- Department of Neurosurgery, Max Planck University Center, Indaiatuba, Brazil
- Department of Neurosurgery, Faculty of Medicine, Santa Casa de São Paulo School of Medical Sciences, Sao Paulo, Brazil
- Department of Medicine, Serra dos Órgãos University Center, Teresópolis, Rio de Janeiro, Brazil
- Department of Medicine, Faculty of Medicine, Universidade Nove de Julho, Bauru, São Paulo, Brazil
- Department of Neurosurgery, Lenox Hill Hospital/Northwell Health, New York, United States
- Department of Medicine, Faculty of Medicine, University Ninth of July, São Paulo, Brazil
- Department of Medical Genetics, State University of São Paulo, Ribeirão Preto, Brazil
- Faculty of Medicine, Max Planck University Center, Indaiatuba, São Paulo, Brazil
- Department of Medicine, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil
- 0Department of Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- 1Department of Medicine, Faculty of Medicine, Federal University of Amazonas, Manaus, Amazonas, Brazil
- 2Department of Medicine, Barão de Mauá University Center, Faculty of Medicine, Ribeirão Preto, Brazil
- 3Department of Neurosurgery, University of São Paulo, São Paulo, Brazil
- 4Department of Neurosurgery, Federal Fluminense University, Niterói, Brazil
Correspondence Address:
Lucca B. Palavani, Department of Neurosurgery, Max Planck University Center, Indaiatuba, São Paulo, Brazil. lucca.palavani730@al.unieduk. com.br
DOI:10.25259/SNI_836_2024
Copyright: © 2025 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.How to cite this article: Lucca B. Palavani1, Lucas Pari Mitre2, Bernardo Vieira Nogueira3, Fabiana Honorato4, Marcio Yuri Ferreira5, Carlos Alexandre Farias6, Paulo Victor Zattar Ribeiro7, Isabela Vilas Banderali8, Leonardo O. Brenner9, Fernando Cotrim Gomes10, Gisele Lúcia Canto Gomes11, Filipe Virgilio Ribeiro12, Raphael Bertani13, Jose Alberto Landeiro14. Exploring efficacy: A comprehensive review of extended transsphenoidal approach in anterior skull base meningiomas. 24-Jan-2025;16:22
How to cite this URL: Lucca B. Palavani1, Lucas Pari Mitre2, Bernardo Vieira Nogueira3, Fabiana Honorato4, Marcio Yuri Ferreira5, Carlos Alexandre Farias6, Paulo Victor Zattar Ribeiro7, Isabela Vilas Banderali8, Leonardo O. Brenner9, Fernando Cotrim Gomes10, Gisele Lúcia Canto Gomes11, Filipe Virgilio Ribeiro12, Raphael Bertani13, Jose Alberto Landeiro14. Exploring efficacy: A comprehensive review of extended transsphenoidal approach in anterior skull base meningiomas. 24-Jan-2025;16:22. Available from: https://surgicalneurologyint.com/?post_type=surgicalint_articles&p=13345
Abstract
Background: Anterior skull base meningiomas can cause significant symptoms such as mass effect and neuropsychological decline, necessitating surgical resection. The endoscopic extended transnasal approach has emerged as a minimally invasive alternative to craniotomy, offering a means to address these tumors despite challenges due to the proximity of critical neurovascular structures and the high risk of complications such as cerebrospinal fluid (CSF) leaks. This systematic review and meta-analysis evaluate the safety and efficacy of extended transsphenoidal techniques in anterior skull base meningiomas.
Methods: This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook. A search was performed in Medline, Embase, Cochrane, and Ovid. Eligible studies included those (1) in English, (2) with patients having anterior skull base meningiomas, and (3) who underwent endoscopic surgical management. Endpoints included CSF leak, length of stay, complications, and mortality.
