Brainstem glioma

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Brainstem glioma
Classification and external resources
eMedicine neuro/40

A brainstem glioma is a cancerous glioma tumor in the brainstem.

Around 75% are diagnosed in children and young adults under the age of twenty, but have been known to affect older adults as well.[1] Brainstem gliomas start in the brain or spinal cord tissue and typically spread throughout the nervous system.[2] Brainstem gliomas are often primary brain tumors, and rarely metastasize, or spread, to affect another part of the body.[citation needed]

Cause[edit]

The cause is still unknown. Researchers have not found any direct genetic link. Children irradiated for tinea capitis have been found to have an increased risk for other central nervous system tumors, such as meningiomas, gliomas, and nerve sheath tumors, but not necessarily tumors of the brain stem.[citation needed]

Signs and symptoms[edit]

Common symptoms include, but are not necessarily limited to:

  • Lack of facial control, (droopy eyelids)
  • Double vision
  • Headache or headache that gets better after vomiting
  • Nausea and vomiting
  • Weakness and fatigue
  • Seizures
  • Balance problems

Symptoms can develop slowly and subtly and may go unnoticed for months. In other cases, the symptoms may arise abruptly. A sudden onset of symptoms tends to occur with more rapidly growing, high-grade tumors.[citation needed]

Diagnosis[edit]

Neuroimaging, such as MRI, is the main diagnostic tool for brain stem gliomas. In very rare cases, surgery and biopsy are performed.

Treatment[edit]

Unlike most brain tumors, brainstem glioma is not often treated with neurosurgery due to complications in vital parts of the brain. More often, it is treated with chemotherapy and/or radiation therapy (though past use of radiation therapy has yielded mixed results.)[3]

There are several new clinical trials in process. One such trial is dendritic cell immunotherapy which uses the patient’s tumor cells and white blood cells to produce a chemotherapy that directly attacks the tumor.[citation needed]

However, these treatments do produce side effects; most often including nausea, the breakdown of the immune system, and fatigue. Hair loss can occur from both chemotherapy and radiation, but usually grows back after chemotherapy has ceased. Steroids such as Decadron may be required to treat swelling in the brain. Decadron can lead to weight gain and infection. Patients may also experience seizures, which need to be treated to avoid complications. For some patients there is a chance of a neurological break down, this can include, but is not limited to, confusion and memory loss.

The use of topotecan has been investigated.[4]

Prognosis[edit]

Brainstem glioma is an aggressive and dangerous cancer. Without treatment, the life expectancy is typically a few months from the time of diagnosis. With appropriate treatment, 37% survive more than one year, 20% survive 2 years. and 13% survive 3 years.[5]

Diffuse Intrinsic Pontine Gliomas (DIPG/D.I.P.G)[edit]

A Diffuse Intrinsic Pontine Glioma (DIPG) is a tumour located in the pons (middle) of the brain stem. The brain stem is the bottom most 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 neurons within the spinal cord as well as important structures involved in eye movements and face and throat muscle control and sensation.[6][7]

Prognosis[edit]

DIPG has a 0 percent 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 paediatric malignancies.[8] 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.[9] 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.[9] 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.[9]

Treatment[edit]

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.[10] Neurosurgery: Surgery to attempt tumor removal is usually not possible or advisable 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.[11][12][13]

Research[edit]

Without research into brainstem tumours no cure can be found. Currently funding is the major issue that is limiting brain and brainstem research. [14]

Current Research[edit]

Tumour Tissue Analysis[15][edit]

  • Children's National Medical Center, Washington DC: Comprehensive Protein Analysis (Proteomic Profiling) of Pediatric Brainstem Gliomas using Paraffin Embedded Tissues
  • Memorial Sloan Kettering Cancer Center: Our hypothesis is that unravelling the genomic alterations of diffuse infiltrating pontine gliomas or DIPGs will lead to improved understanding of the biology of such tumours and improved therapeutic options.[16]
  • National Institutes of Health: DNA Analysis of Tumor Tissue Samples using Paraffin-Embedded Blocks from Patients with Diffuse Pontine Glioma
  • St. Jude Children's Research Hospital:Our goal is to perform an extensive genetic analysis of tumor samples obtained from patients with DIPG.[17]
  • St. Jude Children's Research Hospital:Gene sequencing project discovers mutations tied to deadly brain tumors in young children[18]
  • UCLA's Jonsson Comprehensive Cancer Center:New system uses nanodiamonds to deliver chemotherapy drugs directly to brain tumors[19]
  • UT Southwestern Medical Center:Researchers identify a switch that controls growth of most aggressive brain tumor cells[20]
  • The Institute of Cancer Research, London:Genetic flaw may hold key to deadly childhood brain tumour[21]
  • Patrick Couvreur, Professor and Director of the Physical Chemistry, Pharmacotechnology and Biopharmacy Unit at Paris-Sud University in France:Fighting cancer with nanotechnology[22]
  • The Hospital for Sick Children, Toronto, Canada: Genetics of Paediatric Brain Stem Gliomas
  • University of California, San Francisco: Central Nervous System Development and Brainstem Glioma Tumorigenesis

