Increased MIB-1 Labeling Index Is Associated with Abducens Nerve Morbidity in Primary Sporadic Petroclival Meningioma Surgery: Beyond Location and Approach

Round 1

Reviewer 1 Report

This is a very interesting paper. Congratulations to the authors.

One minor comment, on which the authors perhaps could elaborate further:

Is it possible that there is a selection bias here due to the choice of a single approach (retrosigmoid), i.e. could it be the approach is a confounder affecting the outcomes? Could it be that some of these cases with VI palsy would have been better off with a different approach?

 

Just a thought to consider.

Otherwise, very well written and an original concept.

Author Response

Dear Reviewer

Thank you for reading our manuscript and critically reviewing it, which will help us improve it to a better scientific level and make it more understandable to the readership.

In the following we would like to respond to your remarks:

The reviewer is absolutely right that the chosen approach itself can play an essential role regarding the preservation of specific cranial nerve functioning. Hence, each case has to be carefully evaluated regarding the origin of dural attachment, growth pattern, involvement of the Meckel´s cave, cavernous sinus and the internal auditory meatus. Due to the known potential confounding effect of various neurosurgical approaches regarding the investigation of the association between pathological characteristics and cranial nerve functioning, we included only patients in this study who underwent surgery via the retrosigmoid approach. Generally, there are four types of petroclival meningiomas which can be frequently observed: Clivus type, petroclival type, petroclivosphenoidal type, and sphenopetroclival type [1]. Despite it is not a primary objective of the present study, we have included our institutional treatment algorithm for petroclival meningiomas in order to improve the understanding of each chosen individual treatment schedule: Petroclivosphenoidal types of PC MNG, which invade into the middle cranial fossa were treated by a subtemporal transtentorial transpetrosal approach. Sphenopetroclival meningiomas which originate within the cavernous sinus or from the lateral wall of the cavernous sinus expanding into the parasellar region compromising the optic nerve or the cranial nerves III, IV, and VI were treated by an expanded pterional approach which predominantly results in a partial resection with the main goal of cranial nerve decompression. Institutional individual treatment scheduling regarding adjuvant radiotherapy is based on the extent of resection, WHO grade, and the patient´s performance status. Treatment algorithm is in line with the current recommendations of the EANO: Gross totally resected WHO grade 1 or 2 PC MNGs underwent a further observational regimen. Subtotally resected WHO grade 1 PC MNGs routinely undergo an observational management. Partially or biopsied WHO grade 1 PC MNGs with a substantial residual tumor mass undergo a fractionated stereotactic radiotherapy. All patients who do not undergo a gross total resection of a WHO grade 2 PC MNG are strongly recommended to perform a postoperative fractionated stereotactic radiotherapy if the postoperative performance status of the individual patient allows an adjuvant treatment [2]. New local tumor lesions or growing/progressive residual PC MNGs on a follow-up MRI examination were defined as meningioma progression [3].

 

References

1. Zhao, Z.; Yuan, X.; Yuan, J.; Cai, L.; Jiang, W.; Xie, Y.; Wanggou, S.; Zhang, C.; Tang, G.; Peng, Z.; Li, X.; Liu, Q. Treatment Strategy for Petroclival Meninigomas Based on a Proposed Classification in a Study of 168 Cases. Sci Rep. 2020, 10(1), 4655
2. Goldbrunner, R.; Stavrinou, P.; Jenkinson, M.D.; Sahm, F.; Mawrin, C.; Weber, D.C.; Preusser, M.; Minniti, G.; Lund-Johansen, M.; Lefranc, F.; Houdart, E.; Sallabanda, K.; Le Rhun, E.; Nieuwenhuizen, D.; Tabatabai, G.; Soffietti, R.; Weller, M. EANO guideline on the diagnosis and management of meninigiomas. Neuro Oncol. 2021,23(11), 1821-1834
3. Masalha, W.; Heiland, D.H.; Steiert, C.; Krueger, M.T.; Schnell, D.; Scheiwe, C.; Grosu, A.L.; Schnell, O.; Beck, J.; Grauvogel, J. A Retrospective Evaluation of the Retrosigmoid Approach for Petroclival Meningioma Surgery and Prognostic Factors Affecting Clinical Outcome. Front Oncol. 2022, 12, 786909

