Just One More Day for Love, Hope & a Cure
A searchable blog on DIPG research, DIPG news, recent publications, DIPG Foundations, DIPG researchers, clinical trials as well as other issues relating to Diffuse Intrinsic Pontine Tumors- both Diffuse Intrinsic Pontine Gliomas (DIPGs) and Atypical Pontine Lesions (APLs).
Monday, May 25, 2009
Radiologic Study (can be in conjunction with other therapeutic studies)Proton Nuclear Magnatic Resonance Spectroscopic Imaging Compared with Fludeoxyglucose F 18 Positron Emission Tomography Scanning in Determining Biologic or Metabolic Tumor Activity in Young Persons with Brain Tumors
Eligible Age- 1 to 21
Location- Bethesda, MD (NIH)
Study Chair- Katherine Warren, MD
Open Therapeutic TrialsArsenic Trioxide and Radiation Therapy in Treating Young Patients With Newly Diagnosed Gliomas
Eligible Age- 3 to 21
Location- Johns Hopkins, MD
Study Chair- Kenneth J Cohen, MD
Interferon Alfa After Radiation Therapy in Treating Young Patients With Glioma
Eligible Age- up to 21
Study Chair- Katherine Warren, MD
Location- Bethesda, MD (NIH)
Combination Chemotherapy and Radiation Therapy With and Without Methotrexate in Treating Young Patients with Newly Diagnosed Gliomas
Eligible Age- 3 to 18
Study Chair- Christoph Kramm, MD
Location- MD Anderson (sponsor from Germany)http://clinicaltrials.gov/ct2/show/NCT00278278?term=pontine+glioma&rank=8
A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High Grade Gliomas and Diffuse Intrinsic Pontine Gliomas
Eligible Age- 3 to 30
Principal Investigator- Maryam Fouladi, MDUS
Location- Cincinnati, Ohio
Temozolomide and Radiation Therapy in Treating Young Patients with Pontine Glioma
Eligible Age- 2 to 21
Study Chair- Simon Bailey, MD
Locations- Multiple throughout the UK
Vandetanib and Radiation Therapy in Treating Young Patients with Newly Diagnosed Diffuse Brainstem Glioma
Eligible Age- 2 to 20
Study Chair- Alberto Broniscer, MD
Location- St Jude, Memphis, TN
Capceitabine and Radiation Therapy in Treating Young Patients with Newly Diagnosed, Nonmetastatic Brain Stem Glioma or High Grade Glioma
Eligible Age- 3 to 21
Study Chair- Susan Blaney, MD
Location – PBTC sites in the US
Vaccine Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma
Eligible Age- 3 to 20
Study Chair- Regina Jakacki, MD
Location- Pittsburgh, Pennsylvania
Trials on Clinicaltrials.gov but Not Yet Opened for the Newly Diagnosed Child with a DIPG (at the time of being placed on the site but could be now)
Valproic Acid and Radiation Followed by Maintenance Valproic Acid and Bevacizumab in Children with High Grade Gliomas
Eligible Age- 3 to 21
Study Chair- Susan Blaney MD
Location- Texas Children’s
As of May 25, 2009
Wednesday, May 20, 2009
Dr. Ohlfest is an Assistant Professor and the Director of the gene therapy program in Department of Neurosurgery and a faculty member of the Stem Cell Institute. Dr. Ohlfest studied molecular biology as an undergraduate at Iowa State University and received his Ph.D. in molecular genetics and cell biology at the University of Minnesota. He then did post-doctoral research with Dr. Andrew Freese at the University of Minnesota focusing on gene therapy in the central nervous system. Dr. Ohlfest's research interests are focused on using gene transfer to correct disease and manipulating endogenous progenitor cells by gene transfer. In addition, targeted therapies for the eradication of so called "brain tumor stem cells", the tumor cells capable of self-renewal and the cause of tumor relapse, is an area of ongoing investigation in his lab.
Questions & Answers:
Dr Ohlfest, it seems that you have a super hero, Batman, that just might be making a difference for children with brain tumors. How is that?
Batman was the first dog to undergo an experimental treatment for glioma, an aggressive form of brain cancer. Batman was treated with the combination of surgery, gene therapy, and anti-tumor vaccination in the summer of 2008. Remarkably, Batman is alive and tumor-free nearly one year later. This novel treatment could only be tested in a large animal because mice, the standard preclinical "model" for testing new therapy, are just too small. Specifically, the brains of mice are not amenable to surgery where the gene therapy can be deposited into the resection site to hit the tumor cells left behind. In dogs we can use the same dose of gene therapy and vaccine that would be given to people. Because of this, we not only help the dog, we also get answers about effectiveness and safety that can be extrapolated to human patients.
We feel the treatment of dogs can revolutionize the way clinical trials are done for brain tumor patients. By using the dog data to justify dose, timing, and drug choices, it may become possible to test several experimental agents in a single phase I trial, a scenario that seldom happens in modern neuro-oncology. This is important because history has shown that combination therapy is better than mono therapy, yet for brain tumor patients, most phase I clinical trial are restricted to single experimental drugs.
