10 and 15 year Survivors

Meet Connor and Tori.

Their names have been around the internet for some time.  I absolutely believe that their parents were told the awful prognosis of DIPG at diagnosis and although I have never seen the MRIs I don't doubt that the lesion in these children's brains were diffuse and intrinsic and pontine.

Connor was just 5 weeks old when he was diagnosed with a DIBSG (diffuse intrinsic branstem glioma).  The parents knew something wasn't right about a week earlier when he wasn't latching on and seemed exhausted.   A seizure sent him to Cincinnati Children's ER.   During the admission for failure to thrive a golfball size tumor was found in his brainstem.   At that young age there were no therapeutic options.  He was sent home with a feeding tube to die.  In those first  two years he had spectroscopy scans which showed high levels of choline and other cancerous indications but it didn't change.   As far as I can tell his last MRI still had residual tumor at age 2.  In September, this happy healthy boy will have his 10 year anniversary from diagnosis.    His mom has a caringbridge site to give hope to other DIPG parents.

Tori seems like a regular teenage girl.   However, not long after she was born that thought that we would ever know seemed beyond impossible.  Tori was born in June 1998 and a few weeks later was found to have some typical DIPG symptoms.   Her eyes had trouble tracking and the side of her face seemed stiff.  AN MRI showed a brainstem glioma (that is what they all were called at that time).  The doctors told her parents she would die.   With no conventional options, they searched for alternatives.  This year she wrote her own update.  This fall will be 15 years since diagnosis for her!

One can ask a million times but no one knows why these children have survived.  What we do know is that there have been other cases of spontaneous regression of diffuse pontine lesions in neonates.   It has been reported in the literature before.

A case from Germany is remarkable similar to the two above.  A 7 week old infant was found to have an MRI "strongly suggestive of diffuse pontine glioma".  By 27 months the lesion was gone.

A slightly different situation (also from Germany) is the first reported case of spontaneous remission that I am aware of.   A 2-year-old boy was found to have a large, diffuse pontine tumor extending into the midbrain.   A biopsy showed a fibrillary astrocytoma.   He received a shunt but no other conventional therapy.   By the age of 6.6 years the tumor was no longer visible on imaging.

In 2005, two US neurosurgeons reported two cases of spontaneous regression of diffuse brainstem lesions in neonates.  These two newborns were found to have limb weakness and cranial nerve abnormalies.  MRIs in the first week after birth revealed a large pontomedullary tumor.  Neither child received conventional treatment.   The authors related that the children were normal at age 4 and 10.

A followup letter to the editor to the above case report came from Texas Children's relating a similar story although the child presented at 11 weeks of age.   At the time of publication she was 12.

These authors stressed that nearly all patients with diffuse brainstem lesions do poorly-  including neonates.   In 2008 Sick Kids published a case report on  two infants with "large, expansive, non-enhancing, intrinsic pontine masses diagnosed as DIPGs.   They were treated only with supportive care and died by 2 weeks of age.   One of the children underwent autopsy and was found to have a brainstem PNET.

We have no idea how often this happens.  This is why the DIPG Registry  is critical in understanding this disease.  Both families and physicians can enroll patients including children who have died.

The bottom line is:  1) we really don't understand DIPGs, and 2) there are children who have been diagnosed with DIPGs-based on the incomplete knowledge that we currently have- who truly have had spontaneous regression of their tumors and 3) most of the children with report spontaneous regression have been very young.

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