Imaging Research[15][edit]

  • Children's Hospital Los Angeles: Pilot Study|Predicting response to radiation therapy by evaluating choline levels with MRS before and after radiotherapy
  • Children’s of Los Angeles: Imaging Study|Impact of steroids on metabolism of tumours (animal research)
  • DIPG Registry:[23]
Hurdles for DIPG Research[edit]

A major difficulty in treating brain tumors is overcoming the blood-brain barrier. This is no less true with diffuse intrinsic pontine gliomas.[24][25]

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 to get 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.[26]
  • 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.[27]
  • 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.[28]
  • 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.[25]

Footnotes[edit]

  1. ^ Landolfi, Joseph (30 June 2009). "Brainstem Gliomas". eMedicine. Retrieved 15 August 2010. 
  2. ^ Salmaggi A, Fariselli L, Milanesi I, et al. (February 2008). "Natural history and management of brainstem gliomas in adults. A retrospective Italian study". J. Neurol. 255 (2): 171–7. doi:10.1007/s00415-008-0589-0. PMID 18293027. 
  3. ^ Broniscer A, Laningham FH, Kocak M, et al. (March 2006). "Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma". Cancer 106 (6): 1364–71. doi:10.1002/cncr.21749. PMID 16463390. 
  4. ^ Sanghavi SN, Needle MN, Krailo MD, Geyer JR, Ater J, Mehta MP (January 2003). "A phase I study of topotecan as a radiosensitizer for brainstem glioma of childhood: first report of the Children's Cancer Group-0952". Neuro-oncology 5 (1): 8–13. doi:10.1215/15228517-5-1-8. PMC 1920667. PMID 12626128. [dead link]
  5. ^ DIPG (Diffuse Intrinsic Pontine Glioma) Facts
  6. ^ American Brain Tumour Foundation http://www.abta.org/siteFiles/SitePages/1DA98D1B9B8D924603E99AA4C241B3A5.pdf
  7. ^ Diffuse Intrinsic Pontine Glioma (DIPG)
  8. ^ 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
  9. ^ a b c Recurrence/Relapse | DIPG Registry
  10. ^ St Jude Childrens Research Hospital http://www.stjude.org/stjude/v/index.jsp?vgnextoid=b86c061585f70110VgnVCM1000001e0215acRCRD&vgnextchannel=bc4fbfe82e118010VgnVCM1000000e2015acRCRD
  11. ^ childhood brain tumor http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/81-brain-stem-gliomas-in-childhood.
  12. ^ 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.
  13. ^ Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brain stem gliomas. J Clin Oncol 24:1266-1272, 2006.
  14. ^ miettesjourney.com - miettesjourney Resources and Information. This website is for sale!
  15. ^ a b Just One More Day
  16. ^ Milestone Clinical Trial for DIPG Approved | Weill Cornell Brain and Spine Center
  17. ^ http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=504457&version=patient&protocolsearchid=3083672
  18. ^ Gene sequencing project discovers mutations tied to deadly brain tumors in young children
  19. ^ New system uses nanodiamonds to deliver chemotherapy drugs directly to brain tumors
  20. ^ Researchers identify a switch that controls growth of most aggressive brain tumor cells
  21. ^ Genetic flaw may hold key to deadly childhood brain tumour
  22. ^ EPO - Fighting cancer with nanotechnology
  23. ^ Registry Research | DIPG Registry
  24. ^ Just One More Day
  25. ^ a b Getting into the Brain: Approaches to enhance brain drug delivery CNS Drugs 2009;23(1):35-58.
  26. ^ http://www.gliadel.com/consumer/about/moa_video.aspx
  27. ^ Osmotic blood-brain barrier - disruption chemotherapy for diffuse pontine gliomas|J Neurooncol. 2006 May;77(3):279-84. Epub 2005 Nov 29
  28. ^ Real-time image-guided direct convection perfusion of intrinsic brainstem lesions.|J Neurosurg. 2007 Jul;107(1):190-7.

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