic pontine glioma.
Am J Clin Oncol. 2012 Feb;35(1):51-7. 
http://www.ncbi.nlm.nih.gov/pubmed/21297433

Dana Farber DIPG Research Receives a Half Million Dollars

Mikey loved baseball and the New York Yankees, the Doobie Brothers and his dog named Cody.   On Mikey's 11th birthday, January 6, 2008, life as this family knew it ceased to exist.   They first heard the letters- DIPG.  After radiation and a radiosensitizer trial ( Motexafin Gadolinium), his tumor shrank about 85% by April; but byAugust, he started to have right sided numbness, problems walking and difficulty swallowing.     Mikey Czech died on September 7, 2008.

In Mikey's memory, the Stephen J Czech family founded the Mikey Czech foundation with a mission  to establish a leading neuro-oncology translational research laboratory, raise awareness of DIPG, fund research and cure pediatric brain tumors.

In their search to find research trying to cure DIPG, they found a physician, Mark Kieran MD, PhD, completely frustrated at the lack of prognostic change for DIPG in 30 years and a desire to try a new approach.   Biopsies were essentially stopped in the early 1990s before it was even possible to study tumor molecular biology and now seemed to be the right time to take advantage of all the knowledge gained in neurosurgical technique, cancer pharmacology and tumor molecular biology to try to make a difference for DIPG kids.

Dogma doesn't change easily.  For year, Dr Kieran challenged his colleagues on this front.   Little by little others came to the same perspective.  In December 2012, a multi-institutional clinical trial with molecularly determined treatment for the newly diagnosed child with DIPG commenced at Boston Children's.   Today, five other institutions (Lurie Children's in Chicago, Johns Hopkins,  Seattle Children's, Cook Children's in Texas and Washington University in St Louis) also have this trial open.
Watch Dr Kieran discuss a one minute presentation on DIPG research  (open in a different window)

This trial faced other difficulties as well- in particular, funding.   This trial is using already known drugs  so isn't a trial that would be funded by a pharmaceutical company.   It was up to private funding to make this happen.   Mikey Czech Foundation has been a big part of this- and with the donation of a half million dollars today continues to be a sustained supporter of Dana Farber's leading edge work.

One should note that the Boston researchers have not been sitting around waiting for the trial to start.   Biospies have been happening for years in France.  With the financial backing of these foundations,  the researchers in France and Boston collaborated to look at 20 newly diagnosed DIPG specimens- before they could be changed by radiation and chemotherapy.  Here is a link to the abstract published last year.

In this fight we will take Mikey's motto:

"Never, Never, Never Give Up!"

Note- I am aware of several organizations that have come together to fund this innovative research- The Zach Carson DIPG Fund, the Ellie Kavalieros DIPG Fund, The Prayers From Maria Foundation, Children's Hospital of Los Angeles Imaging Center, The Pediatric Brain TUmor Research and Clinical Fund at Dana-Farber Cancer Institute,Stop and Shop Pediatric Brain Tumor Research Fund and Hope for Caroline

References:
The Mikey Czech Foundaiton Contributes $500,000 to DIPG Research at Dana-Farber Cancer Institute-Harvard Medical School (2013)
http://finance.yahoo.com/news/mikey-czech-foundation-contributes-500-121400450.html

The Mikey Czech Foundation Funds New Hope for Cancer Research (2012)
http://thecristianriverafoundation.blogspot.com/2012/01/mikey-czech-foundation-funds-new-hope.html

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
http://clinicaltrials.gov/show/NCT01182350

Mikey Czech Foundation
http://www.mikeyczech.org/

Focus On Researh- Xiao Nan Li

Dedicated to a special boy,  Paul Alexander Coleman III, who is continuing to make an impact.....

Because of the trifecta of basic science hurdles- no tissue, no cell lines, no animal models- DIPG bench research has only recently begun.  This has only been possible because of the efforts of a few individuals struggling to make the previously impossible possible- make animal models from an inoperable tumor.  One of these pioneers- Xiao Nan Li MD, PhD (Baylor College of Medicine/Texas Children's Cancer Center).

Dr Li's interest is in the fields of cancer stem cells, experimental therapeutics and diagnostic markers with a particular focus on developing "clinically relevant animal models" for preclinical testing.

I first became aware of Dr Li when a fellow brain tumor parent sent her son's post-mortem specimen across the from the east coast to Texas to try to make a difference for medulloblastoma.  The lab wasn't only interested in medulloblastoma.   Dr Li has established more than 25 xenograft mouse models of several different pediatric brain tumors.  At some time,  a post mortem DIPG specimen was obtained and through the lab's work a door was unlocked for DIPG.  Dr Li was able to establish a DIPG animal mouse model from this tissue and the scientific value of DIPG autopsy specimens skyrocketed.

