J Neurooncol (2015) 123:317–318 DOI 10.1007/s11060-015-1790-5
LETTER TO THE EDITOR
Influence of 1p19q status and Ki67 index to predict extent of resection in WHO grade II gliomas: a virtual patient model Dominik Cordier1 • Sabine Scha¨delin2 • Hugues Duffau3
Received: 22 December 2014 / Accepted: 20 April 2015 / Published online: 28 April 2015 Ó Springer Science+Business Media New York 2015
To the Editor, In WHO grade II gliomas (GIIG), a higher extent of resection (EOR) has been shown to be correlated with an improved overall survival [1]. In a recent study with 200 consecutive GIIG patients, we have demonstrated that the achievable EOR in GIIG was significantly influenced by the 1p19q status and the Ki67 index [2]. Indeed, missing co-deletion 1p19q and higher Ki67 values were found to be significantly correlated to higher EORs. Therefore, these observations showed that a higher EOR was not attributable to favorable molecular markers such as 1p19q co-deletion or low Ki67 index, and supported maximal surgical resection as an important therapeutic factor per se to optimize prognosis, independently of the genetic pattern [2]. Here, our aim is to build a virtual patient model to investigate whether these statistical numbers can be translated into prognostically relevant factors with regard to EOR. In order to quantify the ability to predict EOR as percentage of the preoperative tumor volume based upon the 1p19q status and the Ki67 value, we performed further analysis of our cohort composed of 200 GIIGs (patient characteristics in [2]). Data were processed using a Betaregression model with logit link function, a methodology & Hugues Duffau [email protected] 1
University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland
2
University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland
3
Department of Neurosurgery, Hoˆpital Gui de Chauliac, CHU Montpellier, Montpellier University Medical Center, 80 Av Augustin Fliche, 34295 Montpellier, France
extensively described in our previous article [2]. By evaluating this Beta-regression function, the expected EORs were estimated in different constellations of the 1p19q status and the Ki67 value, representing the ‘‘average patient’’ exhibiting this constellation. Depending on these two variables, the presented virtual GIIG patient model shows expected EORs in a range from 0.86 to 0.96 (Table 1). These values are comparable to the reported range of EORs in awake GIIG resection in the literature [1]. It is important to emphasize that the database for this virtual GIIG patient model was obtained on the basis of maximal tumor resections achieved according to individual functional boundaries, which was made possible by the use of intraoperative electrostimulation mapping. This means that the resections have been pursued until eloquent structures have been encountered, with no margin around critical cortical and subcortical regions with the goal to optimize the EOR. This operative technique has been shown to be associated with a significant increase of the EOR with fewer late neurological deficits, even in eloquent areas, in a meta-analysis with 8091 patients [3]. According to our model, a missing 1p19q deletion is correlated with an improvement of the EOR of up to 5 % in comparison with the EOR in case of no deletion 1p19q. In the same vein, a higher proliferative activity as indicated by a high Ki67 index is correlated with an improvement of the EOR of up to 6 % in comparison with the EOR in case of a low Ki67 index. Thus, by comparing a patient with a paradoxically ‘‘unfavorable’’ profile from a surgical point of view—while favorable from a molecular point of view, i.e. 1p19q co-deletion and low Ki67 index (virtual patient V2, Table 1)—and a patient with a ‘‘favorable’’ profile, i.e. missing 1p19q deletion and high Ki67 index (virtual patient V7, Table 1), there may be a difference of the expected EOR of up to 10 %—even though the calculated
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318
J Neurooncol (2015) 123:317–318
Table 1 1p19q status, Ki67 index and EOR Virtual patient
1p19q status
Ki67 index
EOR predicted
V1
0
Min
0.91
V2
1
Min
0.86
V3
2
Min
0.89
V4
0
Mean
0.92
V5
1
Mean
0.88
V6
2
Mean
0.91
V7
0
Max
0.96
V8
1
Max
0.93
V9
2
Max
0.95
Virtual constellations of 1p19q status and Ki67 index with resp. EOR predictions 1p19q status ‘‘0’’: no deletion 1p19q; ‘‘1’’: deletion 1p or deletion 19q; ‘‘2’’: codeletion 1p19q
difference in the prediction of EOR may finally result in a subtotal resection versus total resection—with distinct impact on overall survival [1]. In practice, in a subset of patients with known 1p19q status and Ki67 value from previous biopsy or surgery, our model may be helpful to elaborate further therapeutic planning thanks to an improved reliability in the preoperative estimation of EOR, not only based on functional considerations as tumor location but also on the basis of molecular pattern. Further studies are needed to validate this virtual patient model. Acknowledgments This work was supported by the Research Fund of the University of Basel and the Voluntary Academic Society of Basel. Conflict of interest of interest.
