Diffuse intrinsic pontine glioma

A diffuse intrinsic pontine glioma (DIPG) is a tumour located in the pons (middle) of the brain stem. The brain stem is the bottommost portion of the brain, connecting the cerebrum with the spinal cord. The majority of brain stem tumours occur in the pons (middle brain stem), are diffusely infiltrating (they grow amidst the nerves), and therefore are not able to be surgically removed. Glioma is a general name for any tumour that arises from the supportive tissue called glia, which help keep the neurons ("thinking cells") in place and functioning well. The brain stem contains all of the afferent (incoming) neurons within the spinal cord as well as important structures involved in eye movements and face and throat muscle control and sensation.^[1][2]

Prognosis

DIPG has a 0% survival rate. The median overall survival of children diagnosed with DIPG is approximately 9 months. The 1 and 2 year survival rates are approximately 30% and less than 10%, respectively. These statistics make it one of the most devastating pediatric malignancies.^[3] Although 75–85% of patients show some improvement in their symptoms after radiation therapy, DIPGs almost always begin to grow again (called recurrence, relapse, or progression). Clinical trials have reported that the median time between radiation therapy treatment and progression is 5–8.8 months.^[4] Patients whose tumours begin to grow again may be eligible for Pilot, Phase I, or Phase II clinical trials. These clinical trials use experimental drugs or other experimental therapeutic approaches to try to slow or stop the growth of the tumour. Unfortunately, clinical trials have not shown any significant benefit from these experimental therapies so far.^[4] However, researchers are always working to develop new potential therapies for DIPGs. By participating in clinical trials, patients and families can help researchers learn more about DIPG and perhaps help future patients. Unfortunately, DIPGs that progress usually grow quickly and affect important parts of the brain. Clinical trials have reported that the median time from tumour progression to death is usually very short, between 1 and 4.5 months. During this time, doctors focus on controlling symptoms and helping children to feel as comfortable as possible.^[4]

Treatment

The standard treatment for DIPG is 6 weeks of radiation which often dramatically improves symptoms. Unfortunately, problems usually recur after 6 to 9 months, and progress rapidly.^[5]

Neurosurgery

Surgery to attempt tumor removal is usually not possible or is inadvisable for DIPG. By their very nature, these tumours invade diffusely throughout the brain stem, growing between normal nerve cells. Aggressive surgery would cause severe damage to neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness.

Surgery with less than total removal can be performed for many focal brain stem gliomas. Such surgery often results in quality long-term survival, without administering chemotherapy or radiotherapy immediately after surgery, even when a child has residual tumour. Surgery is particularly useful for tumours that grow out (exophytic) from the brain stem.

Focal brain stem tumours that arise at the top back of the midbrain (tectal gliomas) should be managed conservatively, without surgical removal. Nevertheless, shunt placement or ventriculostomy for hydrocephalus (see below) is frequently necessary. These tumours have been described to be stable for many years or decades without any intervention other than shunting.

Radiotherapy

Conventional radiotherapy, limited to the involved area of tumor, is the mainstay of treatment for DIPG. A total radiation dosage ranging from 5400 to 6000 cGy, administered in daily fractions of 150 to 200 cGy over 6 weeks, is standard. Hyperfractionated (twice-daily) radiotherapy was used previously to deliver higher irradiation dosages, but such did not lead to improved survival. Radiosurgery (e.g., gamma knife, Cyberknife) has no role in the treatment of DIPG.