Although the lab is interested in fighting all pediatric brain tumors there seems to have been a special focus on DIPG.   Texas Children's has cell lines and thus became one of the initial members of the DIPG Pre-clincal consortium which is collaboratively working on rapid analysis of the cell lines and drug testing.

The lab has at least 5 different DIPG mouse xenografts that can be used for other types of research.  One of these research endeavors is using oncolytic viruses in the DIPG mice he developed.  Dr Xaio Nan Li will be presenting his work in a mouse model on eliminating therapy resistant DIPGs with an oncolytic virus at the DIPG Symposium in Cincinnati on May 3rd.   A link to the grant executive summary funded by the Cure Starts Now is listed below.

This oncolytic virus research is exciting especially in light of the recent publication out of University of Alabama looking at this issue in pediatric gliomas.   Although the publication is a different virus, the idea is essentially the same.  Novel therapies are going to be needed to eliminate treatment resistent subpopulations while sparing normal tissue.  Oncolytic virus have been one of the innovative treatment that might be a weapon in the future against DIPG as well as other gliomas and brain tumors.

References:
Neuro-Oncology Research Lab of Dr Xiao Nan Li
http://ccitonline.org/tccc_production_old/cancer-genomics-li/

Harnessing Autopsied DIPG Tumor Tissues for Orthotopic Xenograft Model Development in the Brain Stems of SCID mice- Grant Award Final Report
http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA568355

Eliminating Therapy-Resistant Diffuse Intrinsic Pontine Gliomas with Oncolytic Picorna Virus SVV-001: an in vivo Study in Intra-brain Stem Xenograft Mouse Models- Grant Executive Summary
http://www.thecurestartsnow.org/_pdfs/grant_2011-11_texas.pdf

Pediatric glioma stem cells: biologic strategies for oncolytic HSV viral therapy.
Front Oncol. 2013;3:28. doi: 10.3389/fonc.2013.00028. Epub 2013 Feb 28.
http://www.ncbi.nlm.nih.gov/pubmed/234506

Are there survivors?

Are there any survivors of DIPG- even just one?

This is the fervent plea of so many parents whose children were just diagnosed with this terrible tumor. A  search of the internet yields conflicting information.  Here are some statements I have found:
*There are no long term survivors of DIPG.
*There are long term survivors.
*The long term survivors are atypical.
*If there are long term survivors then they were mis-diagnosed.

What is a parent to think?  Who do you believe?   Why are these statements so divergent?  Is there an answer one can trust on survivors?

My short answer:
*There are long term survivors of DIPG (meaning more than 5 years).

*Most of the reported long term survivors are atypical in some way especially the very young (under 3), prolonged symptoms before diagnosis or atypical features on imaging- but not all.

* It is hard to say that a long term survivor was misdiagnosed since the diagnosis is based on imaging. The assumption has been if the lesion is uniformly diffuse and encompasses a large part of the pons then the lesion is a glioma.  It is then called a DIPG.   Since we have not have routine biopsied it is impossible to know the histology so all might not be gliomas.   However, one can tell on imaging if the lesion is diffuse, intrinsic and pontine.   It might be semantics but it seems hard to be a misdiagnosis per se but rather currently there is an inadequate understanding of these lesion.

I am virtually certain that the parents of prolonged survivors were given the exact dismal prognosis as those parents whose children had only a short time.   I think it is extremely unfair to then go back and tell these parents that "well, it wasn't really a DIPG".   It seems more valid to say that we don't understand these tumor.  Some unpredictably and inexplicably do better than the vast majority of others.

So, why can I be so certain that there is at least one term survivor?   One doesn't need to take my word for it.   I would recommend viewing a 2009 video of a top St Jude researcher, Alberto Bronsicer.
http://justonemoreday.org/DIPGConference/NewClinicalTrialsfromStJude.html
(go in to 15:49 minutes)

Transcript:
I swear to you- typical brainstem glioma.  I work her up- was one of my first patients at St. Jude.  Full blown findings.  We have spectroscopy.  You name it.  This is the MRI to show and 5 years later.  She has some sequela of her treatment.  One thing I point to all my parents- she never had complete response.  A partial response.   You see changes there 5 years later and she is out and about.

So yes, there is at least one long term survivor of what appeared to be a very typical DIPG.  Unfortunately, the vast majority of children with these tumors will follow this path but for those that find hope in just one- here is one.

A New Era for Children with Diffuse Intrinsic Pontine Glioma: Hope for A Cure?

"A new era for DIPG has just begun."

So starts the conclusion of this expert review article written last  year by two prominent DIPG researchers from the Netherlands- Marc Jansen and Gertjan Kaspers.   It will behoove one interested in DIPG research to be aware of those names.  They are ones that keep coming up in DIPG issues- publications and European DIPG worshops.   

These experts highlight that there has been a rapid increase in biological understanding of DIPGs.     This has only been able to occur because of the recent availability of DIPG tumor tissue which from  the French re-introduction of biopsies and the North American/Dutch focus on autopsy donation.  This DIPG tissue is critical to the further understanding of DIPG although biopsies and post-mortem tissue each have advantages and disadvantages.

