Cranial base reconstruction
Fredric B. Meyer
Jennifer A. Moliterno, Lynn L. Mubita, Clark Huang, and John A. Boockvar
Endoscopic endonasal transsphenoidal surgery (ETSS) is an effective, minimally invasive approach for the resection of anterior skull base tumors. Cerebrospinal leakage is a common complication, and repair of the anterior skull base defect with alloplastic materials has been used to minimize the risk of postoperative CSF rhinorrhea and meningitis. Injectable cements, such as low-viscosity polymethylmethacrylate (PMMA), are useful for cranial base reconstruction because they are easy to shape to the contour of the defect. These low-viscosity materials, however, are more susceptible to leakage into the nasal cavity prohibiting their use and are prone to cracking upon hardening. Cement extravasation not only obstructs the operator's view during placement, but it is also associated with significant local and systemic complications. High-viscosity (HV) PMMA–based cement and its specialized delivery system have recently been shown to be safe and effective in human applications. Moreover, its constant high viscosity significantly reduces cement leakage and its associated complications. The authors hypothesized that this type of cement would therefore be ideal for ETSS to repair anterior skull base defects. The authors report their experience using HV-PMMA to reconstruct the anterior skull base in 12 patients following ETSS. The unique puttylike consistency of this material is easy to work, malleable, does not leak into the nasal cavity, does not aspirate into suction tubing, and hardens without cracks in less than 10 minutes. None of the 12 patients suffered postoperative CSF leaks or infections more than 8 months, on average, after surgery. Although not necessary in all cases of ETSS, the authors conclude that HV-PMMA, if needed, may be an excellent choice for reconstructing the anterior skull base after ETSS. Further studies are needed to better assess the long-term outcomes of HV-PMMA cement and its use in repairing skull base defects after extended ETSS.
Jennifer Moliterno, William P. Cope, Emma D. Vartanian, Anne S. Reiner, Roselyn Kellen, Shahiba Q. Ogilvie, Jason T. Huse, and Philip H. Gutin
While most meningiomas are benign, 1%–3% display anaplastic features, with little current understanding regarding the molecular mechanisms underlying their formation. In a large single-center cohort, the authors tested the hypothesis that two distinct subtypes of anaplastic meningiomas, those that arise de novo and those that progress from lower grade tumors, exist and exhibit different clinical behavior.
Pathology reports and clinical data of 37 patients treated between 1999 and 2012 for anaplastic meningioma at Memorial Sloan–Kettering Cancer Center (MSKCC) were retrospectively reviewed. Patients were divided into those whose tumors arose de novo and those whose tumors progressed from previously documented benign or atypical meningiomas.
Overall, the median age at diagnosis was 59 years and 57% of patients were female. Most patients (38%) underwent 2 craniotomies (range 1–5 surgeries) aimed at gross-total resection (GTR; 59%), which afforded better survival when compared with subtotal resection according to Kaplan-Meier estimates (median overall survival [OS] 3.2 vs 1.3 years, respectively; p = 0.04, log-rank test). Twenty-three patients (62%) presented with apparently de novo anaplastic meningiomas. Compared with patients whose tumors had progressed from a lower grade, those patients with de novo tumors were significantly more likely to be female (70% vs 36%, respectively; p = 0.04), experience better survival (median OS 3.0 vs 2.4 years, respectively; p = 0.03, log-rank test), and harbor cerebral hemispheric as opposed to skull base tumors (91% vs 43%, respectively; p = 0.002).
Based on this single-center experience at MSKCC, anaplastic meningiomas, similar to glial tumors, can arise de novo or progress from lower grade tumors. These tumor groups appear to have distinct clinical behavior. De novo tumors may well be molecularly distinct, which is under further investigation. Aggressive GTR appears to confer an OS advantage in patients with anaplastic meningioma, and this is likely independent of tumor progression status. Similarly, those patients with de novo tumors experience a survival advantage likely independent of extent of resection.
Jennifer A. Moliterno, Michael L. DiLuna, Shreya Sood, Kurt E. Roberts, and Charles C. Duncan
✓ Gastric bypass surgery has become a safe and acceptable surgical weight loss treatment for individuals who suffer from morbid obesity. Patients who undergo this procedure are subject to vitamin deficiencies due to an iatrogenic malabsorptive state. Folate, a vitamin known for its role in the prevention of neural tube defects (NTDs), can be part of the deficiency spectrum resulting from this procedure. The authors describe the case of a woman who was nonadherent to multivitamin treatment after undergoing gastric bypass surgery. Her lack of understanding and appreciation of the relationship between gastric bypass surgery, folate deficiency, and NTDs may have contributed to her noncompliance with daily multivitamin consumption. As a result, her potential problems with folate absorption could have contributed to her subsequently giving birth to a child with a myelomeningocele. Thus, patient awareness and counseling along with aggressive vitamin supplementation among this particular population may help prevent the occurrence of NTDs after gastric bypass surgery.