Reviewer 2 Report

The authors have retrospectively reviewed 32 sporadic petroclival meningioma patients who had surgical resection via retrosigmoid approach and investigated factors related to new-onset cranial nerve dysfunctions. They found peritumoral edema and MIB-1>=4% increase the risk of new-onset abducens palsy.

The authors should address these issues:

1.           Intraoperative monitoring has an important role in preserving cranial nerve function. Authors should describe intraoperative monitoring in detail.

2.           Authors should describe the treatment strategies for petroclival meningiomas in their institution. This paper focused only retrosigmoid approach. How did they select the surgical approach, and how did they treat intracavernous lesion?

3.           Authors described 8 patients had abducens palsy before surgery. Did they have brainstem edema and elevated MIB-1? Did they deteriorate the abducens palsy after surgery? Authors should describe these patients in detail.

 

4.           Authors described the new-onset cranial nerve (II-XII) deficit. Was there new-onset cranial nerve palsy associated with brainstem edema or elevated MIB-1 other than abducens palsy?

Author Response

Dear Reviewer

Thank you for reading our manuscript and critically reviewing it, which will help us improve it to a better scientific level and make it more understandable to the readership.

In the following we would like to respond to your remarks:

1. The reviewer is absolutely right that intraoperative monitoring plays a tremendous role in neuro-oncological surgery regarding preservation of neurological functioning. We have implemented our institutional neuromonitoring technique to the section “2.4 Surgical Workflow”: Intraoperative electromyogram (EMG) monitoring of the facial and trigeminal nerve was performed in all cases. Electromyographic responses of the orbicularis oculi and oris muscles were used to monitor the facial nerve. Bipolar stimuli with an intensity of 0.05 to 1 mA and a duration of 0.1 ms were used. Furthermore, motor and somatosensory evoked potentials were routinely recorded. Monitoring of the lower cranial nerve groups were decided for each individual case and performed if deemed necessary. To date, intraoperative monitoring of the abducens nerve is not routinely performed in our institution due to the technical difficulties (susceptibility to interferences) with risk of accidental injuries of the globe or intraorbital hemorrhage caused by the needle tips [1]. However, the reviewer addresses an important issue and a broader introduction of the intraoperative monitoring of extraocular cranial nerves is an essential challenge in modern skull base surgery. We strive to improve our intraoperative neuromonitoring regarding the extraocular cranial nerves.
2. The reviewer is absolutely right that the chosen neurosurgical approach itself can play an important role regarding the preservation of specific cranial nerve functioning. Hence, each patient has to be carefully evaluated regarding the origin of dural attachment, growth pattern, involvement of the Meckel´s cave, cavernous sinus and the internal auditory meatus. Due to the known potential confounding effect of various neurosurgical approaches regarding the investigation of the association between pathological characteristics and cranial nerve functioning, we included selected only patients in this study who underwent surgery via the retrosigmoid approach. Generally, there are four types of petroclival meningiomas which can be frequently observed: Clivus type, petroclival type, petroclivosphenoidal type, and sphenopetroclival type [2]. Despite it is not a primary objective of the present study, we have included our institutional treatment algorithm for petroclival meningiomas in order to improve the understanding of each chosen individual treatment schedule: Petroclivosphenoidal types of PC MNG, which invade into the middle cranial fossa were treated by a subtemporal transtentorial transpetrosal approach. Sphenopetroclival meningiomas which originate within the cavernous sinus or from the lateral wall of the cavernous sinus expanding into the parasellar region compromising the optic nerve or the cranial nerves III, IV, and VI were treated by an expanded pterional approach which predominantly results in a partial resection with the main goal of cranial nerve decompression. Institutional individual treatment scheduling regarding adjuvant radiotherapy is based on the extent of resection, WHO grade, and the patient´s performance status. Treatment algorithm is in line with the current recommendations of the EANO: Gross totally resected WHO grade 1 or 2 PC MNGs underwent a further observational regimen. Subtotally resected WHO grade 1 PC MNGs routinely undergo an observational management. Partially or biopsied WHO grade 1 PC MNGs with a substantial residual tumor mass undergo a fractionated stereotactic radiotherapy. All patients who do not undergo a gross total resection of a WHO grade 2 PC MNG are strongly recommended to perform a postoperative fractionated stereotactic radiotherapy if the postoperative performance status of the individual patient allows an adjuvant treatment [3]. New local tumor lesions or growing/progressive residual PC MNGs on a follow-up MRI examination were defined as meningioma progression [4].
