Section Editor
®
WriteClick Editor’s Choice
Robert C. Griggs, MD
Editors’ Note: Commenting on “Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes,” Chamberlain argues that, because of the retrospective nature of the study and the heterogeneity in treatment, the article mainly serves to generate a hypothesis. Sanson responds. Lee and Berkowitz discuss the role and utility of neurology missions. —Chafic Karam, MD, and Robert C. Griggs, MD
COMBINED ANALYSIS OF TERT, EGFR, AND IDH STATUS DEFINES DISTINCT PROGNOSTIC GLIOBLASTOMA CLASSES
Marc C. Chamberlain, Seattle: Labussière et al.1 analyzed 395 glioblastoma (GBM) patients for mutations in the promoter of the telomerase reverse transcriptase (TERTp) gene and determined survival based on the presence or absence of TERTp mutation. In addition, the authors correlated survival with amplification of the epidermal growth factor receptor (EGFR) and isocitrate dehydrogenase 1 (IDH1) mutation.1 This was a retrospective study with marked heterogeneity in treatment, age, and Karnofsky Performance Status scale score, which are all variables that influence survival. As a result, this study only serves to generate a hypothesis. The authors did not provide the numbers within the defined subset genotype categories, yet they were probably small, given the comparatively low incidence of these gene alterations. For example, IDH1 mutation is seen in less than 8% of all primary GBM cases.2–4 Determining a new biomarker of clinical significance in GBM as the authors reported requires either a prospective or retrospective-prospective study. When defining biomarkers, it is also common to utilize both a training and validation set. While this is a thoughtprovoking study, the authors’ proposal of a new molecular classification of GBM based on TERTp mutation, EGFR amplification, and IDH1 mutation is premature.1,4 Author Response: Marc Sanson, Paris: The authors thank Dr. Chamberlain for his comments. To limit potential bias due to the retrospective design, we performed a multivariate analysis including age, treatments,
Karnofsky Performance Scale score, isocitrate dehydrogenase status, extent of surgery, and methylguanine methyltransferase status. We found that TERTp mutation was an independent factor of poor outcome in GBMs.1 Two other studies have also shown the poor prognostic impact of TERTp mutation in GBM.5,6 We analyzed 214 additional GBMs. Although this second series is currently underpowered and has not yet confirmed the complete, original findings, it shows again that IDHmut TERTpmut GBMs had a poorer outcome than IDHmut TERTpwt (mean survival 5 20 months vs 36 months). This finding also suggests that EGFRamp GBMs may do better than EGFRwt in the TERTpmut population, but may fare worse in the TERTpwt population. We agree with Dr. Chamberlain that an independent, confirmatory analysis is warranted before using these markers in clinical practice. © 2015 American Academy of Neurology 1.
2.
3.
4.
5.
6.
Labussière M, Boisselier B, Mokhtari K, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 2014;83: 1200–1206. Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell 2013;155: 462–477. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 2013;110:6021–6026. Labussière M, Di Stefano AL, Gleize V, et al. TERT promoter mutations in gliomas, genetic associations and clinicopathological correlations. Br J Cancer 2014;111:2024–2032. Simon M, Hosen I, Gousias K, et al. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro Oncol 2015;17:45–52. Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol 2013;126:931–937.
NEUROLOGY MISSION(S) IMPOSSIBLE
Liesly Lee, Toronto: Dr. Berkowitz1 described the role of neurology missions, which can be futile due to inappropriate recommendations for unavailable investigations and management options in these settings. However, it is just as important to recognize Neurology 84
May 12, 2015
2007
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
that these endeavors have taken a culturally sensitive approach and adapted the neurologic expertise and protocols to provide sustainable contributions in these resource-limited settings. In the daily work at mission hospitals—where neurologists can volunteer on a short-term basis—there is no debate concerning deep brain stimulation for a parkinsonian patient pending response to dopaminergic agents with evidence-based medicine. There is discussion about whether a tremor is extrapyramidal or essential, which is frequently misdiagnosed and mismanaged. Both conditions can be treated with medications that are generally available but it is the correct diagnosis and management plan given to the local physicians that is beneficial, long after the consultant neurologist is gone. The inability to control refractory “seizures” with escalating toxic dosages of phenytoin by local physicians is quickly recognized by the neurologist as a pseudoseizure. Another example requiring clinical acumen from a neurologist is that a particular limb paralysis is due to a myelopathy from upper motor neuron findings vs peripheral neuropathy. These diagnostic skills can be taught to local health workers and can be done without sophisticated laboratory tests, MRIs, or newer anticonvulsants. Neurologic conditions in the developing world are common; 20% of a typical outpatient practice2 and likely higher numbers in inpatient settings comprise neurologic disorders.3 There is a striking lack of neurologic expertise in much of the developing world. Leaving this work to the generalists to manage is not consistent with the mandate of global neurology. We can make a difference and, as neurologists, we should tackle the burden of neurologic disease in every setting. Author Response: Aaron L. Berkowitz, Boston: Dr. Lee highlighted the importance of neurologic education in global health, a core goal of the emerging
field of global neurology. Dr. Lee and others should be commended for having “taken a culturally sensitive approach and adapted the neurologic expertise and protocols” to provide “sustainable contributions.” Unfortunately, this is not always the case. Short-term visits by neurologists have been recently described as “extraordinarily disruptive to the host program,” when “visitors do not recognize the local needs, are unfamiliar with cultural differences, and are illsuited to providing any meaningful care.”4 I echo these authors’ sentiment that “The only way to ensure sustainable growth of neurologic care in developing nations is to promote capacity building through stable, long-term partnerships offering regularly scheduled teaching visits, reciprocity of training, and appropriate educational donations in a coordinated fashion.”4 Through long-term collaborations rather than short-term volunteer missions, neurologists can help to develop and support neurology in resource-limited settings by combining their neurologic expertise with local expertise.5 Then, the impact of global neurology efforts will truly be sustainable “long after the consultant neurologist is gone.” © 2015 American Academy of Neurology 1. 2.
