Diffuse midline glioma

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Diffuse midline glioma
Palliative Care Options for a Young Adult Patient with a Diffuse Intrinsic Pontine Glioma - Fig. 1 (cropped).png
Magnetic resonance imaging of a diffuse intrinsic pontine glioma.
Usual onset5–10 years old [1]
TreatmentRadiation
Chemotherapy
(Surgery to biopsy or remove the tumor is not safe due to its location) [1]
Prognosis Average overall survival generally ranges from 8 to 11 months [2]
Frequency~10–20% of childhood brain tumors [1]

Diffuse midline glioma, H3 K27-altered (DMG) is a fatal tumour that arises in midline structures of the brain, most commonly the brainstem, thalamus and spinal cord. When located in the pons it is also known as diffuse intrinsic pontine glioma (DIPG). [3]

Contents

DMG is believed to be caused by genetic mutations that cause epigenetic changes in cells of the developing nervous system, resulting in a failure of the cells to properly differentiate. [4] [5] Currently, the standard of care is fractionated external beam radiotherapy, as the tumour location precludes surgery, and chemotherapy has shown to be ineffective. [6] [7] However, the estimated survival post-diagnosis remains only 9–15 months. DMGs primarily affect children: the median age of diagnosis is around 6-7 years old. [8]

Current understanding has shown several genes are involved in the pathology of the glioma. The pathology is resistant to treatment, suggesting that a major driver is that cellular apoptosis mechanisms are disabled. [9]

Diagnosis

Biopsy sample from a diffuse intrinsic pontine glioma. Palliative Care Options for a Young Adult Patient with a Diffuse Intrinsic Pontine Glioma - Fig. 2 (cropped).png
Biopsy sample from a diffuse intrinsic pontine glioma.
Magnetic resonance spectroscopy of a diffuse intrinsic pontine glioma showing elevated choline and creatine peaks with a decreased NAA peak. Palliative Care Options for a Young Adult Patient with a Diffuse Intrinsic Pontine Glioma - Fig. 1D (cropped).png
Magnetic resonance spectroscopy of a diffuse intrinsic pontine glioma showing elevated choline and creatine peaks with a decreased NAA peak.

Like most brainstem tumors, diagnosing diffuse intrinsic pontine glioma usually involves non-invasive brain imaging like MRI, in addition to neurologic physical exam. Biopsies and other procedures are very uncommon. Similar to DIPG, diffuse midline gliomas (DMG) often fall into similar categories for both diagnosis and treatment as DIPG and are often categorized together. [10] More recently, biopsies are performed so that the best option for clinical trials can be chosen. [11]

In studies resulting from the DIPG/DMG Registry and in connection with the DIPG/DMG Collaborative, statistics reveal that approximately 150–300 patients are diagnosed with DIPG in the USA per year, the median age of patients with DIPG is approximately 6–7 years old, and the male/female ratio of DIPG patients is 1:1. [8]

Treatment

The standard treatment for DIPG is 6 weeks of radiation therapy, which often dramatically improves symptoms. However, symptoms usually recur after 6 to 9 months and progress rapidly. [12]

Neurosurgery

Surgery to attempt tumour removal is usually not possible or advisable for DIPG. By nature, these tumors 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.

A neurosurgically performed brainstem biopsy for immunotyping of diffuse intrinsic pontine glioma has served a limited recent role in experimental clinical studies and treatment trials. This, however, is not the current standard of care, as it presents considerable risk given the biopsy location, and thus is appropriately performed only in the context of participation in an ongoing clinical treatment trial.

Pontine biopsy is in no way a therapeutic or curative surgery, and the risks (potentially catastrophic and fatal) are only outweighed when the diagnosis is uncertain (extremely unusual) or the patient is enrolled in an approved clinical trial.

Radiotherapy

Radiotherapy for a young adult patient with a diffuse intrinsic pontine glioma. Color indicates radiation dose. Palliative Care Options for a Young Adult Patient with a Diffuse Intrinsic Pontine Glioma - Fig. 3 (cropped).png
Radiotherapy for a young adult patient with a diffuse intrinsic pontine glioma. Color indicates radiation dose.

Conventional radiotherapy, limited to the involved area of tumour, 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 radiation dosages, but did not lead to improved survival. Radiosurgery (e.g., gamma knife or cyberknife) has a role in the treatment of DIPG and may be considered in selected cases.

