Predictors of salvage therapy for parasagittal meningiomas treated with primary surgery, radiosurgery, or surgery plus adjuvant radiotherapy.

OBJECTIVE: Parasagittal meningiomas (PM) are treated with primary microsurgery, radiosurgery (SRS), or surgery with adjuvant radiation. We investigated predictors of tumor progression requiring salvage surgery or radiation treatment. We sought to determine whether primary treatment modality, or radiologic, histologic, and clinical variables were associated with tumor progression requiring salvage treatment. METHODS: Retrospective study of 109 consecutive patients with PMs treated with primary surgery, radiation (RT), or surgery plus adjuvant RT (2000-2017) and minimum 5 years follow-up. Patient, radiologic, histologic, and treatment data were analyzed using standard statistical methods. RESULTS: Median follow up was 8.5 years. Primary treatment for PM was surgery in 76 patients, radiation in 16 patients, and surgery plus adjuvant radiation in 17 patients. Forty percent of parasagittal meningiomas in our cohort required some form of salvage treatment. On univariate analysis, brain invasion (OR: 6.93, p < 0.01), WHO grade 2/3 (OR: 4.54, p < 0.01), peritumoral edema (OR: 2.81, p = 0.01), sagittal sinus invasion (OR: 6.36, p < 0.01), sagittal sinus occlusion (OR: 4.86, p < 0.01), and non-spherical shape (OR: 3.89, p < 0.01) were significantly associated with receiving salvage treatment. On multivariate analysis, superior sagittal sinus invasion (OR: 8.22, p = 0.01) and WHO grade 2&3 (OR: 7.58, p < 0.01) were independently associated with receiving salvage treatment. There was no difference in time to salvage therapy (p = 0.11) or time to progression (p = 0.43) between patients receiving primary surgery alone, RT alone, or surgery plus adjuvant RT. Patients who had initial surgery were more likely to have peritumoral edema on preoperative imaging (p = 0.01). Median tumor volume was 19.0 cm3 in patients receiving primary surgery, 5.3 cm3 for RT, and 24.4 cm3 for surgery plus adjuvant RT (p < 0.01). CONCLUSION: Superior sagittal sinus invasion and WHO grade 2/3 are independently associated with PM progression requiring salvage therapy regardless of extent of resection or primary treatment modality. Parasagittal meningiomas have a high rate of recurrence with 80.0% of patients with WHO grade 2/3 tumors with sinus invasion requiring salvage treatment whereas only 13.6% of the WHO grade 1 tumors without sinus invasion required salvage treatment. This information is useful when counseling patients about disease management and setting expectations.

Building Team Medicine in the Management of CNS Metastases.

CNS metastases are often terminal for cancer patients and occur at an approximately 10-fold higher rate than primary CNS tumors. The incidence of these tumors is approximately 70,000-400,000 cases annually in the US. Advances that have occurred over the past two decades have led to more personalized treatment approaches. Newer surgical and radiation techniques, as well as targeted and immune therapies, have enanled patient to live longer, thus increasing the risk for the development of CNS, brain, and leptomeningeal metastases (BM and LM). Patients who develop CNS metastases have often been heavily treated, and options for future treatment could best be addressed by multidisciplinary teams. Studies have indicated that patients with brain metastases have improved survival outcomes when cared for in high-volume academic institutions using multidisciplinary teams. This manuscript discusses a multidisciplinary approach for both parenchymal brain metastases as well as leptomeningeal metastases implemented in three academic institutions. Additionally, with the increasing development of healthcare systems, we discuss optimizing the management of CNS metastases across healthcare systems and integrating basic and translational science into our clinical care to further improve outcomes. This paper summarizes the existing therapeutic approaches to the treatment of BM and LM and discusses novel and emerging approaches to optimizing access to neuro-oncologic care while simultaneously integrating multidisciplinary teams in the care of patients with BM and LM.

Secondary CNS myeloma with remission after systemic CNS-penetrating agents.