3.
4.
5.
Berkowitz AL. Neurology mission(s) impossible. Neurology 2014;83:1450–1452. Tegueu CK, Nguefack S, Doumbe J, Fogang YF, Mbonda PC, Mbonda E. The spectrum of neurological disorders presenting at a neurology clinic in Yaoundé, Cameroon. Pan Afr Med J 2013;14:148. Bower JH, Asmera J, Zebenigus M, Sandroni P, Bower SM, Zenebe G. The burden of inpatient neurologic diseases in two Ethiopian hospitals. Neurology 2007;68:338–342. Tafessa A, Johnston JC. From the front lines of Ethiopia: a plea for the global health section to reconsider priorities. Neurol Today 2014;14(16):4. August 21. Birbeck GL, Hanna MG, Griggs RC. Global opportunities and challenges for clinical neuroscience. JAMA 2014;311: 1609–1610.
WriteClick® rapid online correspondence Have a comment on a recent Neurology® article you would like to share? Now it is easier and more convenient. Neurology.org has launched WriteClick on the home page and sidebars of each article to encourage remarks and debate among users. WriteClick is restricted to comments about studies published in Neurology within the last eight weeks. Learn more at Neurology.org/letters
Author disclosures are available upon request ([email protected]). 2008
Neurology 84
May 12, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Neurology mission(s) impossible Liesly Lee and Aaron L. Berkowitz Neurology 2015;84;2007-2008 DOI 10.1212/01.wnl.0000465785.11047.77 This information is current as of May 11, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/19/2007.2.full.html
References
This article cites 5 articles, 2 of which you can access for free at: http://www.neurology.org/content/84/19/2007.2.full.html##ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
®
WriteClick Editor’s Choice
Robert C. Griggs, MD
Editors’ Note: Commenting on “Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes,” Chamberlain argues that, because of the retrospective nature of the study and the heterogeneity in treatment, the article mainly serves to generate a hypothesis. Sanson responds. Lee and Berkowitz discuss the role and utility of neurology missions. —Chafic Karam, MD, and Robert C. Griggs, MD
COMBINED ANALYSIS OF TERT, EGFR, AND IDH STATUS DEFINES DISTINCT PROGNOSTIC GLIOBLASTOMA CLASSES
Marc C. Chamberlain, Seattle: Labussière et al.1 analyzed 395 glioblastoma (GBM) patients for mutations in the promoter of the telomerase reverse transcriptase (TERTp) gene and determined survival based on the presence or absence of TERTp mutation. In addition, the authors correlated survival with amplification of the epidermal growth factor receptor (EGFR) and isocitrate dehydrogenase 1 (IDH1) mutation.1 This was a retrospective study with marked heterogeneity in treatment, age, and Karnofsky Performance Status scale score, which are all variables that influence survival. As a result, this study only serves to generate a hypothesis. The authors did not provide the numbers within the defined subset genotype categories, yet they were probably small, given the comparatively low incidence of these gene alterations. For example, IDH1 mutation is seen in less than 8% of all primary GBM cases.2–4 Determining a new biomarker of clinical significance in GBM as the authors reported requires either a prospective or retrospective-prospective study. When defining biomarkers, it is also common to utilize both a training and validation set. While this is a thoughtprovoking study, the authors’ proposal of a new molecular classification of GBM based on TERTp mutation, EGFR amplification, and IDH1 mutation is premature.1,4 Author Response: Marc Sanson, Paris: The authors thank Dr. Chamberlain for his comments. To limit potential bias due to the retrospective design, we performed a multivariate analysis including age, treatments,
Karnofsky Performance Scale score, isocitrate dehydrogenase status, extent of surgery, and methylguanine methyltransferase status. We found that TERTp mutation was an independent factor of poor outcome in GBMs.1 Two other studies have also shown the poor prognostic impact of TERTp mutation in GBM.5,6 We analyzed 214 additional GBMs. Although this second series is currently underpowered and has not yet confirmed the complete, original findings, it shows again that IDHmut TERTpmut GBMs had a poorer outcome than IDHmut TERTpwt (mean survival 5 20 months vs 36 months). This finding also suggests that EGFRamp GBMs may do better than EGFRwt in the TERTpmut population, but may fare worse in the TERTpwt population. We agree with Dr. Chamberlain that an independent, confirmatory analysis is warranted before using these markers in clinical practice. © 2015 American Academy of Neurology 1.
