DIPG Foundation Spotlight- Team Julian Foundation

DIPG Foundation Spotlight is a new series of posts intended to highlight the work of so many parent lead foundations that are creating awareness, supportting other families, funding research as well as other developing other endeavors to better the lives of other kids and their families.

Team Julian Foundation- In Support of a Little Super Hero
The exceptional, imaginative, dark-haired 4-year-old sounded like every parent's dream.   He was a soccer player, a lover of books and music, a social little being that could make people laugh, and a fighter of bad guys.  On November 29, 2010, this family's world was turned upside down when that Monday morning he woke up disoriented.  In a Detroit ER, Julian was diagnosed with a brain tumor that was later classified an atypical brainstem glioma.  He was eventually airlifted to St Jude and began radiation on December 23,  2010.

Unfortunately his post radiation scans in February 2011 showed spread through the brain and lower spine.   Julian endured more radiation and returned to Michigan for chemotherapy.  The tumor was relentless.  Only seven months after diagnosis the little superhero died.

His family and friends were inspired by Julian's charm and courage.    They became "fiercely determined to keep his spirit alive by helping other kids and their families get a fighting chance against this devastating disease."Team Julian Foundation came into being.

As always pictures are worth a thousand words.  Here is an eight minute video about Julian and the foundation......

In two years they have raised 200K which has gone to support DIPG research as well as other things.   There has been 130K to research at St Jude Research Hospital, Keller Lab at OHSU(primary coordinator for the DIPG Preclinical Consortium) and the DIPG Collaborative.   They have also supported Make A Wish and the distribution of the ACCO book on Understanding the DIPG Journey.

At the very end of the video, there was  a hint of what will come in 2013.   It looks like the foundation will become Julian B Bovins Courage for Cures Foundation.    Looking forward to finding out more about the developments with this organization.


Team Julian Foundation-
http://www.teamjulianfoundation.com/

Clinical Trial Update- Arsenic Trioxide (ATO) with Radiation in the Newly Diagnosed (Phase 1)

On March 3^rd, the Journal Neuro-Oncology electronically published the results of the phase 1 trial using arsenic trioxide (ATO) in combination with radiation for newly diagnosed pediatric high-grade gliomas.   This phase 1 trial, exclusively opened at Johns Hopkins (primary investigator Kenneth Cohen), was first submitted to clinicaltrials.gov in November 2004 and was completed in January 2011.    As a phase 1, the aim was to determine toxicity and dosing information--not effectiveness against the tumor.  

Rationale:   Arsenic trioxide affects cells in a different way than radiation.   In mice, ATO has shown destruction of the tumor vasculature and near-complete blockage of blood flow to the tumor.   This has resulted in central tumor death (necrosis).   The hope was that ATO would kill the poorly perfused, hypoxic, radio-resistant areas of a tumor while radiation would kill the tumor in well-oxygenated areas.

Format:  The format was to have groups of 3-6 patients receive escalating doses of arsenic trioxide until the MTD was established.  Each child received radiation once daily for 5 days a week for 6 weeks.  A child also received arsenic trioxide over 1 hour with radiation.   The first group received the ATO only once a week.  Each subsequent group had another day of the week added until the last group received ATO with every radiation treatment.  A total of 24 children entered the trial.   Those that progressed during radiation or family chose to stop treatment was removed from the study.  Twenty-one children had evaluable results. 

Results:  The trial included 12 DIPGs, 4 AAs and 5 GBMs.  Because children could receive additional therapy after 30 days from radiation, no response assessment was done.   The study does note that all children died of their tumor.   With DIPG the median time to death was 10 months (range 2-22 months).    There was no dose limiting toxicity.

Conclusion:  The article concluded that arsenic trioxide could be given with each radiation treatment.

 Interestingly, the article states that there have been a number of recent preclinical studies that have shown an effect on cancer stem cells trough an effect on Notch and Sox2.   Other research has shown that the hedgehog pathway might be antagonized and thus be helpful in other tumors as well (such as Sonic hedgehog driven medulloblastomas).  Although there is one adult glioma study using arsenic trioxide in combination with temozolmide and radiation on clinicaltrials.gov, there are no pediatric glioma studies open using arsenic trioxide.    The question now is whether there will be a phase 2 trial.

For those families that participated in this trial- thank you.   This work provides important information to move forward in trying to find a cure for DIPG.  Even if it doesn't provide the cure hope for, research tends to stimulate research.  There is much, much more research into DIPG than when when this study initially opened in late 2004.  People are searching for a cure.

References:

A phase 1 trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood

http://www.ncbi.nlm.nih.gov/pubmed/23460318

Arsenic Trioxide and Radiation Therapy in Treating Young Patients with Newly Diagnosed Gliomas

http://clinicaltrials.gov/ct2/show/NCT00095771?term=arsenic+trioxide+glioma&rank=3

The Clinical Trial Process

http://www.dukehealth.org/health_library/health_articles/the_clinical_trial_process

DIPG Around the World: SIOPE-DIPG

During the 2012 European DIPG meeting in Barcelona Spain,  a European DIPG network and registry was presented by Dannis Van Vuurden of the Netherlands.