Background: CNS myeloma is a rare manifestation of multiple myeloma and is often associated with a dismal prognosis; however, cases are increasing in frequency as overall survival improves for MM. There is currently no standardized treatment for CNS myeloma; however, different chemotherapy and radiotherapy regimens have been described. Methods: We had previously reported on the efficacy of proton-based craniospinal irradiation in a patient with CNS myeloma; here we present a patient with a history of extramedullary plasmacytoma, 10 years in remission status post standard systemic chemotherapy, with biopsy-proven CNS myeloma successfully treated with systemic chemotherapy as a first-line treatment. Results: The patient achieved clinical and radiographic remission on 2 separate occasions with systemic chemotherapy alone. Conclusions: This case demonstrates that systemically administered agents may have activity in CNS myeloma. Further investigations are necessary to establish the optimal combination of agents and treatment schedules.

Practice patterns in the management of recurrent and residual non-functioning pituitary adenomas: Results from a Canada-wide survey.

BACKGROUND: There is no consensus regarding the management and postoperative follow-up of non-functioning pituitary adenomas (NFAs) in the setting of recurrent or residual disease. Subsequent treatment options include continued follow-up, re-resection or radiotherapy. To address this gap and better understand current practice patterns, we surveyed neurosurgeons and radiation oncologists in Canada. METHODS: Neurosurgeons and radiation oncologists (ROs) across Canada were invited to complete a standardized online questionnaire. Summary statistics were computed, and Fisher's Exact tests were performed to assess significance. Qualitative analyses were performed through open and axial coding. RESULTS: Thirty-three participants completed the questionnaires, with neurosurgeons representing a majority of respondents (n = 20 vs n = 13). When treating giant (>3 cm) tumors, 90.9% of neurosurgeons in practice for less than 10 years reported using an endoscopic approach, as compared to only 66.7% of neurosurgeons in practice for 10 years of more. Additionally, neurosurgeons who were newer to practice had a greater tendency to advocate for stereotactic radiosurgery (SRS) or re-resection (54.5% and 36.4%, respectively), as compared to older surgeons who showed a higher propensity (22.2%) to advocate for observation. The presence of cavernous sinus extension appeared to encourage ROs to offer radiotherapy sooner (61.4%), as compared to 40% of neurosurgeons. CONCLUSIONS: Our results identified both variations and commonalities in practice amongst Canadian neurosurgeons. Approaches deviated in the setting of residual tumor based on years of practice. This work provides a critical foundation for future studies aiming to define evidence-based best practices in the management of NFAs.

Unilateral Lumbar Facet Dislocation: Case Report and Review of the Literature.

BACKGROUND: Facet dislocations of the lumbar spine, particularly without neurologic injury, are rare occurrences after major trauma. Although there are documented cases of lumbosacral dislocation in the published literature, strictly lumbar unilateral facet dislocation is rare. CASE DESCRIPTION: We report a case of a unilateral facet dislocation at L4-L5 after a single vehicle motorcycle accident. This injury was treated with posterior open reduction and instrumented stabilization with good results. CONCLUSIONS: Given the rarity of this injury pattern, the management of this type of injury is not established. Careful imaging to make the diagnosis is crucial, and we recommend a surgical treatment in the form of an open reduction and instrumented stabilization. In our case, we achieved good outcomes with a posterior approach.

Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution?

An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.

"The Actualized Neurosurgeon": A Proposed Model of Surgical Resident Development.