2.
3.
4.
5.
6.
Labussière M, Boisselier B, Mokhtari K, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 2014;83: 1200–1206. Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell 2013;155: 462–477. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 2013;110:6021–6026. Labussière M, Di Stefano AL, Gleize V, et al. TERT promoter mutations in gliomas, genetic associations and clinicopathological correlations. Br J Cancer 2014;111:2024–2032. Simon M, Hosen I, Gousias K, et al. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro Oncol 2015;17:45–52. Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol 2013;126:931–937.
NEUROLOGY MISSION(S) IMPOSSIBLE
Liesly Lee, Toronto: Dr. Berkowitz1 described the role of neurology missions, which can be futile due to inappropriate recommendations for unavailable investigations and management options in these settings. However, it is just as important to recognize Neurology 84
May 12, 2015
2007
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
that these endeavors have taken a culturally sensitive approach and adapted the neurologic expertise and protocols to provide sustainable contributions in these resource-limited settings. In the daily work at mission hospitals—where neurologists can volunteer on a short-term basis—there is no debate concerning deep brain stimulation for a parkinsonian patient pending response to dopaminergic agents with evidence-based medicine. There is discussion about whether a tremor is extrapyramidal or essential, which is frequently misdiagnosed and mismanaged. Both conditions can be treated with medications that are generally available but it is the correct diagnosis and management plan given to the local physicians that is beneficial, long after the consultant neurologist is gone. The inability to control refractory “seizures” with escalating toxic dosages of phenytoin by local physicians is quickly recognized by the neurologist as a pseudoseizure. Another example requiring clinical acumen from a neurologist is that a particular limb paralysis is due to a myelopathy from upper motor neuron findings vs peripheral neuropathy. These diagnostic skills can be taught to local health workers and can be done without sophisticated laboratory tests, MRIs, or newer anticonvulsants. Neurologic conditions in the developing world are common; 20% of a typical outpatient practice2 and likely higher numbers in inpatient settings comprise neurologic disorders.3 There is a striking lack of neurologic expertise in much of the developing world. Leaving this work to the generalists to manage is not consistent with the mandate of global neurology. We can make a difference and, as neurologists, we should tackle the burden of neurologic disease in every setting. Author Response: Aaron L. Berkowitz, Boston: Dr. Lee highlighted the importance of neurologic education in global health, a core goal of the emerging
field of global neurology. Dr. Lee and others should be commended for having “taken a culturally sensitive approach and adapted the neurologic expertise and protocols” to provide “sustainable contributions.” Unfortunately, this is not always the case. Short-term visits by neurologists have been recently described as “extraordinarily disruptive to the host program,” when “visitors do not recognize the local needs, are unfamiliar with cultural differences, and are illsuited to providing any meaningful care.”4 I echo these authors’ sentiment that “The only way to ensure sustainable growth of neurologic care in developing nations is to promote capacity building through stable, long-term partnerships offering regularly scheduled teaching visits, reciprocity of training, and appropriate educational donations in a coordinated fashion.”4 Through long-term collaborations rather than short-term volunteer missions, neurologists can help to develop and support neurology in resource-limited settings by combining their neurologic expertise with local expertise.5 Then, the impact of global neurology efforts will truly be sustainable “long after the consultant neurologist is gone.” © 2015 American Academy of Neurology 1. 2.
3.
4.
5.
Berkowitz AL. Neurology mission(s) impossible. Neurology 2014;83:1450–1452. Tegueu CK, Nguefack S, Doumbe J, Fogang YF, Mbonda PC, Mbonda E. The spectrum of neurological disorders presenting at a neurology clinic in Yaoundé, Cameroon. Pan Afr Med J 2013;14:148. Bower JH, Asmera J, Zebenigus M, Sandroni P, Bower SM, Zenebe G. The burden of inpatient neurologic diseases in two Ethiopian hospitals. Neurology 2007;68:338–342. Tafessa A, Johnston JC. From the front lines of Ethiopia: a plea for the global health section to reconsider priorities. Neurol Today 2014;14(16):4. August 21. Birbeck GL, Hanna MG, Griggs RC. Global opportunities and challenges for clinical neuroscience. JAMA 2014;311: 1609–1610.
WriteClick® rapid online correspondence Have a comment on a recent Neurology® article you would like to share? Now it is easier and more convenient. Neurology.org has launched WriteClick on the home page and sidebars of each article to encourage remarks and debate among users. WriteClick is restricted to comments about studies published in Neurology within the last eight weeks. Learn more at Neurology.org/letters
Author disclosures are available upon request ([email protected]). 2008
Neurology 84
May 12, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Neurology mission(s) impossible Liesly Lee and Aaron L. Berkowitz Neurology 2015;84;2007-2008 DOI 10.1212/01.wnl.0000465785.11047.77 This information is current as of May 11, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/19/2007.2.full.html
References
This article cites 5 articles, 2 of which you can access for free at: http://www.neurology.org/content/84/19/2007.2.full.html##ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