3. The reviewer is absolutely right that there is also a significant number of patients who already preoperatively had an abducens nerve palsy. Hence, we implemented the data of potential variables being associated with a baseline dysfunction of the sixth cranial nerve to the manuscript. The data regarding the baseline characteristics of those patients was added to the section “3.1 Baseline Patient characteristics”. Patients with a preoperative abducens nerve palsy had a mean (± SD) MIB- 1 labeling index of 5.1 ± 4.1, whereas those without a preoperative abducens nerve dysfunction had a mean MIB-1 labeling index of 3.8 ± 1.9 (independent t-test: p = 0.23). Peritumoral edema in those with a baseline abducens nerve palsy was present in one patient (1/8; 12.5%), and those without a baseline CN VI palsy had a peritumoral edema in 7 cases (7/24; 29.2%), respectively (Fisher´s exact test (two-sided): p = 0.64). Mean tumor volume (± SD) in those patients with a preoperative CN VI palsy was 21.8 ± 13.3 cm³, and 17.3 ± 12.4 cm³ in those without a preoperative CN VI palsy, respectively (independent t-test: p = 0.41). Further baseline patient characteristics were also not associated with an already preoperatively existing sixth CN palsy. The data regarding the perioperative development of already preoperatively present CN VI palsies was added to the newly created section “3.5 Perioperative development of preoperatively existing abducens nerve palsy after PC MNG surgery”.Two patients (2/8; 25.0%) of those with an abducens nerve palsy as presenting symptom had a regression of the abducens nerve dysfunction immediately after surgery (period until discharge) for sporadic PC MNG. Stable dysfunction was observed in 5 (5/8; 62.5%), and a progressive palsy was observed in only one case (1/8; 12.5%) after surgery. Mean (± SD) MIB-1 labeling index in those patients with a regression of the abducens nerve dysfunction after surgery was 3.0 ± 1.4, and in those with a stable or progressive already preoperatively existing dysfunction was 5.8 ± 4.5, respectively (p = 0.44). Baseline peritumoral edema was not present in those two cases with a regression of the preoperatively existing abducens nerve palsy, and the single case with a further progression of the preoperatively present CN VI palsy had a peritumoral edema. Mean tumor volume (± SD) in those patients with a regression of the preoperatively present CN VI palsy was 7.95 ± 7.1 cm³, and 26.35 ± 11.6 cm³ in those with a stable or progressive already preoperatively existing CN VI palsy, respectively (independent t-test: p = 0.09)
4. We agree with the reviewer that it is also important to include data regarding the association of MIB-1 and peritumoral edema with the incidence new-onset cranial nerve palsies of the other cranial nerves. We have added these data to the newly created section “3.6 MIB-1 index and other new-onset cranial nerve palsies". MIB-1 labeling indices and the preoperative presence of a peritumoral edema were investigated in all patients with or without palsies of the other cranial nerves (except for CN II due to no postoperative event).  The most common new-onset cranial nerve palsy after surgery was observed regarding the sixth cranial nerve. Further event rates of other postoperative new-onset cranial nerve palsies and their associations with MIB-1 labeling index as well as the presence of peritumoral edema were investigated. Statistical analysis using independent t-test comparing the mean (± SD) values of MIB-1 labeling indices in patients with or without other new-onset cranial nerve palsies was performed and identified no significant association. Furthermore, Fisher´s exact test (two-sided) was used to evaluate the association between peritumoral edema and new-onset palsies of other cranial nerves. Peritumoral edema was observed in all patients (2/2; 100%) of each group with either new-onset CN V palsy or CN VIII palsy, whereas peritumoral edema was present in only 22.2% of those patients without a new-onset palsy of the CNs V or VIII (Fisher´s exact test (two-sided): p = 0.06). The newly created Table 4 summarizes the results of those analyses. We strive to further investigate the role of MIB-1 labeling index and macrophage infiltrates regarding functional endpoints in various anatomic subtypes of meningioma after surgery. We are right now still in the identification process of location-specific dysfunctions which are directly influenced by the proliferative activity and the tumor microenvironment. Interestingly, we have previously identified that patients with a medial skull base meningiomas (sphenoid wing, olfactory groove, planum sphenoidale, tuberculum sellae, and spheno-orbital) affecting the optic nerve and optic canal presented significantly more often with reduced vision in case of an MIB-1 index ≥5%. [5]