Results: The analysis included data from 23 studies involving 573 patients with a median age of 54.77 (range 39.5–67.3) years. Approximately 71% of participants were female. The mean length of stay was 7.50 days (95% confidence interval [CI]: 6.64–8.47). The overall complication rate was 35% (95% CI: 0.22–0.49), with minor complications also occurring in 6% of cases (95% CI: 0.02–0.10). Major complications were reported in 20% of cases (95% CI: 0.10–0.30). The CSF leak rate was 7% (95% CI: 0.04–0.10).
Conclusion: In the setting of complex anatomical challenges and inherent risks, the technique showed a moderate complication rate and length of hospital stay. This method demonstrated lower CSF leak and complication rates compared to previously published studies from the past decade.
Keywords: Cerebrospinal fluid leak, Endoscopic surgery, Meningiomas, Skull base, Transnasal
INTRODUCTION
Meningiomas are common intracranial tumors and correspond to nearly one-third of all primary central nervous system lesions.[
Anterior skull base meningiomas, according to their dimensions, may cause symptoms, namely mass effect, edema in adjacent neurovascular structures, loss of olfaction, loss of vision, and neuropsychological decline, and surgical resection is recommended as part of the treatment.[
The complexity of the skull-base meningiomas surgical removal derives from the intimate kinship between the meningiomas and the neurovascular brain structures.[
In the context of the complexity of anterior skull base meningiomas resection and the incidence of adverse events, notably the CSF leak episodes, it is relevant to quantitatively evaluate, as a minimally invasive alternative, endoscopic surgery technique complications occurrence; however, consistent data describing both intraoperative and postoperative outcome challenges of anterior skull base endoscopic approaches remains scarce.[
MATERIALS AND METHODS
Search strategy
A systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[
Eligibility criteria
Key inclusion criteria included: (1) full-text available and published in the English language, (2) any study design characteristic, either retrospective or prospective, (3) reporting outcomes of interest, (4) on anterior skull base meningiomas about the tuberculum sellae, sphenoid bone, olfactory groove, and cribriform plate, confirmed through imaging or biopsy, and (5) that underwent surgical management in any phase of the treatment though an extended endoscopic transsphenoidal approach. Studies were excluded if they were published in a foreign language or full text was unavailable, on tumors other than meningiomas, undergoing other types of treatment than the surgical possibilities stated in the inclusion criteria, or reporting data outside of the outcomes of interest or in an aggregate fashion.
Outcomes definitions
Outcomes of interest included baseline demographic characteristics of patients, such as age and gender, the histologic examination and subtype of tumors, along with meningioma World Health Organization grade, mean follow-up, preoperative magnetic resonance imaging (MRI) findings, such as preoperative tumor volume, volume of tumor edema, planum, and tuberculum involvement; postoperative MRI findings, such as change in fluid-attenuated inversion recovery volume, porencephalic change in volume, mean postoperative tumor volume, and total change in volume (tumor + edema), extent of resection (Gross total, near total, and subtotal resections), and Simpson’s Scale of Resection. Additional outcomes of interest were assessed, such as data on preoperative symptomatology and initial tumor findings, such as Karnofsky Performance Scale on the immediate postoperative functional outcome, meningioma diameter size, initial symptoms, presence of visual symptoms, preoperative and postoperative visual impairment scores, preoperative and postoperative Glasgow outcome scale scores, and initial interval from onset diagnosis to surgery. Other outcomes of interest, such as data on visual field and acuity outcomes, major and minor complications, and mortality, were considered. Major complications were considered when presented as permanent and requiring further invasive interventions, while minor complications were considered transient and did not need further interventions. Tumor-related mortality was defined as any mortality related to or caused by tumor presentation, procedure, subsequent treatment, and postoperative course and follow-up.
