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
Showing posts with label St Jude. Show all posts
Showing posts with label St Jude. Show all posts
Saturday, April 27, 2013
Friday, April 12, 2013
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
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
Monday, April 1, 2013
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.
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.
Friday, March 29, 2013
Results of St Jude Phase 1 Trial Published
The results of the St Jude Phase 1 trial using a combination of small molecule inhibitors, vandetanib and dasatinib, have just been published electronically (ahead of print) in the journal Clinical Cancer Research.
In a look back at DIPG history, this is a really a new kind of trial. In the past many trials have been radiation and a single agent. I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies. These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.
In addition, there seems to be rational basis to chose these agents specifically for DIPG. Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor. This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs). Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha). Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.
In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation. Eight days later oral vandetanib twice a day was added. Overall the treatment was tolerated well.
In a look back at DIPG history, this is a really a new kind of trial. In the past many trials have been radiation and a single agent. I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies. These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.
In addition, there seems to be rational basis to chose these agents specifically for DIPG. Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor. This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs). Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha). Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.
In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation. Eight days later oral vandetanib twice a day was added. Overall the treatment was tolerated well.
- The M:F ratio was 12:13.
- The age range was 2.3 years to 17.2 with a median age of 5.8 years.
- The median treatment time was 184 days.
- The most significant toxicity was diarrhea.
- Myelosuppresion (drop in blood counts) was seen in three children.
- Two of the children had tumor biospies.
- There were 12 post mortem tumor donations.
- All patients progressed on treatment.
- The one year overall survival was 52% + 10%.
- The 2 year survival was 9% + 6%.
- The two patient who were on treatment for more than 2 years had typical clinical and radiologic appearance of DIPG
Three of the young children developed symptomatic radiation necrosis in uninvolved brain areas. Although there was no institutional knowledge of other patients treated with more than standard radiation fields developing radiation necrosis in uninvolved areas, it was felt that the larger margins may have lead to symptomatic radiation necrosis. Thus the authors do not recommend to use of enlarged radiation fields.
Another interesting finding was that the researchers showed "for the first time that CSF exposure of vandetanib and dasatinib in humans is modest". They point out that CSF levels is often used as a surrogate marker for brain penetration but that this assumption is not necessarily valid particularly in places where there is a blood brain barrier disruption. They also point out that although the dasatinib CSF level was low that it did reach sustained levels "similar to those causing significant inhibition of other drug targets.
Additionally, the researchers looked at plasma angiogenic factors (seeing what factors are in the blood). Surprisingly, increased VEGF in this study was associated with longer overall survival whereas in a prior study it was associated with shorter survival. The hypothesis is that this might be because of an improved inhibition of alternative pathways because of the combination. Regardless of the reason, it seems to me that we don't understand plasma factor levels yet.
Despite the continued poor results for DIPG clinical trials, there were some interesting findings in this trial. There is hope the drug testing (such as what we should see with the pre-clinical consortium) might find new promising targets or drug therapies.
Note-
This work was supported by the U.S. National Institutes of Health Cancer Center
Support (CORE) Grant P30 CA21765, by the Cure Starts Now Foundation, by
AstraZeneca, and by the American Lebanese Syrian Associated Charities (ASLAC).
References:
Phase 1 Trial, Pharmacokinetics and Pharmacodynamics of Vandertanib and Dasatinib in Children with Newly Diagnosed Intrinsic Pontine Gliomas
Clin Cancer Res. 2013 Mar 27. [Epub ahead of print]
Clinical Trials Entry
Wednesday, March 27, 2013
St Jude Study on Kid's Bones in Antiangiogenesis Trials
1- Angiogenesis (can be thought of as new blood vessel formation) is considered to be a key process in the development and growth of glioblastomas.
2- Most DIPGs so far have been found to be glioblastomas.
Given these above two facts, researchers at St Jude Children Research Hospital in Memphis designed two phase 1 trials using antiangiogenic drugs in during radiation and after for newly diagnosed kids with DIPG tumors. The first study used vandetanib and the second used a combination of vandetanib and dasatinib. Both of these drugs are oral and affect targeted areas in the molecular pathways. Vandetanib is a potent VEGFR-2 (vascular endothelial growth factor receptor-2) inhibitor.
Pediatric patients are not just little adults. A significant difference is that kids grow and mature. This could be a problem with antiangiogenesis drugs as animal studies showed that this type of inhibition could negatively affect skeletal growth. Since little had been reported on the effects of these drugs on children's skeletal development, St Jude researchers included this as part of their study.