 

References

1. Schlake, H.P.; Goldbrunner, R.; Siebert, M.; Behr, R.; Roosen, K. Intra-operative electromyographic monitoring of extra-ocular motor nerves (Nn. III, VI) in skull base surgery. Acta Neurochir. 2001, 143, 251-261
2. Zhao, Z.; Yuan, X.; Yuan, J.; Cai, L.; Jiang, W.; Xie, Y.; Wanggou, S.; Zhang, C.; Tang, G.; Peng, Z.; Li, X.; Liu, Q. Treatment Strategy for Petroclival Meninigomas Based on a Proposed Classification in a Study of 168 Cases. Sci Rep. 2020, 10(1), 4655
3. Goldbrunner, R.; Stavrinou, P.; Jenkinson, M.D.; Sahm, F.; Mawrin, C.; Weber, D.C.; Preusser, M.; Minniti, G.; Lund-Johansen, M.; Lefranc, F.; Houdart, E.; Sallabanda, K.; Le Rhun, E.; Nieuwenhuizen, D.; Tabatabai, G.; Soffietti, R.; Weller, M. EANO guideline on the diagnosis and management of meninigiomas. Neuro Oncol. 2021,23(11), 1821-1834
4. Masalha, W.; Heiland, D.H.; Steiert, C.; Krueger, M.T.; Schnell, D.; Scheiwe, C.; Grosu, A.L.; Schnell, O.; Beck, J.; Grauvogel, J. A Retrospective Evaluation of the Retrosigmoid Approach for Petroclival Meningioma Surgery and Prognostic Factors Affecting Clinical Outcome. Front Oncol. 2022, 12, 786909
5. Wach, J.; Lampmann, T.; Güresir, A.; Vatter, H.; Herrlinger, U.; Becker, A.; Cases-Cunillera, S.; Hölzel, M.; Toma, M.; Güresir, E. Proliferative Potential, and Inflammatory Tumor Microenvironment in Meningioma Correlate with Neurological Function at Presentation and Anatomical Location-From Convexity to Skull Base and Spine. Cancers (Basel). 2022, 14(4), 1033

 