Stephen A. Sands, Jessica S. Milner, Judith Goldberg, Vandana Mukhi, Jennifer A. Moliterno, Carol Maxfield, and Jeffrey H. Wisoff
The authors set out to evaluate the quality of life (QOL), social—emotional functioning, and behavioral functioning of children treated surgically for craniopharyngiomas.
Twelve girls and 17 boys with a mean age at diagnosis of 8 ± 3.8 years were surgically treated between 1985 and 1998 at the New York University Medical Center. After a mean follow-up period of 6.8 ± 3.5 years, these 29 patients were administered either the 36-item Short Form Health Survey version 2 or the Child Health Questionnaire—Parent Form to assess QOL, as well as the Achenbach Child Behavior Checklist or Young Adult Checklist to measure social—emotional and behavioral functioning. Patients older than 19 years of age and parents of patients younger than 19 years of age reported low average overall physical QOL, with overall psychosocial QOL in the average range. Behavioral difficulties were noted, including internalizing, attention, somatic, and social difficulties. Further analyses indicated that retrochiasmatic tumor location, recurrence, and additional surgery were associated with poorer outcomes. In contrast, hydrocephalus, tumor size, and sex were not prognostic variables, and patients significantly improved as postoperative time increased.
Attention toward late effects arising after the treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning, is warranted. Future approaches to treatment should consider the documented effects of either gross-total resection or limited surgery followed by cranial irradiation on QOL, with specific evaluation for those with retrochiasmatic tumors, a recurrent tumor, or the need for additional surgery. Psychosocial QOL and social—emotional functioning should be maintained through ongoing counseling and education.
Brian M. Shear, Lan Jin, Yawei Zhang, Wyatt B. David, Elena I. Fomchenko, E. Zeynep Erson-Omay, Anita Huttner, Robert K. Fulbright, and Jennifer Moliterno
Intracranial epidermoid tumors are slow-growing, histologically benign tumors of epithelial cellular origin that can be symptomatic because of their size and mass effect. Neurosurgical resection, while the treatment of choice, can be quite challenging due to locations where these lesions commonly occur and their association with critical neurovascular structures. As such, subtotal resection (STR) rather than gross-total resection (GTR) can often be performed, rendering residual and recurrent tumor potentially problematic. The authors present a case of a 28-year-old man who underwent STR followed by aggressive repeat resection for regrowth, and they report the results of the largest meta-analysis to date of epidermoid tumors to compare recurrence rates for STR and GTR.
The authors conducted a systemic review of PubMed, Web of Science, and the Cochrane Collaboration following the PRISMA guidelines. They then conducted a proportional meta-analysis to compare the pooled recurrence rates between STR and GTR in the included studies. The authors developed fixed- and mixed-effect models to estimate the pooled proportions of recurrence among patients undergoing STR or GTR. They also investigated the relationship between recurrence rate and follow-up time in the previous studies using linear regression and natural cubic spline models.
Overall, 27 studies with 691 patients met the inclusion criteria; of these, 293 (42%) underwent STR and 398 (58%) received GTR. The average recurrence rate for all procedures was 11%. The proportional meta-analysis showed that the pooled recurrence rate after STR (21%) was 7 times greater than the rate after GTR (3%). The average recurrence rate for studies with longer follow-up durations (≥ 4.4 years) (17.4%) was significantly higher than the average recurrence rate for studies with shorter follow-up durations (< 4.4 years) (5.7%). The cutoff point of 4.4 years was selected based on the significant relationship between the recurrence rate of both STR and GTR and follow-up durations in the included studies (p = 0.008).
STR is associated with a significantly higher rate of epidermoid tumor recurrence compared to GTR. Attempts at GTR should be made during the initial surgery with efforts to optimize success. Surgical expertise, as well as the use of adjuncts, such as intraoperative MRI and neuromonitoring, may increase the likelihood of completing a safe GTR and decreasing the long-term risk of recurrence. The most common surgical complications were transient cranial nerve palsies, occurring equally in STR and GTR cases when reported. In all postoperative epidermoid tumor cases, but particularly following STR, close follow-up with serial MRI, even years after surgery, is recommended.
Andy J. Redmond, Michael L. DiLuna, Ryan Hebert, Jennifer A. Moliterno, Rani Desai, Jonathan P. S. Knisely, and Veronica L. Chiang
Gamma Knife surgery (GKS) improves overall survival in patients with malignant melanoma metastatic to the brain. In this study the authors investigated which patient- or treatment-specific factors influence survival of patients with melanoma brain metastases; they pay particular interest to pre- and post-GKS hemorrhage.
Demographic, treatment, and survival data on 59 patients with a total of 208 intracranial metastases who underwent GKS between 1998 and 2007 were abstracted from treatment records and from the Connecticut Tumor Registry. Multivariate analysis was used to identify factors that independently affected survival.