How does this type of treatment differ from other forms of treatment?
It does not involve chemotherapy or radiation, which those people familiar with DIPG know causes toxicity. Instead, we attempt to get the body to take care of the problem by activating a tumor-specific immune response. The vaccine and gene therapy we are using have been optimized for potency over the last 4 years. They are superior to some of the first generation vaccines and gene therapies that were developed in the 1990s and first part of this decade.
What have the results been so far with the dogs?
We have documented stable disease, and tumor regressions, with minimal side effects. Four dogs have been treated to date, although we are going to enroll dozens more.
It seems that this approach is something that you feel strongly about, why is that?
I have seen first hand what brain cancer and brain cancer therapy does to people. My grandmother died from therapy-induced toxicity after her ovarian cancer spread into her brain. She was participating in a clinical trial where chemotherapy was directly administered into the brain. At that time, I thought “we can do better” and I still believe that today. I think we have pushed radiation and chemotherapy to the upper limit. Fresh ideas are long over due. There is mounting evidence that the immune response controls cancer in many people spontaneously. We just need to learn how to direct the immune response to the right target.
Do you feel that this is something that truly can be translated to children- and specifically children with DIPGs? If so, how long would it take to get such a trial open?
Absolutely. DIPG is an ideal target for vaccine therapy in particular. In many cases, after radiation there is a large reduction in tumor burden, a perfect time to harness the immune response to target those few tumor cells that are left behind. A trial for DIPG using immunotherapy could be open in a year or less. That’s the best case. The rate limiting steps to getting this trial open are time (required to go through the process of FDA approval) and funding (to pay all costs associated with vaccine production and immune monitoring).
What sort of funding are you in need of?
Because DIPG is very rare, it can be difficult to get funding from the usual sources to focus on this particular tumor. We are in need of funding to conduct preclinical research focused on DIPG experimental therapeutics specifically. Additionally, funding is needed to support the first phase I clinical trial.
Besides raising money, is there anything that DIPG parents can do to help with your research?
Yes, spread the word. Learn more about our research by visiting www.braintumorlab.com and tell your friends.
Any dog with a brain tumor is eligible for consideration in one of our canine clinical trials. Most dog owners don’t know we are offering to pay for the entire cost of their dog’s therapy. We are treating these dogs with the intent to cure; this is not research for research’s sake.
In addition, tell your congressman and senators about the lack of funding for brain tumor research, and DIPG in particular. Less than 20% of grants submitted to the National Institutes of Health are funded. The state of Minnesota could develop a brain cancer research bill, similar to California (stem cells) or Texas (cancer research). We can do better, but it will require a change in priorities at the state and federal level.
To see a video clip featuring Batman and Dr. Ohlfest, click here:
Tuesday, May 12, 2009
Saturday, May 9, 2009
Although typical DIPGs (without focality or exophytic components) can not even be partially resected because the tumor tissue intertwines with normal tissue in an area that houses most critical functions of the body in a small space, it is possible to biopsy these lesions via an open or a stereotactic technique. Dr Michael Handler, pediatric neurosurgeon from Children’s in Denver, presented an overview of stereotactic biopsy technique and a review of the literature specific for brainstem biopsies.
Stereotactic neurosurgery is a minimally invasive procedure where tumor imaging is used in conjunction with external reference points on the head (either with a frame or frameless via fiducial markers) to develop a three dimensional image to precisely localize a location within the brain. The idea of this technique has been around for more than a century. Horsley and Clarke used a frame on experiments with monkeys in analyzing the cerebellum back in 1906. Stereotactic biopsies for humans really did not take off until the 1970’s with the advent of CT scans which allowed for detailed imaging and 3D localization. The technique rapidly adapted to MRIs when this technology became readily available.
Dr. Handler pointed out that during the 80’s there was a rapid expansion of experience. It was found that-
- The safety of this technique became well established.
- This technique was applicable to deep lesions in the brain.
- Questions about sample adequacy subsided
- It was found to be an unquestionably effective technique.
Dr. Handler presented the results of 13 different studies on stereotactic brainstem biopsies to try to give background on the ability to get diagnoses from a small sample, morbidity and mortality. Some of the most interesting articles include-
Brainstem stereotactic biopsies sampling in children.Neurosurgery 2006 Feb;104 (2 supplement): 108-114In this study 10 children underwent frameless biopsy. All samples were diagnostic and there was one case of transient diplopia.
Stereotactic biopsy of brainstem masses: decision analysis and literature review.Surg Neurol 2006 Nov; 66(5): 484-90This was a metanalysis of 378 patients. The results included-- 6.6% transient complications,. 1.5% permanent new deficit and a 0.5% mortality.
Prospective feasibility study of outpatient brain biopsies. Neurosurgery 2002 51 (2): 358-361In this series of 76 patients which were slated for outpatient brain biopsies only 3 got admitted. One was for IV antibiotics after an infection developed and the other was a failed biopsy (a hard lesion which the needle could not penetrate).