Reviewer 3 Report

   The authors retrospectively analyzed the factors that cause postoperative abductor nerve palsy in a series of 35 petroclical meningioma experienced during 14 years. In particular, they focused on the MIB-1 index determined by histopathology, and showed that when the value of the MIB-1 index is high, there is a high possibility that postoperative abducens nerve palsy will appear. In addition, the threshold of the MIB-1 index was 4% shown by statistical analysis.
   First, this study is a collection of rare surgical cases that are performed only a few times a year. Factors such as the experience of multiple surgeons and their learning curves, evolution of surgical techniques for years, and other factors on the side of intervention were not carefully evaluated.
   Second, the mean of the MIB-1 index is 4.0 and the variability of all data is 3.0-5.0, which is too uniform for the test results of the population including WHO grade I and grade II. Usually, there seems to be greater variability.
   Third, the MIB-1 index is a value indicating the proliferative ability in cell biology. It is believed that the increase in physical tumor volume mechanically compresses the abducens nerve, resulting in postoperative nerve paralysis. Therefore, the value of MIB-1 index is an indirect prognostic factor and cannot be a direct prognostic factor.
   Finally, from the perspective of patient benefit, the MIB-1 index, which gives results after surgery, has no benefit in predicting prognosis. Any method that can be predicted to cause abducens nerve palsy after surgery in a non-invasive manner before surgery is expected to provide meaningful information for treatment selection.

Author Response

 

Dear Reviewer

Thank you for reading our manuscript and critically reviewing it, which will help us improve it to a better scientific level and make it more understandable to the readership.

In the following we would like to respond to your remarks:

We agree with the reviewer that petroclival meningiomas are a rare disease and they constitute a very challenging skull base tumor in terms of surgical therapy. Furthermore, it is absolutely right that the decision making regarding the preferred approach and the surgical techniques in this challenging entity are always under a continuous development. However, we applied highly selective inclusion criteria regarding our endpoint to investigate neuropathological characteristics being associated with postoperative sixth cranial nerve morbidity. We added our institutional treatment algorithm for petroclival meningiomas and strived to more precisely describe our institutional surgical workflow to make the present manuscript more understandable. Each case was carefully evaluated regarding the origin of dural attachment, growth pattern, involvement of the Meckel´s cave, cavernous sinus and the internal auditory meatus. Due to the known potential confounding effect of various neurosurgical approaches regarding the investigation of the association between pathological characteristics and cranial nerve functioning, we included only patients in this study who underwent surgery via the retrosigmoid approach. Generally, there are four types of petroclival meningiomas which can be frequently observed: Clivus type, petroclival type, petroclivosphenoidal type, and sphenopetroclival type [1]. Despite it is not a primary objective of the present study, we have included our institutional treatment algorithm for petroclival meningiomas in order to improve the understanding of each chosen individual treatment schedule: Petroclivosphenoidal types of PC MNG, which invade into the middle cranial fossa were treated by a subtemporal transtentorial transpetrosal approach. Sphenopetroclival meningiomas which originate within the cavernous sinus or from the lateral wall of the cavernous sinus expanding into the parasellar region compromising the optic nerve or the cranial nerves III, IV, and VI were treated by an expanded pterional approach which predominantly results in a partial resection with the main goal of cranial nerve decompression. Institutional individual treatment scheduling regarding adjuvant radiotherapy is based on the extent of resection, WHO grade, and the patient´s performance status. Treatment algorithm is in line with the current recommendations of the EANO: Gross totally resected WHO grade 1 or 2 PC MNGs underwent a further observational regimen. Subtotally resected WHO grade 1 PC MNGs routinely undergo an observational management. Partially or biopsied WHO grade 1 PC MNGs with a substantial residual tumor mass undergo a fractionated stereotactic radiotherapy. All patients who do not undergo a gross total resection of a WHO grade 2 PC MNG are strongly recommended to perform a postoperative fractionated stereotactic radiotherapy if the postoperative performance status of the individual patient allows an adjuvant treatment [2]. New local tumor lesions or growing/progressive residual PC MNGs on a follow-up MRI examination were defined as meningioma progression [3].

The cited values “4.0 (3.0-5.0)” constitute the median and the interquartile range in the present cohort. We added the information regarding the mean MIB-1 index (± SD) to the section “3.2 Neuropathological grading, extent of resection, and postoperative functioning”. The mean MIB-1 index in the present study is 4.2 ± 2.6.The present study included only sporadic primary PC MNG patients who did not underwent any kind of therapy before surgical resection. Mean (± SD) MIB-1 labeling index in WHO grade PC MNGs was 3.6 ± 1.3, and mean (± SD) MIB-1 in WHO grade 2 meningiomas was 8.0 ± 5.6, respectively (independent t-test: p = 0.22).