The authors declare that they have no conflict
Ki67 Index ‘‘Min’’: 1.0 %; ‘‘Mean’’: 5.2 %; ‘‘Max’’: 20.0 %
References values do not strictly follow the logical pattern ‘‘worst constellation—lowest EOR’’. We can hypothesize that EOR is greater compared to GIIG with favorable molecular markers, because a more diffuse and infiltrative behavior of tumors with 1p 19q co-deletion. Indeed, studies comparing MRI patterns of intact 1p 19q and co-deleted 1p 19q gliomas reported that the former had a sharp and smooth border whereas the second ones had an indistinct border [4]. Logically, sharp margins were more amenable to gross total resection [2]. Therefore, an adverse molecular profile should not discourage surgeons attempting radical resections. These results issued from our original virtual model provide evidence that 1p19q status and Ki67 index are among the factors influencing the EOR in LGG and highlight the actual significance of 1p19q status and Ki67 index, because, at the individual level, up to 10 % of
123
1. Capelle L, Fontaine D, Mandonnet E, Taillandier L, Golmard JL, Bauchet L, Pallud J, Peruzzi P, Baron MH, Kujas M, Guyotat J, Guillevin R, Frenay M, Taillibert S, Colin P, Rigau V, Vandenbos F, Pinelli C, Duffau H (2013) Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article. J Neurosurg 118:1157–1168 2. Cordier D, Goze C, Schadelin S, Rigau V, Mariani L, Duffau H (2015) A better surgical resectability of WHO grade II gliomas is independent of favorable molecular markers. J Neurooncol 121:185–193 3. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS (2012) Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol 30:2559–2565 4. Megyesi JF, Kachur E, Lee DH, Zlatescu MC, Betensky RA, Forsyth PA, Okada Y, Sasaki H, Mizoguchi M, Louis DN, Cairncross JG (2004) Imaging correlates of molecular signatures in oligodendrogliomas. Clin Cancer Res 10:4303–4306
LETTER TO THE EDITOR
Influence of 1p19q status and Ki67 index to predict extent of resection in WHO grade II gliomas: a virtual patient model Dominik Cordier1 • Sabine Scha¨delin2 • Hugues Duffau3
Received: 22 December 2014 / Accepted: 20 April 2015 / Published online: 28 April 2015 Ó Springer Science+Business Media New York 2015
To the Editor, In WHO grade II gliomas (GIIG), a higher extent of resection (EOR) has been shown to be correlated with an improved overall survival [1]. In a recent study with 200 consecutive GIIG patients, we have demonstrated that the achievable EOR in GIIG was significantly influenced by the 1p19q status and the Ki67 index [2]. Indeed, missing co-deletion 1p19q and higher Ki67 values were found to be significantly correlated to higher EORs. Therefore, these observations showed that a higher EOR was not attributable to favorable molecular markers such as 1p19q co-deletion or low Ki67 index, and supported maximal surgical resection as an important therapeutic factor per se to optimize prognosis, independently of the genetic pattern [2]. Here, our aim is to build a virtual patient model to investigate whether these statistical numbers can be translated into prognostically relevant factors with regard to EOR. In order to quantify the ability to predict EOR as percentage of the preoperative tumor volume based upon the 1p19q status and the Ki67 value, we performed further analysis of our cohort composed of 200 GIIGs (patient characteristics in [2]). Data were processed using a Betaregression model with logit link function, a methodology & Hugues Duffau [email protected] 1
University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland
2
University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland
3
Department of Neurosurgery, Hoˆpital Gui de Chauliac, CHU Montpellier, Montpellier University Medical Center, 80 Av Augustin Fliche, 34295 Montpellier, France