BACKGROUND: Modern neurosurgical training is both physically and emotionally demanding, posing significant challenges, new and old, to residents as well as programs attempting to train safe, competent surgeons. Models to describe resident development, such as the Accreditation Council for Graduate Medical Education competencies and milestones, address the acquisition of specific skills but largely ignore the stresses and pressures unique to each stage of resident training. METHODS: We propose an alternative model of resident development adapted from the developmental psychology literature. RESULTS: Our model identifies the challenges that must be met at each stage of junior, intermediate, and senior and chief residency, leading ultimately to an "actualized" neurosurgeon (i.e., one who has maximized his or her potential). Failure to overcome any 1 of these challenges can lead to specific long-lasting consequences, including regret, identity crisis, incompetence, and bitterness. In contrast, the actualized surgeon is one who has successfully acquired the virtues of hope, will, purpose, fidelity, productivity, leadership, competence, and wisdom. The actualized surgeon not only functions safely, confidently, and professionally, but also successfully navigates the challenges of residency and emerges from them having fulfilled his or her maximal potential. CONCLUSIONS: This developmental perspective provides an individualized description of healthy surgical development. Our model allows programs to identify the basis for residents who fail to progress, counsel residents during their training, and perhaps help identify resident candidates who are better prepared to meet the developmental challenges of residency training.

The genomic landscape of schwannoma.

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Surgically resected skull base meningiomas demonstrate a divergent postoperative recurrence pattern compared with non-skull base meningiomas.

OBJECTIVE The objective of this study was to identify the natural history and clinical predictors of postoperative recurrence of skull base and non-skull base meningiomas. METHODS The authors performed a retrospective hospital-based study of all patients with meningioma referred to their institution from September 1993 to January 2014. The cohort constituted both patients with a first-time presentation and those with evidence of recurrence. Kaplan-Meier curves were constructed for analysis of recurrence and differences were assessed using the log-rank test. Cox proportional hazard regression was used to identify potential predictors of recurrence. RESULTS Overall, 398 intracranial meningiomas were reviewed, including 269 (68%) non-skull base and 129 (32%) skull base meningiomas (median follow-up 30.2 months, interquartile range [IQR] 8.5-76 months). The 10-year recurrence-free survival rates for patients with gross-total resection (GTR) and subtotal resection (STR) were 90% and 43%, respectively. Skull base tumors were associated with a lower proliferation index (0.041 vs 0.062, p = 0.001), higher likelihood of WHO Grade I (85.3% vs 69.1%, p = 0.003), and younger patient age (55.2 vs 58.3 years, p = 0.01). Meningiomas in all locations demonstrated an average recurrence rate of 30% at 100 months of follow-up. Subsequently, the recurrence of skull base meningiomas plateaued whereas non-skull base lesions had an 80% recurrence rate at 230 months follow-up (p = 0.02). On univariate analysis, a prior history of recurrence (p < 0.001), initial WHO grade following resection (p < 0.001), and the inability to obtain GTR (p < 0.001) were predictors of future recurrence. On multivariate analysis a prior history of recurrence (p = 0.02) and an STR (p < 0.01) were independent predictors of a recurrence. Assessing only patients with primary presentations, STR and WHO Grades II and III were independent predictors of recurrence (p < 0.001 for both). CONCLUSIONS Patients with skull base meningiomas present at a younger age and have less aggressive lesions overall. Extent of resection is a key predictor of recurrence and long-term follow-up of meningiomas is necessary, especially for non-skull base tumors. In skull base meningiomas, recurrence risk plateaus approximately 100 months after surgery, suggesting that for this specific cohort, follow-up after 100 months can be less frequent.

Draf III Extension in the Endoscopic Endonasal Transethmoidal, Transcribriform Approach Through the Back Wall of the Frontal Sinus: A Cadaveric Study.

BACKGROUND: The Draf III (modified endoscopic Lothrop) procedure has been proposed to extend the endonasal transethmoidal, transfovea ethmoidalis, and transcribriform approach through the back wall of the frontal sinus. The exposure is time-consuming and increases the risk of cerebrospinal fluid leak, and the indications for use are not well described. There are few data quantifying the advantage it conveys over the approach without the Draf III procedure. METHODS: An endoscopic, endonasal transfovea, transcribriform approach was performed in 5 fresh, injected cadaveric heads. Anatomic boundaries and measurements of the exposure were compared before and after addition of a Draf III procedure. Computed tomography scans were performed before and after dissection, and additional radiographic measurements were made to quantify the additional exposure provided by the Draf III procedure. Also, 2 clinical cases are presented in which a Draf III procedure was used. RESULTS: The mean anterior to posterior boundary from the frontal sinus to the planum sphenoidale before the Draf III procedure was 3.0 cm and after the Draf III procedure was 3.8 cm with an average change of 0.8 cm. After the Draf III procedure, the mean anterior to posterior boundary from the posterior wall of frontal sinus to the planum sphenoidale increased from 3.0 cm to 4.3 cm. There was an average increase of 1.3 cm with an average increased area of view of 1.79 cm(2). CONCLUSIONS: This study quantifies the increased field of view provided by the Draf III procedure during anterior skull base dissection. Recommendations for preoperative examination of radiographic evidence are provided to help identify which individuals would benefit from the additional exposure.