The reviewer is absolutely right that MIB-1 labeling index is not directly a predictor, and we replaced the term “predicts” by “is associated with” in the title of the manuscript. Furthermore, we have also adapted this change of the term in the sections result and discussion. However, we applied highly selective inclusion criteria and investigated only patients who underwent the retrosigmoid approach in order to reduce the potential confounding effect by including heterogenous surgical approaches in the analysis of new-onset abducens nerve palsies.

The reviewer is absolutely right that MIB-1 labeling index does not have a direct benefit for the patient in terms of perioperative cranial nerve morbidity at the current standard treatment regimen for skull base meningiomas. However, there is evidence that the cyclooxygenase-2 expression and the MIB-1 index are strongly associated [4]. Moreover, the formation of scar tissue is an essential part of prolonged inflammatory processes, which are strongly induced by cyclooxygenase-2 expression [5]. Therefore, there might be a potential therapeutic avenue of non-steroidal anti-inflammatory drugs against the proliferative activity in meningiomas to enhance local tumor progression-free survival time as well as functional clinical endpoints such as cranial nerve functioning in skull base meningiomas. However, we strive to investigate the potential association between COX-2 and MIB-1 index in a future prospective trial. Furthermore, there is emerging research on novel methods to intraoperatively determine the proliferative activity and inflammatory burden of neoplastic tissues. One method might be rapid immunohistochemistry using alternating current electric fields might be an option to enhance the interaction between antigens and antibodies. This novel approach enables a faster determination of the MIB-1 index and the proliferative potential intraoperatively [6, 7]. Hence, this potential novel methods might support neurosurgeons in the intraoperative surgical decision making process regarding extent of resection because increased MIB-1 labeling indices seem to be associated with the new-onset of sixth cranial nerve deficits after PC MNG surgery as well as new cranial nerve deficits after Simpson grade I resections of frontal skull base meningiomas [8].

 

References

1. Zhao, Z.; Yuan, X.; Yuan, J.; Cai, L.; Jiang, W.; Xie, Y.; Wanggou, S.; Zhang, C.; Tang, G.; Peng, Z.; Li, X.; Liu, Q. Treatment Strategy for Petroclival Meninigomas Based on a Proposed Classification in a Study of 168 Cases. Sci Rep. 2020, 10(1), 4655
2. Goldbrunner, R.; Stavrinou, P.; Jenkinson, M.D.; Sahm, F.; Mawrin, C.; Weber, D.C.; Preusser, M.; Minniti, G.; Lund-Johansen, M.; Lefranc, F.; Houdart, E.; Sallabanda, K.; Le Rhun, E.; Nieuwenhuizen, D.; Tabatabai, G.; Soffietti, R.; Weller, M. EANO guideline on the diagnosis and management of meninigiomas. Neuro Oncol. 2021,23(11), 1821-1834
3. Masalha, W.; Heiland, D.H.; Steiert, C.; Krueger, M.T.; Schnell, D.; Scheiwe, C.; Grosu, A.L.; Schnell, O.; Beck, J.; Grauvogel, J. A Retrospective Evaluation of the Retrosigmoid Approach for Petroclival Meningioma Surgery and Prognostic Factors Affecting Clinical Outcome. Front Oncol. 2022, 12, 786909
4. Kato, Y.; Nishihara, H.; Mohri, H.; Kanno, H.; Kobayashi, H.; Kimura, T.; Tanino, M.; Terasaka, S.; Tanaka, S. Clinicopathological evaluation of cyclooxygenase-2 expression in meningioma immunohistochemical analysis of 76 cases of low and high-grade meningioma. Brain Tumor Pathol. 2014, 31(1), 23-30
5. Wilgus, T.A.; Bergdall, V.K.; Tober, K.L.; Hill, K.J.; Mitra, S.; Flavahan, N.A.; Oberyszyn, T.M. The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am J Pathol. 2004, 165, 753-761
6. Moriya, J.; Tanino, M.A.; Takenami, T.; Endoh, T.; Urushido, M.; Kato, Y.; Wang, L.; Kimura, T.; Tsuda, M.; Nishihara, H.; Tanaka, S. Rapid immunocytochemistry based on alternating electric field using squash smear preparation of central nervous system tumors. Brain Tumor Pathol. 2016, 33, 13-18
7. Terata, K.; Saito, H.; Nanjo, H.; Hiroshima, Y.; Ito, S.; Narita, K.; Akagami, Y.; Nakamura, R.; Konno, H.; Ito, A.; Motoyama, S.; Minamiya, Y. Novel rapid-immunohistochemistry using an alternating current electric field for intraoperative diagnosis of sentinel lymph nodes in breast cancer. Sci Rep. 2017, 7, 2810
8. Schneider, M.; Borger, V.; Güresir, A.; Becker, A.; Vatter, H.; Schuss, P.; Güresir, E. High MIB-1-score correlates with new cranial nerve deficits after surgery for frontal skull base meningioma. Neurosurg Rev. 2021, 44(1), 381-387