Risk of bias assessment
The included studies’ bias was assessed using the Risk of Bias In Non-randomized Studies–of Interventions (ROBINS-I) tool.[
Statistical analysis
This systematic review and meta-analysis were performed according to the Cochrane Collaboration and the PRISMA statement guidelines.[
RESULTS
Study selection
On searching PubMed, Embase, Cochrane, and Ovid, we identified 1060 studies. After deduplication, 724 non-duplicated studies were screened, with 668 excluded due to their lack of relevance based on title and abstract screening. The remaining 56 articles underwent a full-text review to assess their eligibility. Ultimately, 23 studies[
Baseline characteristics
The data for this meta-analysis were derived from 23 studies evaluating the transsphenoidal approach for treating meningiomas in the anterior fossa, encompassing a total of 573 patients. Within this cohort, the median age was 54.77 (range 39.5–67.3) years. Female patients constituted the majority, approximately 71%, of the study population. Included studies reported tumors invading the Tuberculum Sellae, Olfactory Groove, Planum Sphenoidale, Olfactory Sulcus, and Orbital Roof. More detailed information is available in
In the studies analyzed, a total of 184 complications were reported among 573 patients, categorized as either major or minor. Specifically, there were 123 major complications and 45 minor complications. The most common complications included CSF leaks, occurring in 44 cases (20.05%), meningitis in 19 cases (9.09%), and anosmia in 10 cases (4.7%).
Quality assessment
The assessments of methodological risk of bias are visually displayed in
To better elucidate the influence of bias across the included studies,
Pooled analysis of studies
CSF leak
The CSF leak was assessed in all 23 studies for the entire population of 573 patients. The analysis revealed an estimated 7% rate of CSF Leak (Proportion = 0.07; 95% CI [0.04–0.10]; I2 = 47% [
Lumbar drain (LD)
In our analysis, the LD was performed on 15% of patients (Proportion = 0.15; 95% CI [0.01–0.29]; I2 = 89% [
Complications
Complications were reported in 23 studies, encompassing a total of 573 patients. Detailed findings from individual studies are presented in
Length of stay
Regarding length of stay, five studies with a total population of 156 were analyzed. In this pooled analysis, the mean length of stay was 7.50 days (Mean = 7.50 [6.64–8.47]; I2 = 38% [
Mortality
The analysis of the mortality rate directly related to the procedure in patients treated through a transsphenoidal approach for meningioma was assessed by 21 studies, with a total of 497 patients. In our pooled analysis, a total of 3 deaths were reported – the estimated mortality rate was 1% (Proportion = 0.01; 95% CI [0.00–0.02]; I2 = 0% [
DISCUSSION
This systematic review and meta-analysis, encompassing 23 studies with a cumulative patient population of 573, comprehensively evaluates the EEA in meningiomas of the anterior fossa. The primary outcomes from the analysis performed within this population were as follows: (1) the CSF leak was presented in 7% of the patients; (2) LD was performed on 15% of patients; (3) major and minor postoperative complication rate, was 20% and 6%, respectively; (4) mean length of hospital stay was 7.50 days; and (5) mortality was reported in 1% of patients.
Meningiomas are the most common type of primary brain tumor, and those located within the anterior fossa present unique clinical considerations and challenges. The anterior fossa is a critical region of the skull base, housing vital structures such as the olfactory bulbs, optic nerves, and frontal lobes of the brain. Despite advancements in surgical techniques and adjuvant therapies, the management of anterior fossa meningiomas remains complex, and optimal outcomes require careful consideration of individual patient factors and tumor characteristics. The EEA for anterior skull base meningiomas was developed with the expectation of achieving more complete resection (Simpson grade I) using a less invasive approach.