The biopsy issues has been very controversial.   The French group has now preformed over 100 stereotactic biopsies with 0% mortality and a 4% transient morbidity.   An advantage of pre-treated biopsy specimens is that there is a significant risk treatment will change the original molecular characteristics.  The tumor that the children start with very likely is not the tumor molecularly that they die with.

Post mortem tissue carries a high risk of treatment-related genetic changes.   Still, there are advantages.   There is a much greater tissue volume available for study.   This also allows study on tumor hetergeneity (how varied the tumor is) as well as "treatment-resistent subclones".   In addition, it has been from these tumor donations that cell lines and animal models have been developed (greatly adding to research potential).

Even with this "avalanache of gene profiling studies" in DIPG, this will probably not provide the entire answer for cure.  There is at least one other prong to the problem.  The authors pose some thoughtful questions for consideration:

• Why  are all chemotherapy regimens ineffective in DIPG while  some show activity in supratentorally located gliomas, such as  temozolomide?
• Why does imatinib, an inhibitor of the  DIPG key target PDGFRA, not improve survival ? 
• Could  poor drug distribution be at least partly the answer to these  questions?

The short answer likely lies in the blood brain barrier (BBB).  The huge hurdle BBB presents in DIPG will be a subject of future posts, but suffice it to say that we need better studies to investigate drug resistance and drug distribution as well as  new drug delivery options.

It is a new era.   There are researchers focused on understanding this tumor.   There has been a virtual explosion of clinical trials and publications.  There is excitement.

We are, though, at the beginning.    We have just gotten some of the tools to fight, --to understand , --to research, --to make a difference.  It is unlikely that the cure is around the next bend but research is finally moving for children with DIPG.   There is reason to hope that someday there might be a cure.

Note-  DIPG research at the VU University Medical  Center is financially supported by Stichting Semmy (Weesp, The Netherlands).

References: 
A new era for diffuse intrinsic pontine glioma: hope for a cure? 
Gertjan J Kaspers and Marc Jansen 
Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands Expert Rev. Anticancer Ther. 12(9), 1109–1112 (2012) 
Full Text:  http://www.brainlife.org/reprint/2012/Kaspers_GJ120900.pdf

Stichting Semmy-
http://dipg.blogspot.com/2013/03/foundation-spotlight-stichting-semmy.html

Miette- Sweet Little Crumb

She loved princesses as well as castles, faires and all magical things .

She loved animals- giraffes, elephants and kittens.

She was sweet, courageous, thoughtful, light and bright.

Miette's gorgeous blue eyes, impish smile and golden locks hid a fatal tumor.

Her parents were determined to tell her story from the beginning to the end.  The beginning started on July 25th 2011,  when 5-year-old Miette was diagnosed with a brainstem tumor.   The next day her parents were told there "with radiation there would be a 50% chance she would be here in 1 year and a zero percent chance in two." The end came this week on Tuesday.   Australia's Sweet Little Crumb left this world.

A special thing on this journey- Chicken Mick and his band of merry helpers.   This "big hearted Aussie bloke"put together a Wiggly Whirlwind Weekend sending Miette to Melbourne to meet the Wiggles.  

The story didn't end there though.  They were met by a TV crew at the airport on the flight home and taken home in a fairy pink Hummer.   Although they had agreed to a "lick of paint on her cubby" while they were away and told Chicken Mike that Miette liked animals,  they were not expecting what waited at home.    The front yard was transformed into a little farm and her cubby into an "area fit for a princess".   Here is the story in their own words...

http://www.miettesjourney.com/2012/09/thank-you-chicken-mick-and-his-merry.html

or better yet watch this special video.....

http://au.news.yahoo.com/today-tonight/article/-/14742263/chicken-mick-and-miette

Because of Miette, the Wiggles are now ambassadors to raise awareness of through the Isabella and Marcus Paediatric Brainstem Tumour Fund.  Both Isabelle and Marcus died from DIPG.  The two families started this foundation with the mission to fund Australian research into pediatric brainstem tumors with a focus on DIPG.   Miette joined in with her support making hairclips and bands, selling them online and giving 50% of the proceeds to the charity.

A vision of the  foundation is "to established an Endoswed Chair at the Univeristy of Melbourne, with an affiliated research laboratory in the Victorian Comprehensive Cancer Centre that will perform research to understand the nature of these tumors, develop novel treatments and to participate in international clinical trials."

Miette you will be remembered.

Reference:

Miette's Journey - https://www.facebook.com/miettesjourney

Miette's Journey- http://www.miettesjourney.com/

Chicken Mick-

http://chickenmick.com/index.php?option=com_content&view=article&id=36&Itemid=37

Isabella and Marcus Paediatric Brainstem Tumour Fund- http://www.isabellaandmarcusfund.org.au/index.html