 

Reviewer 4 Report

This study investigated that the increased MIB-1 labeling index can predict a new-onset postoperative abducens nerve palsy after the surgery for petroclival meningioma. This is a well-written manuscript. However, based on the statistics used in the project I agree that there might be an association between the nerve palsy and MIB-1 index, but I don’t support the word predict.

 

Importantly, there is missing data regarding the median and range of clinical and imaging follow-ups. The mean follow-up of 38 months for a non-malignant meningioma study seems a bit short. Meanwhile, I am curious to see the outcome of local tumor control, which is important to further understand the impact of the Ki-67 expression level. The limitations of the current study are small patient numbers (only 7 out of a total of 32 patients developed a new palsy) and short clinical follow-up. 

Author Response

Dear Reviewer

Thank you for reading our manuscript and critically reviewing it, which will help us improve it to a better scientific level and make it more understandable to the readership.

In the following we would like to respond to your remarks:

The reviewer is absolutely right that the present study compromises a small study cohort which did not allow a reliable multivariable analysis. Hence, we agree that MIB-1 labeling index is not directly a predictor, and we replaced the term “predicts” by “is associated with” in the title of the manuscript. Furthermore, we have also adapted this change of the term in the sections result and discussion.

However, we applied highly selective inclusion criteria and investigated only patients who underwent the retrosigmoid approach in order to reduce the potential confounding effect by including heterogenous surgical approaches in the analysis of new-onset abducens nerve palsies.

Due to the low incidence of petroclival meningiomas and the need to create a homogeneous study cohort by including only primary petroclival meningioma patients who underwent a retrosigmoid approach the investigation of the MIB-1 index regarding PFS is limited to univariable analyses.  We absolutely agree with the reviewer that there is emerging data supporting the role of MIB-1 labeling index / Ki67-index regarding PFS in meningioma [1-4]. We have added a newly created section “3.7 MIB-1 index and probability of progression-free survival after petroclival meningioma surgery via retrosigmoid approach“ to the chapter results.