Neurosurgical management of adult diffuse low grade gliomas in Canada: a multi-center survey.

Adult diffuse low-grade gliomas are slow growing, World Health Organization grade II lesions with insidious onset and ultimate anaplastic transformation. The timing of surgery remains controversial with polarized practices continuing to govern patient management. As a result, the management of these patients is variable. The goal of this questionnaire was to evaluate practice patterns in Canada. An online invitation for a questionnaire including diagnostic, preoperative, perioperative, and postoperative parameters and three cases with magnetic resonance imaging data with questions to various treatment options in these patients was sent to practicing neurosurgeons and trainees. Survey was sent to 356 email addresses with 87 (24.7%) responses collected. The range of years of practice was less than 10 years 36% (n = 23), 11-20 years 28% (n = 18), over 21 years 37% (n = 24). Twenty-two neurosurgery students of various years of training completed the survey. 94% (n = 47) of surgeons and trainees (n = 20) believe that we do not know the "right treatment". 90% of surgeons do not obtain formal preoperative neurocognitive assessments. 21% (n = 13) of surgeons and 23% of trainees (n = 5) perform a biopsy upon first presentation. A gross total resection was believed to increase progression free survival (surgeons: 75%, n = 46; trainees: 95%, n = 21) and to increase overall survival (surgeons: 64%, n = 39, trainees: 68%, n = 15). Intraoperative MRI was only used by 8% of surgeons. Awake craniotomy was the procedure of choice for eloquent tumors by 80% (n = 48) of surgeons and 100% of trainees. Of those surgeons who perform awake craniotomy 93% perform cortical stimulation and 38% performed subcortical stimulation. Using the aid of three hypothetical cases with progressive complexities in tumor eloquence there was a trend for younger surgeons to operate earlier, and use awake craniotomy to obtain greater extent of resection with the aid of cortical stimulation when compared to senior surgeons who still more often preferred a "wait-and-see" approach. Despite the limitations of an online survey study, it has offered insights into the variability in surgeon practice patterns in Canada and the need for a consensus on the workup and surgical management of this disease.

Serum lactate as a potential biomarker of non-glial brain tumors.

We assess whether serum lactate is a potential biomarker for non-glial cell brain tumors. Rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin and produce lactate even in the presence of oxygen. This phenomenon is called the Warburg effect. We recently showed that serum lactate levels can be used as a potential non-invasive biomarker in glial cell brain tumors, which correlates with both tumor grade and the extent of malignancy. In the present study, we found that patients with metastatic brain tumors had significantly higher baseline serum lactate levels compared to patients with meningioma and pituitary tumors. There was a statistically significant association between metastatic brain tumors and elevated serum lactate. We demonstrate that lactate can be used as a non-invasive biomarker to determine malignancy for brain tumors. Further analyses of larger populations will be needed to establish the value of serum lactate in determining the response to therapy or early recurrence.

Serum lactate as a potential biomarker of malignancy in primary adult brain tumours.