Chemotherapy and other drug therapies

The role of chemotherapy in DIPG remains unclear. Studies 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 that increase the effect of radiotherapy (radiosensitizers) have shown no added benefit, but promising new agents are under investigation. Immunotherapy with beta-interferon and immune checkpoint inhibitors has also had little effect in trials. Neoepitope specific peptide vaccines targeting the clonal driver mutation H3 K27M have been shown to elicit cytotoxic T-cell and T-helper cell responses in patients with diffuse midline glioma. [13] [14] Intensive or high-dose chemotherapy with autologous bone marrow transplantation or peripheral blood stem cell rescue has not demonstrated any effectiveness in brain stem gliomas. Future clinical trials may involve medicines designed to interfere with cellular pathways (signal transfer inhibitors), or other approaches that alter the tumor or its environment. [15] [16] [17]

Prognosis

Summary of a meta analysis of over 1,000 cases of DIPG and high-grade pediatric gliomas, highlighting the mutations involved as well as generic outcome information. Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma - graphical abstract.jpg
Summary of a meta analysis of over 1,000 cases of DIPG and high-grade pediatric gliomas, highlighting the mutations involved as well as generic outcome information.

DIPG is a terminal illness, since it has a 5-year survival rate of <1%. 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 DIPG one of the most devastating pediatric cancers. [18] 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 and progression is 5–8.8 months. [19] Patients whose tumors begin to grow again may be eligible for experimental treatment through clinical trials to try to slow or stop the growth of the tumor. However, clinical trials have not shown any significant benefit from experimental DIPG therapies so far. [19]

For DIPGs that progress, they usually grow quickly and affect important parts of the brain. The median time from tumor progression to death is usually very short, between 1 and 4.5 months. During this time, doctors focus on palliative care: controlling symptoms and making the patient as comfortable as possible. [19]

Research

Mutations in diffuse intrinsic pontine glioma samples from several anatomical locations. Mutations in diffuse intrinsic pontine glioma samples from several anatomical locations - Ncomms11185-f1.jpg
Mutations in diffuse intrinsic pontine glioma samples from several anatomical locations.
Schematic of a currently experimental approach to DIPG drug delivery involving nanoparticles and stem cells. Drug delivery to diffuse intrinsic pontine glioma (DIPG) - Fphar-08-00495-g004.jpg
Schematic of a currently experimental approach to DIPG drug delivery involving nanoparticles and stem cells.

As is the case with most brain tumors, a major difficulty in treating DIPG is overcoming the blood–brain barrier. [20] [21]

In the brain – unlike in other areas of the body, where substances can pass freely from the blood into the tissue – there is very little space between the cells lining the blood vessels. Thus, the movement of substances into the brain is significantly limited. This barrier is formed by the lining cells of the vessels as well as by projections from nearby astrocytes. These two types of cells are knitted together by proteins to form what are called "tight junctions". The entire structure is called the blood–brain barrier (BBB). It prevents chemicals, toxins, bacteria, and other substances from getting into the brain, and thus serves a continuous protective function. However, with diseases such as brain tumors, the BBB can also prevent diagnostic and therapeutic agents from reaching their target.

Researchers and clinicians have tried several methods to overcome the blood–brain barrier:

Pathology

The definitive genetic marker of a diffuse midline glioma is H3K27me3 loss. Diffuse midline gliomas have three known subtypes: [25]

Prominent patients

Notes Left Behind , a non-fictional book published in 2009, is about a girl named Elena Desserich. Desserich left hundreds of notes to her family before she died of DIPG at age 6. [33]