Chemotherapy and other drug therapies

The role of chemotherapy in DIPG remains unclear. Studies to date with chemotherapy have shown little improvement in survival, although efforts (see below) through the Children's Oncology Group (COG), Paediatric Brain Tumour Consortium (PBTC), and others are underway to explore further the use of chemotherapy and other drugs. Drugs utilized to increase the effect of radiotherapy (radiosensitizers) have thus far shown no added benefit, but promising new agents are under investigation. Immunotherapy with beta-interferon and other drugs to modify biologic response have shown disappointing results. Intensive or high-dose chemotherapy with autologous bone marrow transplant or peripheral blood stem cell rescue has not demonstrated any effectiveness in brain stem gliomas and is not recommended. Future clinical trials may incorporate medicines to interfere with cellular pathways (signal transfer inhibitors) or other approaches that alter the tumor or its environment.^[6][7][8]

DIPG Research

A major difficulty in treating brain tumors is overcoming the blood-brain barrier. This is no less true with diffuse intrinsic pontine gliomas.^[9][10]

Unlike other areas of the body where substances can pass freely from the blood into the tissue because there are some space between the cells lining the blood vessels, in the brain movement of substances is significantly limited. This barrier between the blood and the brain is formed by the lining cells of the vessels as well as projections from nearby astrocytes. These two types of cells are knitted together by proteins to form what is called ‘tight junctions’. The entire structure is called the Blood Brain Barrier (BBB). The result is that chemicals, toxins, bacterial and other substances are often kept from getting into the brain. Thus, it serves a daily protective function preventing substances from getting to the brain. However with disease such as brain tumors the BBB also can prevent diagnostic and therapeutic agents from reaching their target in the central nervous system. Researchers and clinicians have developed ways to try to overcome the blood brain barrier. Here are some examples:

• Intrathecal/Intraventricular Administration – This is chemotherapy directed injected into the cerebral spinal fluid either through a lumbar puncture or a surgically implanted catheter.
• Intracerebral Implants – Formation of a cavity surgically within a tumor allows the potential to place chemotherapy wafers- such as gliadel wafers. Several of these dime sized wafers can be placed at the time of surgery and will release the chemotherapy slowly over time (carmustine). The advantages include a much higher concentration of chemotherapy in the brain than can be obtained over intravenous administration as well as less systemic side effects. Gliadel is an FDA approved indication at initial and subsequent surgeries for malignant gliomas. This is not an option for those patients who do not have surgically resectable tumor so is not available for DIPGs.^[11]
• Osmotic Blood Brain Barrier Disruption (BBBD) – With BBBD the cells of the BBB are shrunk by a concentrated sugar solution (mannitol). This allows the barrier to open up and ten to hundredfold increase of chemotherapy to enter the brain. A catheter is placed into one of the big arteries (usually the one in the groin called the femoral artery) and a catheter threaded up to the carotid or vertebral vessels. The hypertonic mannitol is injected and afterwards a chemotherapeutic agent is injected. Patients spend a few days in the hospital for each administration. This has been attempted with DIPG tumors.^[12]
• Convection Enhanced Delivery – Convection-enhanced delivery allows for chemotherapy to get to the tumor by a surgically implanted catheter under a pressure gradient to achieve more distribution than with diffusion alone. There has been limited experimental experience with brain tumors and one article with a DIPG.^[13]
• Drug Carriers – Trojan horses, liposomes and nanoparticles – Most of this is in an investigatory level and is not clinical relevant to brain tumours treatment at this time. The hope is that a drug can be combined with another agent which will allow it to cross in a protected manner into the brain. Drugs can be linked to agents that normally cross into the brain.^[10]

With a goal of raising awareness for DIPG, Lawrenceburg, Indiana native Lauren Hill made national news headlines in the United States for her performance in high school basketball, followed by playing college basketball at Mount St. Joseph University near Cincinnati. In her last few games, before being incapacitated by the tumor, MSJ and Hiram College held a high-profile, sold-out game at Xavier University's Cintas Center; see 2014 Hiram vs. Mount St. Joseph women's basketball game. Even famed basketball star LeBron James took to Instagram to show his encouragement and support of Lauren's public efforts to raise DIPG awareness, while Pat Summit and the Indiana Pacers gave $5,000 to Lauren's charity, "The Cure Starts Now" .^[14] Doctors said she could be the "face" of DIPG, much in the same way that Lou Gehrig was the public face of Amyotrophic lateral sclerosis. In Lauren's words, she "didn't want to be another local story that disappeared and just became another statistic on a paper. ...and that [she would] do anything she could to be the voice for little kids." ^[15] On April 10, 2015, headlines again circulated upon Lauren's death, again bringing more awareness nationwide to DIPG.^[15][16][17]