One of the notable challenges remains the potential for complications, including CSF leaks. They occur when there is an abnormal communication between the subarachnoid spaces. In the case of anterior fossa meningiomas, the tumor itself can create a breach in the dura mater, allowing CSF to escape into the nasal cavity or sinuses, possibly contributing to CSF leak. The previous studies have shown that the proportion of patients experiencing a CSF leak decreased progressively over time, from 22% (95% CI: 6–43%) in studies published between 2004 and 2010, to 16% (95% CI: 11–23%) between 2011 and 2015, and further to 4% (95% CI: 1–9%) between 2016 and 2020. Our study, covering publications from 2004 to 2023, demonstrates a notable decline in the occurrence of CSF leaks over nearly two decades, with a prevalence of only 8% among patients (95% CI: 4–10%). However, it’s worth noting that our findings slightly exceed those reported in the last published meta-analysis from 2016 to 2020. We hypothesize that this variation may stem from differences in experience among endoscopic surgeons, with practitioners at various stages of their learning curve. In addition, we attempted to pool all anterior fossa meningiomas, not generating subsets of variables pertaining specifically to tuberculum meningiomas and olfactory groove meningiomas, which could lead to lower overall pooled rates of CSF leak, with olfactory groove meningiomas CSF leak rates ranging from 20% to 30%.[
It is recognized that the placement of a LD at the beginning of an operation, followed by drainage post-surgery, has been recommended. The primary advantage is to aid in the healing of the dural defect by reducing intracranial pressure and offering an alternative route for CSF drainage from the subarachnoid space. However, its effectiveness is not universally acknowledged, especially concerning high-flow CSF leaks, as well as the possibility of complications such as spinal headaches, infections, tension pneumocephalus, and uncal herniation. In our analysis, LD placement was observed in 15% of patients (95% CI: 1–29%), highlighting potential concerns in clinical practice regarding the risk-to-benefit ratio, especially given the uncertain utility of this approach.
Regarding the adverse events, we report a 20% incidence of major complications and a 6% of minor complications. Complications are categorized based on the anatomical structures involved during operative stages, primarily as rhinological, CSF leaks, infection, and vascular complications. Endocrinological complications are typically further subdivided into anterior and posterior pituitary dysfunctions. The incidence of complications is notably higher in studies with larger sample sizes and a greater proportion of patients encountering CSF leaks. Nevertheless, the mortality rate remained consistent at 1% among patients (95% CI: 0–1%), indicating stability over time.
Limitations
Our meta-analysis data have limitations inherent to this research design. Specifically, surgery studies have an intrinsic bias due to the surgeons’ experience and management of tumor resection. The small number of published studies with potentially highly selected patient groups introduces the possibility of selection bias and publication bias, which cannot be entirely ruled out, mainly considering the study design most frequently presented, non-randomized. Finally, conceptual disagreements about anatomical delimitations may impair the objective differentiation of tuberculum sellae and planum sphenoidale meningiomas, especially when assessing large masses.
CONCLUSION
This systematic review and meta-analysis, which analyzed data from 23 studies involving 573 patients, assessed the EEA for anterior fossa meningiomas. Key findings include a 7% rate of CSF leaks, 15% of patients undergoing LD placement, major and minor complication rates of 20% and 6%, respectively, a mean hospital stay of 7.5 days, and a 1% mortality rate. The research is significant because it evaluates a minimally invasive surgical option for managing anterior fossa meningiomas, which are located near critical structures such as the olfactory bulbs and optic nerves. This helps in improving surgical techniques and patient outcomes. Future research should aim at conducting prospective, randomized controlled trials to reduce biases and focus on long-term outcomes and quality of life. In addition, exploring advanced surgical techniques and conducting comparative studies with traditional approaches would further enhance the understanding and management of anterior fossa meningiomas.
Authors’ contributions
LBP and LPM: Contributed to study conceptualization, methodology, data curation, and project administration; BVN, FH, MYF, and CA : Responsible for data curation and scientific investigation; PVZR, IVB, LBO, FCG, FVR and GLC :Responsible for writing the original draft and visualization; RB and JAL : Responsible for reviewing the manuscript and supervising the project; All authors read and approved the final version of this manuscript.
Ethical approval
The Institutional Review Board approval is not required.
Declaration of patient consent
Patient’s consent was not required as there are no patients in this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.