The SIOPE-DIPG network began in 2011 Amsterdam meeting by members from the UK, France, Germany, Italy, Spain and the Netherlands.  In the 2012 presentations, membership had increased to 18 members:  Germany, United Kingdom, France, Spain, Italy, Poland, Netherlands,  Czech Republic, Portugal, Belgium, Sweden, Austria, Switzerland, Denmark,  Finland, Norway, Ireland and Iceland.

Each country or coalition has a national coordinator:
Austria-  Irene Slavc
Belgium-  Stefaan Van Gool
Czech Repulic-  David Sumerauer
France-  Pierre Leblond
GPOH- Christof Kramm
Ireland- Jane Pears
Italy- Veronica Biassoni
Netherlands- Dannis van Vuurden
NOPHO- Sanna-Maria Kivivuori
Poland- Marta Perek-Polnik
Portugal- Maria João Gil-da-Costa
Spain- Ofelia Cruz Martinez
UK- Simon Bailey
(Note- NOPHO stands for Nordic Society of Pediatric Haematology and Oncology and includes Denmark, Sweden, Finland and Norway.)

Collaboration is critical for the understanding of  DIPG.   One of the most interesting pages of the DIPG Network and Registry presentation is the estimated number of DIPGs in individual countries (see page 10 of the first reference below).  Two-thirds of the participating countries in SIOPE-DIPG are expected to have more than 10 affected children per year!

The comprehensive DIPG Action Points is another highlight.   This included the issues of corticosteroids, quality of life, palliative care, biopsy, biological studies, treatment protocols, autopsy protocols and further research as well as the registry and network.   Of particular note, each issue had a responsible person named in the spreadsheet.

For those interested in who are the movers and shakers on DIPG research in Europe the below references a must to see.

References:
SIOP Europe- DIPG Network and Registy
http://www.cristianriverafoundation.org/media/DIPGworkshopsmedia/401%20-%20NETHERLANDS%20-%20DIPG%20Network%20and%20Registry%20(Van%20Vuurden).pdf

2012 Barcelona DIPG Meeting and Powerpoint Presentation

http://www.cristianriverafoundation.org/workshops.html

Meeting Action Points Spreadsheet

http://www.cristianriverafoundation.org/media/DIPGworkshopsmedia/402%20-%20Action%20Points%20Barcelona%20Meeting%20(Cruz-Van%20Vuurden).pdf

DIPG in the next WHO classification???

In 1956-7 the World Health Organization (CNS) resolved to develop a classification of tumors that would be used around the world.   This was critical to be able to conduct clinical trials and to be able to compare results internationally.   The first brain tumor WHO classification,published in 1979, was based on pathology.  Changes were made in the subsequent three editions to reflect new knowledge from immunohistochemisty and genomics.   The last WHO CNS classification in 2007 added eight "new" entities as well as some additional variants.

Diffuse intrinsic pontine gliomas have not be recognized as a class of tumors unto itself or a variant-- well, not yet by the World Health Organization.   A review article points out that since 2007 there has been significant progress in understanding the molecular biology and genomics of GBMs.  The article also suggests that there are several GBM variants including DIPG.

Perhaps the next WHO CNS classification revision will include diffuse intrinsic pontine glioma!  

On the other hand, this would seem to be a significant deviation from the other classifications that have relied heavily on histopathology to define a tumor type.   A WHO tumor classification based primarily on anatomic location would seem to be an uphill battle.   However, clearly on clinical grounds DIPG is a fairly distinct entity primarily striking a particular age range (5-9) and failing therapies that have made some progress with adult GBMs.  There have been recent advances showing these pediatric diffuse pontine gliomas are molecularly different from adult GBMs and even pediatric supratentorial GBMs.

Pediatric tumors known by location- this is not an isolated concept.   Clinically tectal gliomas and optic gliomas are recognized by anatomical location.   Recently, thalamic gliomas have been suggested as a distinct clinical group.  We know brainstem gliomas are not all the same.

To make advances and aid in international communication, it would seem logical that DIPGs need to be recognized as an entity unto their own.

Reference:
WHO classification of the tumors of the central nervous system  http://en.wikipedia.org/wiki/WHO_classification_of_the_tumors_of_the_central_nervous_system

The 2007 WHO Classification of Tumours of the Central Nervous System
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1929165/

Review Paper:  Established and emerging variants of glioblastoma multiforme:  a review of morphological and molecular features  http://www.termedia.pl/Review-paper-Established-and-emerging-variants-of-glioblastoma-multiforme-review-of-morphological-and-molecular-features,20,19879,1,1.html

Thalamic high-grade gliomas in children: a distinct clinical subset?
http://neuro-oncology.oxfordjournals.org/content/13/6/680.long