See also

• Brainstem glioma
• Glioma

References

1. American Brain Tumour Foundation http://www.abta.org/siteFiles/SitePages/1DA98D1B9B8D924603E99AA4C241B3A5.pdf
2. Diffuse Intrinsic Pontine Glioma (DIPG)
3. Treatment of newly diagnosed diffuse brain stem gliomas in children – David N. Korones. http://www.expert-reviews.com/doi/abs/10.1586/14737140.7.5.663
4. Recurrence/Relapse | DIPG Registry
5. St Jude Childrens Research Hospital http://www.stjude.org/stjude/v/index.jsp?vgnextoid=b86c061585f70110VgnVCM1000001e0215acRCRD&vgnextchannel=bc4fbfe82e118010VgnVCM1000000e2015acRCRD
6. childhood brain tumor http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/81-brain-stem-gliomas-in-childhood.
7. Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, Foer DR, Goldthwaite PT, Burger PC. A clinicopathologic reappraisal of brainstem tumour classification: identification of pilocytic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 89:1569–1576, 2000.
8. Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brain stem gliomas. J Clin Oncol 24:1266–1272, 2006.
9. Just One More Day
10. Getting into the Brain: Approaches to enhance brain drug delivery CNS Drugs 2009;23(1):35–58.
11. http://www.gliadel.com/consumer/about/moa_video.aspx
12. Osmotic blood-brain barrier – disruption chemotherapy for diffuse pontine gliomas|J Neurooncol. 2006 May;77(3):279-84. Epub 2005 Nov 29
13. Real-time image-guided direct convection perfusion of intrinsic brainstem lesions.|J Neurosurg. 2007 Jul;107(1):190-7.
14. http://espn.go.com/womens-college-basketball/story/_/id/11809823/lauren-hill-mount-st-josephs-brain-tumor-fulfills-hoops-dream
15. http://www.local12.com/news/features/top-stories/stories/Lauren-Hill-1995-2015-113450.shtml
16. http://www.foxsports.com/college-basketball/story/lauren-hill-brain-cancer-women-college-basketball-dies-041015
17. http://www.usatoday.com/story/sports/ncaaw/2015/04/10/lauren-hill-obit-cancer-brain-tumor/21393079/

 18. A standardized autopsy procurement allows for the comprehensive study of DIPG biology.
 Kambhampati M, Perez JP, Yadavilli S, Saratsis AM, Hill AD, Ho CY, Panditharatna E, Markel M, Packer RJ, Nazarian J.
 Oncotarget. 2015 Jan 24. [Epub ahead of print]
 19.Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.
 Saratsis AM, Kambhampati M, Snyder K, Yadavilli S, Devaney JM, Harmon B, Hall J, Raabe EH, An P, Weingart M, Rood BR, Magge SN, MacDonald TJ, Packer RJ, Nazarian J. Acta Neuropathol. 2014 Jun;127(6):881-95. doi:       10.1007/s00401-013-1218-2. Epub 2013 Dec 3.
 20. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas.
 Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, Rodriguez FJ, Raabe E, Nazarian J, Warren K, Quezado MM.
 Am J Surg Pathol. 2013 Sep;37(9):1357–64. doi:10.1097/PAS.0b013e318294e817. PMID 24076776
 21.Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid.
 Saratsis AM, Yadavilli S, Magge S, Rood BR, Perez J, Hill DA, Hwang E, Kilburn L, Packer RJ, Nazarian J.
 Neuro Oncol. 2012 May;14(5):547-60. doi:10.1093/neuonc/nos067. Epub 2012 Apr 5. PMID 22492959*