References
1. Abbassy M, Woodard TD, Sindwani R, Recinos PF. An overview of anterior skull base meningiomas and the endoscopic endonasal approach. Otolaryngol Clin North Am. 2016. 49: 141-52
2. Banu MA, Mehta A, Ottenhausen M, Fraser JF, Patel KS, Szentirmai O. Endoscope-assisted endonasal versus supraorbital keyhole resection of olfactory groove meningiomas: Comparison and combination of 2 minimally invasive approaches. J Neurosurg. 2016. 124: 605-20
3. Bander ED, Singh H, Ogilvie CB, Cusic RC, Pisapia DJ, Tsiouris AJ. Endoscopic endonasal versus transcranial approach to tuberculum sellae and planum sphenoidale meningiomas in a similar cohort of patients. J Neurosurg. 2018. 128: 40-8
4. Berker M, Hazer DB, Yücel T, Gürlek A, Cila A, Aldur MM. Complications of endoscopic surgery of the pituitary adenomas: Analysis of 570 patients and review of the literature. Pituitary. 2012. 15: 288-300
5. Bernat AL, Priola SM, Elsawy A, Farrash F, Pasarikovski CR, Almeida JP. Recurrence of anterior skull base meningiomas after endoscopic endonasal resection: 10 years’ experience in a series of 52 endoscopic and transcranial cases. World Neurosurg. 2018. 120: e107-13
6. Bohman LE, Stein SC, Newman JG, Palmer JN, Adappa ND, Khan A. Endoscopic versus open resection of tuberculum sellae meningiomas: A decision analysis. ORL J Otorhinolaryngol Relat Spec. 2012. 74: 255-63
7. Bowers CA, Altay T, Couldwell WT. Surgical decision-making strategies in tuberculum sellae meningioma resection. Neurosurg Focus. 2011. 30: E1
8. Brunworth J, Padhye V, Bassiouni A, Psaltis A, Floreani S, Robinson S. Update on endoscopic endonasal resection of skull base meningiomas. Int Forum Allergy Rhinol. 2015. 5: 344-52
9. Ceylan S, Anik I, Koc K, Cabuk B. Extended endoscopic transsphenoidal approach infrachiasmatic corridor. Neurosurg Rev. 2015. 38: 137-47
10. Chowdhury FH, Haque MR, Goel AH, Kawsar KA. Endoscopic endonasal extended transsphenoidal removal of tuberculum sellae meningioma (TSM): An experience of six cases. Br J Neurosurg. 2012. 26: 692-9
11. Cook SW, Smith Z, Kelly DF. Endonasal transsphenoidal removal of tuberculum sellae meningiomas: Technical note. Neurosurgery. 2004. 55: 239-44
12. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012. 14: v1-49
13. Fatemi N, Dusick JR, de Paiva Neto MA, Malkasian D, Kelly DF. Endonasal versus supraorbital keyhole removal of craniopharyngiomas and tuberculum sellae meningiomas. Neurosurgery. 2009. 64: 269-84
14. Feng Z, Li C, Cao L, Liu C, Qiao N, Wu W. Comparative analysis of outcomes following craniotomy and expanded endoscopic endonasal approach resection of tuberculum sellae meningiomas: A single-institution study. Front Neurol. 2023. 14: 1139968
15. Gadgil N, Thomas JG, Takashima M, Yoshor D. Endoscopic resection of tuberculum sellae meningiomas. J Neurol Surg B Skull Base. 2013. 74: 201-10
16. Galvez-Ruiz A, Monge KS. Catamenial visual loss associated with an anterior clinoid meningioma. Neuro Ophthalmol. 2023. 36: 253-6
17. Hayashi Y, Kita D, Fukui I, Sasagawa Y, Oishi M, Tachibana O. Preoperative evaluation of the interface between tuberculum sellae meningioma and the optic nerves on fast imaging with steady-state acquisition for extended endoscopic endonasal transsphenoidal surgery. World Neurosurg. 2017. 103: 153-60
18. Hayhurst C, Sughrue ME, Gore PA, Bonney PA, Burks JD, Teo C. Results with expanded endonasal resection of skull base meningiomas technical nuances and approach selection based on an early experience. Turk Neurosurg. 2016. 26: 662-70