“Prospective feasibility study ofIf the reader is interested, this would be most easily reviewed from Dr. Handler’s slides referenced at the bottom (slide 10-17).
Dr Handler ended his presentation with a quote from Dr. Andrew Brodbelt commentary in the British Journal of Neurosugery last October regarding this controversy.“It surprises us treating adults with brainstem tumours that there appears to be reluctance in the paediatric world to perform biopsies….We owe it to current and future patents to biopsy brainstem tumours.”
April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG BiopsyAll presentation slides including Dr. Handler’s are available at the site http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4431s1-00-Index.html
Brainstem stereotactic biopsies sampling in children.
Neurosurgery 2006 Feb;104 (2 supplement): 108-114
Stereotactic biopsy of brainstem masses: decision analysis and literature review.
Surg Neurol 2006 Nov; 66(5): 484-90
Prospective feasibility study of outpatient brain biopsies.
Neurosurgery 2002 51 (2): 358-361
Commentary on diffuse brain stem glioma in children
Br J Neurosurg. 2008 Oct;22(5):625.
Tuesday, May 5, 2009
Dr Foreman gave the dismal background on DIPG treatments. The only treatment known to help prolong life in these children is radiation; however, attempts to intensify radiation treatments have not improved outcome. In addition, chemotherapy has been tried both before and after radiation without success. In fact, the UKCCSG stated, “This approach should be abandoned as toxic and without benefit and with toxicity.” Even high dose chemotherapy with autologous bone marrow rescue has failed.
Given the terrible track record and significant lack of specific tumor biology knowledge, why do we not biopsy these tumors?
The most influential paper that changed the standard method of diagnosing diffuse intrinsic pontine gliomas from biopsy to MRI was published by Albright in 1993 . This paper reviewed the results of a brainstem trial (CCG-9882). In this paper the authors recommended that biopsies not be done because they added nothing to the diagnostic precision of MRI. Dr Foreman noted complication rates were not included as part of the justification for this position, and there was actually no surgical mortality in this study.
In a commentary on the Albright paper, Dr Fred Epstein (a pioneer in the field of pediatric neurosurgery – especially in the brainstem) stated, “Routine biopsy should be relegated to neurosurgical history.”
This is where we are today. As opposed to adults where biopsy of diffuse brainstem masses is common as there is are a greater variety of etiologies, biopsy of pediatric DIPGs is currently only recommended for atypical cases. Yet more and more, authors are publishing such comments as, “Given the lack of efficacy of conventional drugs, a better understanding of the biology of this tumor is the key to more targeted therapy.” 
In an attempt to address whether science has progressed sufficiently to warrant a change in philosophy toward DIPG biopsy, the committee debated the following scientific question:
“Based on your discussion, has the state of the science in drug targeting research progressed to where there is a reasonable expectation of success in identifying drug candidates to move into early phase clinical trials for DIPG?”
The vote was 16 yes, 7 no and 1 abstention. (The reason given for this abstention was inadequate knowledge of this subject.)
1. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group.
Neurosurgery. 1993 Dec;33(6):1026-9; discussion 1029-30
2. Brainstem gliomas in children and adults.
Curr Opin Oncol. 2008 Nov;20(6):662-7
3. April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG Biopsy-Slides
Sunday, May 3, 2009
Biopsying children with diffuse intrinsic pontine gliomas has become increasingly controversial. Clearly there are physicians that strongly hold the opinion that there will likely be no movement to cure these usually fatal tumors until tissue is obtained. Those that take this position tend to feel that the state of the art advances in neurosurgery and genomics have made it possible for DIPGs to be treated in the same way that almost all other brain tumors (as well as virtually all other cancers in the body)- with pathologic diagnosis.
This debate has gained even more attention because of a recent French trial for newly diagnosed diffuse intrinsic pontine glioma patients in which biopsy was mandatory in order to be able to participate. Of the 24 patients, all survived and two had transient neurological problems. In addition, two patients were found to have low grade tumors and were treated differently specifically because of the biopsy results. With respect to the remaining 22 high grade tumors, there was no change in therapeutic intervention as a result of biopsy.
Although there was no specific protocol or agent placed in front of the committee, the obviously increasing interest in the change of direction with this tumor caused the DIPG biopsy issue to be placed before the committee. At this time there appears to be a minimum of two or three potential US protocols on the table that include biopsy of DIPG.
It was stated that biopsies may be routinely recommended for atypical lesions. This is a clinical decision, not an ethical question.
In addition, biopsies performed as part of a determination for therapeutic intervention were also not to be part of the conversation. By definition these would be therapeutic biopsies. However, it was noted by some that the results from selecting agents based on molecular markers has been marginal in the field thus far.
The ethical question brought before the committee was:
“Assuming a reasonable expectation of scientific success, should children with DIPG undergo a non-therapeutic brain biopsy to advance the study of possible drug targets (i.e., for research purposes only)?”
Stereotactic biopsy of diffuse pontine lesions in children.
J Neurosurg. 2007 Jul;107(1 Suppl):1-4
April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG Biopsy- Slides