There were 59 patients (32 girls and 27 boys) evaluated with a total of 119 MRIs and 51 patients had plain knee x-rays. The children ranged from 2.4-17.6 years (median 6.2 years of age). The median treatment was 205 days. Of note, two patients had not progressed- one was 18 months out from diagnosis and the other 60 months.
All of the kids had MRIs of the knees at baseline and 50 had MRIs at 16-19 weeks of therapy. MRIs showed more abnormalities than plain films. MRIs showed:
Plain radiographs did not show these abnormalities.
Although this was a short followup time, this is the largest group of kids studied for skeletal changes on these antiangiogenesis agents. It seems clear that MRI is better in picking up abnormalities. The authors encourage more long term follow-up monitoring in pediatric patients taking these agents.
Note- this work was supported in part by US National Institute of Health Cancer Center Suppport (CORE) Grant P30 CA-21765, a Center of Excellence grant from the State of Tennessee, AMerican Lebanese Syrian Associated Charities (ASLAC), Noyes Brain Tumor Foundation, Musicians Against Childhood Cancer (MACC), AstraZeneca and The Cure Starts Now Foundation.
Reference:
Magnetic Resonance Imaging Is the Preferred Method to Assess Treatment-Related Skeletal Changes in Children with Brain Tumors
Pediatr Blood Cancer. 2013 Mar 22. doi: 10.1002/pbc.24536. [Epub ahead of print]
Department of Radiological Sciences, St. Jude Children's Research Hospital
Kaste SC, Kaufman RA, Gajjar A, Broniscer A.
http://www.ncbi.nlm.nih.gov/pubmed/23526749
What is VEGF? http://www.news-medical.net/health/What-is-VEGF.aspx
St Jude Vandetanib Trials-
http://clinicaltrials.gov/ct2/show/NCT00472017?term=vandetanib+St+Jude&rank=1
2- Most DIPGs so far have been found to be glioblastomas.
Given these above two facts, researchers at St Jude Children Research Hospital in Memphis designed two phase 1 trials using antiangiogenic drugs in during radiation and after for newly diagnosed kids with DIPG tumors. The first study used vandetanib and the second used a combination of vandetanib and dasatinib. Both of these drugs are oral and affect targeted areas in the molecular pathways. Vandetanib is a potent VEGFR-2 (vascular endothelial growth factor receptor-2) inhibitor.
Pediatric patients are not just little adults. A significant difference is that kids grow and mature. This could be a problem with antiangiogenesis drugs as animal studies showed that this type of inhibition could negatively affect skeletal growth. Since little had been reported on the effects of these drugs on children's skeletal development, St Jude researchers included this as part of their study.
There were 59 patients (32 girls and 27 boys) evaluated with a total of 119 MRIs and 51 patients had plain knee x-rays. The children ranged from 2.4-17.6 years (median 6.2 years of age). The median treatment was 205 days. Of note, two patients had not progressed- one was 18 months out from diagnosis and the other 60 months.
All of the kids had MRIs of the knees at baseline and 50 had MRIs at 16-19 weeks of therapy. MRIs showed more abnormalities than plain films. MRIs showed:
- 1 patient with premature physeal fusion (the growth plate closed too soon),
- 1 patient focal thickening of the growth plate,
- 2 patients with bony spicules across the growth plate,
- 8 patients with osteonecrosis (one was present at enrollment in the study).
Plain radiographs did not show these abnormalities.
Although this was a short followup time, this is the largest group of kids studied for skeletal changes on these antiangiogenesis agents. It seems clear that MRI is better in picking up abnormalities. The authors encourage more long term follow-up monitoring in pediatric patients taking these agents.
Note- this work was supported in part by US National Institute of Health Cancer Center Suppport (CORE) Grant P30 CA-21765, a Center of Excellence grant from the State of Tennessee, AMerican Lebanese Syrian Associated Charities (ASLAC), Noyes Brain Tumor Foundation, Musicians Against Childhood Cancer (MACC), AstraZeneca and The Cure Starts Now Foundation.
Reference:
Magnetic Resonance Imaging Is the Preferred Method to Assess Treatment-Related Skeletal Changes in Children with Brain Tumors
Pediatr Blood Cancer. 2013 Mar 22. doi: 10.1002/pbc.24536. [Epub ahead of print]
Department of Radiological Sciences, St. Jude Children's Research Hospital
Kaste SC, Kaufman RA, Gajjar A, Broniscer A.
http://www.ncbi.nlm.nih.gov/pubmed/23526749
What is VEGF? http://www.news-medical.net/health/What-is-VEGF.aspx
St Jude Vandetanib Trials-
http://clinicaltrials.gov/ct2/show/NCT00472017?term=vandetanib+St+Jude&rank=1
Saturday, March 9, 2013
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/
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/
Subscribe to:
Posts (Atom)