Lactate, a by-product of glycolysis, is an indicator of poor tissue perfusion and is a useful biomarker with prognostic value in risk-stratifying patients in several diseases. Furthermore, elevated lactate production is observed in tumour glycolysis, also known as the Warburg effect, and is essential in promoting tumour cell invasion, metastasis, and immune system evasion, promoting resistance to cell death. However, there are no studies of elevated serum lactate in brain tumour patients as a potential biomarker, to our knowledge. The aim of this study is to determine possible correlations between the malignancy of tumours and pre- and intraoperative serum lactate elevation in patients undergoing craniotomy for tumour resection. We provide initial evidence that a rise in serum lactate can be used as a non-invasive biomarker that correlates with brain tumour grade. The results from this study and future prospective studies may allow for determination of tumour progression and response to therapy using serum lactate as a biomarker.

Endoscopic endonasal resection of skull base meningiomas: the significance of a "cortical cuff" and brain edema compared with careful case selection and surgical experience in predicting morbidity and extent of resection.

OBJECT: This paper describes a consecutive series of skull base meningiomas resected using an endoscopic endonasal approach through various corridors at a single institution over 7 years. The impact of case selection and experience, the presence of a cortical cuff between the tumor and surrounding vessels, and brain edema on morbidity and rates of gross-total resection (GTR) were examined. METHODS: A retrospective review of a series of 46 skull base meningiomas from a prospective database was conducted. The series of cases were divided by location: olfactory groove (n = 15), tuberculum and planum (n = 20), sellar/cavernous (n = 9) and petroclival (n = 2). Gross-total resection was never intended in the sellar/cavernous tumors, which generally invaded the cavernous sinus. Clinical charts, volumetric imaging, and pathology were reviewed to assess the extent of resection and complications. Cases were divided based on a time point in which surgical technique and case selection improved into Group 1 (surgery prior to June 2008; n = 21) and Group 2 (surgery after June 2008; n = 25) and into those with and without a cortical cuff and with and without brain edema. RESULTS: Improved case selection had the greatest impact on extent of resection. For the entire cohort, rates of GTR went from 38% to 76% (p = 0.02), and for cases in which GTR was the intent, the rates went from 63% to 84% (not significant), which was mostly driven by the planum and tuberculum meningiomas, which went from 75% to 91.7 % (nonsignificant difference). The presence of a cortical cuff and brain edema had no impact on outcomes. There were 3 CSF leaks (6.5%) but all were in Group 1. Hence, CSF leak improved from 14.2% to 0% with surgical experience. Lessons learned for optimal case selection are discussed. CONCLUSIONS: Surgical outcome for endonasal endoscopic resection of skull base meningiomas depends mostly on careful case selection and surgical experience. Imaging criteria such as the presence of a cortical cuff or brain edema are less important.

Pediatric awake craniotomy and intra-operative stimulation mapping.

The indications for operating on lesions in or near areas of cortical eloquence balance the benefit of resection with the risk of permanent neurological deficit. In adults, awake craniotomy has become a versatile tool in tumor, epilepsy and functional neurosurgery, permitting intra-operative stimulation mapping particularly for language, sensory and motor cortical pathways. This allows for maximal tumor resection with considerable reduction in the risk of post-operative speech and motor deficits. We report our experience of awake craniotomy and cortical stimulation for epilepsy and supratentorial tumors located in and around eloquent areas in a pediatric population (n=10, five females). The presenting symptom was mainly seizures and all children had normal neurological examinations. Neuroimaging showed lesions in the left opercular (n=4) and precentral or peri-sylvian regions (n=6). Three right-sided and seven left-sided awake craniotomies were performed. Two patients had a history of prior craniotomy. All patients had intra-operative mapping for either speech or motor or both using cortical stimulation. The surgical goal for tumor patients was gross total resection, while for all epilepsy procedures, focal cortical resections were completed without any difficulty. None of the patients had permanent post-operative neurologic deficits. The patient with an epileptic focus over the speech area in the left frontal lobe had a mild word finding difficulty post-operatively but this improved progressively. Follow-up ranged from 6 to 27 months. Pediatric awake craniotomy with intra-operative mapping is a precise, safe and reliable method allowing for resection of lesions in eloquent areas. Further validations on larger number of patients will be needed to verify the utility of this technique in the pediatric population.