Survival was significantly better in patients with solitary metastasis (p = 0.04), lesions without evidence of pre-GKS hemorrhage (p = 0.004), and in patients with total tumor volume treated < 4 cm3 (p = 0.02). Intratumoral bleeding occurred in 23.7% of patients pre-GKS. Intratumoral bleeding occurred at a mean of 1.8 months post-GKS at a rate of 15.2%. Unlike the marked effect of pretreatment bleeding, posttreatment bleeding did not independently affect survival. Sex, systemic control, race, metastases location, whole-brain radiation therapy, chemotherapy, history of antithrombotic medications, and cranial surgery had no independent association with survival.
These data corroborate previous findings that tumor burden (either as increased number or total volume of lesions) at the time of GKS is associated with diminished patient survival in those with intracerebral melanoma metastases. Patients who were noted to have hemorrhagic melanoma metastases prior to GKS appear to have a worse prognosis following GKS compared with patients with nonhemorrhagic metastases, despite similar rates of bleeding pre- and post-GKS treatment. Gamma Knife surgery itself does not appear to increase the rate of hemorrhage.
Jennifer A. Moliterno, Jared Knopman, Karishma Parikh, Jessica N. Cohan, Q. Daisy Huang, Grant D. Aaker, Anastasia D. Grivoyannis, Ashwin R. Patel, Roger Härtl, and John A. Boockvar
The use of minimally invasive surgical techniques, including microscope-assisted tubular lumbar microdiscectomy (tLMD), has gained increasing popularity in treating lumbar disc herniations (LDHs). This particular procedure has been shown to be both cost-efficient and effective, resulting in outcomes comparable to those of open surgical procedures. Lumbar disc herniation recurrence necessitating reoperation, however, remains an issue following spinal surgery, with an overall reported incidence of approximately 3–13%. The authors' aim in the present study was to report their experience using tLMD for single-level LDH, hoping to provide further insight into the rate of surgical recurrence and to identify potential risk factors leading to this complication.
The authors retrospectively reviewed the cases of 217 patients who underwent tLMD for single-level LDH performed identically by 2 surgeons (J.B., R.H.) between 2004 and 2008. Evaluation for LDH recurrence included detailed medical chart review and telephone interview. Recurrent LDH was defined as the return of preoperative signs and symptoms after an interval of postoperative resolution, in conjunction with radiographic demonstration of ipsilateral disc herniation at the same level and pathological confirmation of disc material. A cohort of patients without recurrence was used for comparison to identify possible risk factors for recurrent LDH.
Of the 147 patients for whom the authors were able to definitively assess symptomatic recurrence status, 14 patients (9.5%) experienced LDH recurrence following single-level tLMD. The most common level involved was L5–S1 (42.9%) and the mean length of time to recurrence was 12 weeks (range 1.5–52 weeks). Sixty-four percent of the patients were male. In a comparison with patients without recurrence, the authors found that relatively lower body mass index was significantly associated with recurrence (p = 0.005), such that LDH in nonobese patients was more likely to recur.
Recurrence rates following tLMD for LDH compare favorably with those in patients who have undergone open discectomy, lending further support for its effectiveness in treating single-level LDH. Nonobese patients with a relatively lower body mass index, in particular, appear to be at greater risk for recurrence.
Trisha P. Gupte, Chang Li, Lan Jin, Kanat Yalcin, Mark W. Youngblood, Danielle F. Miyagishima, Ketu Mishra-Gorur, Amy Y. Zhao, Joseph Antonios, Anita Huttner, Declan McGuone, Nicholas A. Blondin, Joseph N. Contessa, Yawei Zhang, Robert K. Fulbright, Murat Gunel, Zeynep Erson-Omay, and Jennifer Moliterno
The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients.
Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures.
Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30–5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46–6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03–3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37–9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08–7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09–7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis.
Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.
Mark W. Youngblood, Daniel Duran, Julio D. Montejo, Chang Li, Sacit Bulent Omay, Koray Özduman, Amar H. Sheth, Amy Y. Zhao, Evgeniya Tyrtova, Danielle F. Miyagishima, Elena I. Fomchenko, Christopher S. Hong, Victoria E. Clark, Maximilien Riche, Matthieu Peyre, Julien Boetto, Sadaf Sohrabi, Sarah Koljaka, Jacob F. Baranoski, James Knight, Hongda Zhu, M. Necmettin Pamir, Timuçin Avşar, Türker Kilic, Johannes Schramm, Marco Timmer, Roland Goldbrunner, Ye Gong, Yaşar Bayri, Nduka Amankulor, Ronald L. Hamilton, Kaya Bilguvar, Irina Tikhonova, Patrick R. Tomak, Anita Huttner, Matthias Simon, Boris Krischek, Michel Kalamarides, E. Zeynep Erson-Omay, Jennifer Moliterno, and Murat Günel
Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.
Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher’s exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.
Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among “mutation unknown” samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor’s underlying driver mutation.
Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.