Imaging follow-up was available in 26 (26/32; 81.3%) and the median (range) imaging follow-up was 21 (1-83) months. Four patients (4/26; 3.8%) were identified with a meningioma progression after surgical therapy. ROC curve analysis of the MIB-1 labeling index in the association with tumor progression was performed. The AUC was 0.90 (95% CI: 0.74-1.0). Optimum cut-off value of MIB-1 index in the association with tumor progression was identified at <5/≥5%. The sensitivity and specificity of the optimum threshold was 75.0% and 80.0%, respectively. The mean time to tumor progression in those cases with an increased MIB-1 labeling index (≥5%) was 39.6 (95% CI: 12.7-66.4) months, whereas those with an MIB-1 labeling index <5% had a mean time to tumor progression of 77.6 (95% CI: 67.5-87.8). The corresponding log-rank test (p = 0.023) revealed a significant association between MIB-1 labeling index and PC MNG progression. The newly created Figure 5 summarizes the results of the ROC curve analysis and the subsequent Kaplan-Meier analysis of MIB-1 index in the association with meningioma progression. Three progressive meningioma cases had an increased MIB-1 labeling index (≥5%) and underwent a Simpson grade III resection, whereas the fourth patient with a meningioma progression had no increased MIB-1 labeling index (<5%) and underwent a Simpson grade IV resection. Furthermore, we have added the description of these newly added statistical results (ROC curve & Kaplan-Meier charts/log-rank test) to the section “2.6 Statistical analysis”. The limitations regarding the sample size, inclusion criteria, and absence of multivariable analysis were also further discussed in the section “4 discussion”.

 

References

1. Liu, N.; Song, S.Y.; Jiang, J.B.; Wang, T.J.; Yan, C.X. The prognostic role of Ki-67/MIB-1 in meningioma: A systematic review with meta-analysis. Medicine (Baltimore). 2020, 99(9), e18644
2. Wach, J.; Lampmann, T.; Güresir, Á.; Schuss, P.; Vatter, H.; Herrlinger, U.; Becker, A.; Hölzel, M.; Toma, M.; Güresir, E. FORGE: A Novel Scoring System to Predict the MIB-1 Labeling Index in Intracranial Meningiomas. Cancers (Basel). 2021, 13(14), 3643
3. Mirian, C.; Skyrman, S.; Bartek J. Jr.; Jensen L.R.; Kihlström, L.; Förander, P.; Orrego, A.; Mathiesen, T. The Ki-67 Proliferation Index as a Marker of Time to Recurrence in Intracranial Meningioma. Neurosurgery. 2020, 87(6), 1289-1298
4. Behling, F.; Fodi, C.; Wang, S.; Hempel, J.H.; Hoffmann, Tabatabai, G., Honegger, J.; Tatagiba, M.; Schittenhelm, J.; Skardelly, M. Increased proliferation is associated with CNS invasion in meningiomas. J Neurooncol. 2021, 155(3), 247-254

 

 

 

 

Round 2

Reviewer 2 Report

This manuscript is well revised.

One suggestion is added below:

 

MIB-1 labeling index is associated with new-onset abducens nerve palsy but is not associated with another cranial nerve palsy. Authors should describe the reason.

Author Response

Dear Reviewer

 

Thank you for reading our manuscript and critically reviewing it, which will help us improve it to a better scientific level and make it more understandable to the readership.

 

We have revised the section “4. Discussion” and added a discussion regarding the association between MIB-1 index and postoperative new-onset deficits of other cranial nerves.  In the following we would like to respond to your remark:

 

The reviewer is absolutely right that it remains somewhat unclear whether increased MIB-1 labeling indices might also influence the incidence of postoperative new-onset cranial nerve palsies in other nerve groups. We assume that this potential interesting association whether increased MIB-1 labeling indices might also influence the incidence of postoperative new-onset cranial nerve palsies in other nerve groups cannot be answered entirely in the present investigation. Elevated MIB-1 labeling indices may also influence the postoperative new-onset of other cranial nerve dysfunctions. Except for the CN VII and the lower cranial nerve group, all PC MNG patients with other new postoperative cranial nerve dysfunctions (CN groups: III, IV, V, VIII) had increased MIB-1 labeling indices compared to those patients without a postoperative new-onset palsy of those other cranial nerves. Nevertheless, the event rates of other postoperative cranial nerve deficits compared to postoperative new-onset palsy of the abducens nerve were lower. Therefore, those lower event rates of other postoperative new-onset cranial nerve palsies may have resulted that the univariable analysis revealed no significant association. Future multicentric studies investigating a larger study cohort have to analyze our findings regarding the postoperative abducens nerve functioning and might have a special focus on the residual cranial nerve groups.