extensively described in our previous article [2]. By evaluating this Beta-regression function, the expected EORs were estimated in different constellations of the 1p19q status and the Ki67 value, representing the ‘‘average patient’’ exhibiting this constellation. Depending on these two variables, the presented virtual GIIG patient model shows expected EORs in a range from 0.86 to 0.96 (Table 1). These values are comparable to the reported range of EORs in awake GIIG resection in the literature [1]. It is important to emphasize that the database for this virtual GIIG patient model was obtained on the basis of maximal tumor resections achieved according to individual functional boundaries, which was made possible by the use of intraoperative electrostimulation mapping. This means that the resections have been pursued until eloquent structures have been encountered, with no margin around critical cortical and subcortical regions with the goal to optimize the EOR. This operative technique has been shown to be associated with a significant increase of the EOR with fewer late neurological deficits, even in eloquent areas, in a meta-analysis with 8091 patients [3]. According to our model, a missing 1p19q deletion is correlated with an improvement of the EOR of up to 5 % in comparison with the EOR in case of no deletion 1p19q. In the same vein, a higher proliferative activity as indicated by a high Ki67 index is correlated with an improvement of the EOR of up to 6 % in comparison with the EOR in case of a low Ki67 index. Thus, by comparing a patient with a paradoxically ‘‘unfavorable’’ profile from a surgical point of view—while favorable from a molecular point of view, i.e. 1p19q co-deletion and low Ki67 index (virtual patient V2, Table 1)—and a patient with a ‘‘favorable’’ profile, i.e. missing 1p19q deletion and high Ki67 index (virtual patient V7, Table 1), there may be a difference of the expected EOR of up to 10 %—even though the calculated
123
318
J Neurooncol (2015) 123:317–318
Table 1 1p19q status, Ki67 index and EOR Virtual patient
1p19q status
Ki67 index
EOR predicted
V1
0
Min
0.91
V2
1
Min
0.86
V3
2
Min
0.89
V4
0
Mean
0.92
V5
1
Mean
0.88
V6
2
Mean
0.91
V7
0
Max
0.96
V8
1
Max
0.93
V9
2
Max
0.95
Virtual constellations of 1p19q status and Ki67 index with resp. EOR predictions 1p19q status ‘‘0’’: no deletion 1p19q; ‘‘1’’: deletion 1p or deletion 19q; ‘‘2’’: codeletion 1p19q
difference in the prediction of EOR may finally result in a subtotal resection versus total resection—with distinct impact on overall survival [1]. In practice, in a subset of patients with known 1p19q status and Ki67 value from previous biopsy or surgery, our model may be helpful to elaborate further therapeutic planning thanks to an improved reliability in the preoperative estimation of EOR, not only based on functional considerations as tumor location but also on the basis of molecular pattern. Further studies are needed to validate this virtual patient model. Acknowledgments This work was supported by the Research Fund of the University of Basel and the Voluntary Academic Society of Basel. Conflict of interest of interest.
The authors declare that they have no conflict
Ki67 Index ‘‘Min’’: 1.0 %; ‘‘Mean’’: 5.2 %; ‘‘Max’’: 20.0 %
References values do not strictly follow the logical pattern ‘‘worst constellation—lowest EOR’’. We can hypothesize that EOR is greater compared to GIIG with favorable molecular markers, because a more diffuse and infiltrative behavior of tumors with 1p 19q co-deletion. Indeed, studies comparing MRI patterns of intact 1p 19q and co-deleted 1p 19q gliomas reported that the former had a sharp and smooth border whereas the second ones had an indistinct border [4]. Logically, sharp margins were more amenable to gross total resection [2]. Therefore, an adverse molecular profile should not discourage surgeons attempting radical resections. These results issued from our original virtual model provide evidence that 1p19q status and Ki67 index are among the factors influencing the EOR in LGG and highlight the actual significance of 1p19q status and Ki67 index, because, at the individual level, up to 10 % of
123
1. Capelle L, Fontaine D, Mandonnet E, Taillandier L, Golmard JL, Bauchet L, Pallud J, Peruzzi P, Baron MH, Kujas M, Guyotat J, Guillevin R, Frenay M, Taillibert S, Colin P, Rigau V, Vandenbos F, Pinelli C, Duffau H (2013) Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article. J Neurosurg 118:1157–1168 2. Cordier D, Goze C, Schadelin S, Rigau V, Mariani L, Duffau H (2015) A better surgical resectability of WHO grade II gliomas is independent of favorable molecular markers. J Neurooncol 121:185–193 3. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS (2012) Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol 30:2559–2565 4. Megyesi JF, Kachur E, Lee DH, Zlatescu MC, Betensky RA, Forsyth PA, Okada Y, Sasaki H, Mizoguchi M, Louis DN, Cairncross JG (2004) Imaging correlates of molecular signatures in oligodendrogliomas. Clin Cancer Res 10:4303–4306