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References

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  2. ↑ "Diffuse midline glioma (DIPG) prognosis". thebraintumourcharity.org. Retrieved March 12, 2023.
  3. ↑ Central Nervous System Tumours (5th ed.). International Agency for Research on Cancer. 2022. pp. 69–73. ISBN   9789283245087.
  4. ↑ Vanan MI, Eisenstat DD (2015). "DIPG in Children - What Can We Learn from the Past?". Frontiers in Oncology. 5: 237. doi: 10.3389/fonc.2015.00237 . PMC   4617108 . PMID   26557503.
  5. ↑ Baker SJ, Ellison DW, Gutmann DH (June 2016). "Pediatric gliomas as neurodevelopmental disorders". Glia. 64 (6): 879–895. doi:10.1002/glia.22945. PMC   4833573 . PMID   26638183.
  6. ↑ Williams JR, Young CC, Vitanza NA, McGrath M, Feroze AH, Browd SR, et al. (January 2020). "Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care". Neurosurgical Focus. 48 (1): E4. doi: 10.3171/2019.9.FOCUS19745 . PMID   31896081. S2CID   209671910.
  7. ↑ Bailey CP, Figueroa M, Mohiuddin S, Zaky W, Chandra J (October 2018). "Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)". Bioengineering. 5 (4): 88. doi: 10.3390/bioengineering5040088 . PMC   6315414 . PMID   30340362.
  8. 1 2 "DIPG Statistics". DIPG.org. Retrieved 2024-06-05.
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  11. ↑ Gupta N, Goumnerova LC, Manley P, Chi SN, Neuberg D, Puligandla M, et al. (October 2018). "Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma". Neuro-Oncology. 20 (11): 1547–1555. doi:10.1093/neuonc/noy070. PMC   6176802 . PMID   29741745.
  12. ↑ "Diffuse Intrinsic Pontine Glioma (DIPG)". St Jude Children's Research Hospital.
  13. ↑ Mueller S, Taitt JM, Villanueva-Meyer JE, Bonner ER, Nejo T, Lulla RR, et al. (December 2020). "Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma". The Journal of Clinical Investigation. 130 (12): 6325–6337. doi:10.1172/JCI140378. PMC   7685729 . PMID   32817593.
  14. ↑ Grassl N, Poschke I, Lindner K, Bunse L, Mildenberger I, Boschert T, et al. (October 2023). "A H3K27M-targeted vaccine in adults with diffuse midline glioma". Nature Medicine. 29 (10): 2586–2592. doi: 10.1038/s41591-023-02555-6 . PMC   10579055 . PMID   37735561.
  15. ↑ Fisher PG, Monje M (10 May 2010). "Brain Stem Gliomas in Childhood". Germantown, Maryland: Childhood Brain Tumor Foundation.
  16. ↑ Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, et al. (October 2000). "A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities". Cancer. 89 (7): 1569–1576. doi: 10.1002/1097-0142(20001001)89:7<1569::aid-cncr22>3.0.co;2-0 . PMID   11013373. S2CID   25562391.
  17. ↑ Donaldson SS, Laningham F, Fisher PG (March 2006). "Advances toward an understanding of brainstem gliomas". Journal of Clinical Oncology. 24 (8): 1266–1272. doi:10.1200/JCO.2005.04.6599. PMID   16525181.
  18. ↑ Korones DN (May 2007). "Treatment of newly diagnosed diffuse brain stem gliomas in children: in search of the holy grail". Expert Review of Anticancer Therapy. 7 (5): 663–674. doi:10.1586/14737140.7.5.663. PMID   17492930. S2CID   39928507.
  19. 1 2 3 "Recurrence/Relapse – DIPG Registry". Archived from the original on 9 April 2015. Retrieved 20 December 2018.
  20. ↑ "Getting into the brain: approaches to enhance brain drug delivery". Just One More Day. Archived from the original on 1 July 2012.
  21. 1 2 Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF (2009). "Getting into the brain: approaches to enhance brain drug delivery". CNS Drugs. 23 (1): 35–58. doi:10.2165/0023210-200923010-00003. PMID   19062774. S2CID   26113811.
  22. ↑ "MOA Video". Archived from the original on 2010-05-05. Retrieved 2015-04-13.
  23. ↑ Hall WA, Doolittle ND, Daman M, Bruns PK, Muldoon L, Fortin D, et al. (May 2006). "Osmotic blood-brain barrier disruption chemotherapy for diffuse pontine gliomas". Journal of Neuro-Oncology. 77 (3): 279–284. doi:10.1007/s11060-005-9038-4. PMID   16314949. S2CID   10779089.
  24. ↑ Lonser RR, Warren KE, Butman JA, Quezado Z, Robison RA, Walbridge S, et al. (July 2007). "Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note". Journal of Neurosurgery. 107 (1): 190–197. doi:10.3171/JNS-07/07/0190. PMID   17639894.
  25. ↑ Tauziède-Espariat A, Siegfried A, Uro-Coste E, Nicaise Y, Castel D, Sevely A, et al. (August 2022). "Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!". Acta Neuropathologica Communications. 10 (1): 119. doi: 10.1186/s40478-022-01419-3 . PMC   9392342 . PMID   35986414.
  26. ↑ Findlay IJ, De Iuliis GN, Duchatel RJ, Jackson ER, Vitanza NA, Cain JE, et al. (January 2022). "Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies". Oncogene. 41 (4): 461–475. doi:10.1038/s41388-021-02102-y. hdl: 10852/90951 . PMC   8782719 . PMID   34759345.
  27. ↑ Hansen JR (2005). First Man: The Life of Neil A. Armstrong. New York: Simon & Schuster. pp. 161–164. ISBN   978-0-7432-5631-5. OCLC   937302502.
  28. ↑ "Home". thecurestartsnow.org.
  29. ↑ "Home". notesleftbehind.com.
  30. ↑ Gibson C (14 November 2013). "Federal pediatric medical research act named for Gabriella Miller". The Washington Post. Retrieved 3 February 2021.
  31. ↑ "Our Story". Smashing Walnuts Foundation. Retrieved 3 February 2021.
  32. ↑ "Cure Starts Now reaches $2.2M goal in honor of Lauren Hill". Local 12. January 2016. Retrieved 2021-05-03.
  33. ↑ "Notes left by cancer victim, six, for family turned into book - Telegraph". 2009-11-09. Archived from the original on 2009-11-09. Retrieved 2023-03-04.
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