19. Khan OH, Krischek B, Holliman D, Klironomos G, Kucharczyk W, Vescan A. Pure endoscopic expanded endonasal approach for olfactory groove and tuberculum sellae meningiomas. J Clin Neurosci. 2014. 21: 927-33
20. Koutourousiou M, Fernandez-Miranda JC, Stefko ST, Wang EW, Snyderman CH, Gardner PA. Endoscopic endonasal surgery for suprasellar meningiomas: Experience with 75 patients. J Neurosurg. 2014. 120: 1326-39
21. La Corte E, Younus I, Pivari F, Selimi A, Ottenhausen M, Forbes JA. BRAF V600E mutant papillary craniopharyngiomas: A single-institutional case series. Pituitary. 2018. 21: 571-83
22. Linsler S, Fischer G, Skliarenko V, Stadie A, Oertel J. Endoscopic assisted supraorbital keyhole approach or endoscopic endonasal approach in cases of tuberculum sellae meningioma: Which surgical route should be favored?. World Neurosurg. 2017. 104: 601-11
23. McDowell MM, Jacobs RC, Valappil B, Abou-Al-Shaar H, Zenonos GA, Wang EW. Dural sealants do not reduce postoperative cerebrospinal fluid leak after endoscopic endonasal skull base surgery. J Neurol Surg B Skull Base. 2022. 83: 589-93
24. Ogawa Y, Tominaga T. Extended transsphenoidal approach for tuberculum sellae meningioma--what are the optimum and critical indications?. Acta Neurochir (Wien). 2012. 154: 621-6
25. Ottenhausen M, Banu MA, Placantonakis DG, Tsiouris AJ, Khan OH, Anand VK. Endoscopic endonasal resection of suprasellar meningiomas: The importance of case selection and experience in determining extent of resection, visual improvement, and complications. World Neurosurg. 2014. 82: 442-9
26. Ottenhausen M, Rumalla K, Alalade AF, Nair P, La Corte E, Younus I. Decision-making algorithm for minimally invasive approaches to anterior skull base meningiomas. Neurosurg Focus. 2018. 44: E7
27. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016. 5: 210
28. Padhye V, Naidoo Y, Alexander H, Floreani S, Robinson S, Santoreneos S. Endoscopic endonasal resection of anterior skull base meningiomas. Otolaryngol Head Neck Surg. 2012. 147: 575-82
29. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021. 372: n71
30. Patrona A, Patel KS, Bander ED, Mehta A, Tsiouris AJ, Anand VK. Endoscopic endonasal surgery for nonadenomatous, nonmeningeal pathology involving the cavernous sinus. J Neurosurg. 2017. 126: 880-8
31. Qian K, Nie C, Zhu W, Zhao H, Zhang F, Wang H. Surgical management of tuberculum sellae meningioma: Transcranial approach or endoscopic endonasal approach?. Front Surg. 2022. 9: 979940
32. Song SW, Kim YH, Kim JW, Park CK, Kim JE, Kim DG. Outcomes after transcranial and endoscopic endonasal approach for tuberculum meningiomas-a retrospective comparison. World Neurosurg. 2018. 109: e434-45
33. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016. 355: i4919
34. Truong TT, Pham BT, Nguyen HV, Nguyen AM. Endoscopic endonasal surgery for resection of anterior skull base meningiomas: A single-center prospective study in Vietnam. Interdiscip Neurosurg. 2023. 31: 101671
35. Wardas P, Tymowski M, Piotrowska-Seweryn A, Markowski J, Ładziński P. Hadad-Bassagasteguy flap in skull base reconstruction-current reconstructive techniques and evaluation of criteria used for qualification for harvesting the flap. Wideochir Inne Tech Maloinwazyjne. 2019. 14: 340-7
36. Yu Peng, Xu T, Wu X, Liu Z, Wang Y, Wang Y. The expanded endoscopic endonasal approach for treatment of tuberculum sellae meningiomas in a series of 40 consecutive cases. Sci Rep. 2021. 11: 4993