Faculty Bibliography

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

OBJECTIVE Approximately 75%-92% of patients with trigeminal neuralgia (TN) achieve pain relief after Gamma Knife surgery (GKS), although a proportion of these patients will experience recurrence of their pain. To evaluate the reasons for durability or recurrence, this study determined the impact of trigeminal nerve length and volume, the nerve dose-volume relationship, and the presence of neurovascular compression (NVC) on pain outcomes after GKS for TN. METHODS Fifty-eight patients with 60 symptomatic nerves underwent GKS for TN between 2013 and 2015, including 15 symptomatic nerves secondary to multiple sclerosis (MS). High-resolution MRI was acquired the day of GKS. The median maximum dose was 80 Gy for initial GKS and 65 Gy for repeat GKS. NVC, length and volume of the trigeminal nerve within the subarachnoid space of the posterior fossa, and the ratio of dose to nerve volume were assessed as predictors of recurrence. RESULTS Follow-up was available on 55 patients. Forty-nine patients (89.1%) reported pain relief (Barrow Neurological Institute [BNI] Grades I-IIIb) after GKS at a median duration of 1.9 months. The probability of maintaining pain relief (BNI Grades I-IIIb) without requiring resumption or an increase in medication was 93% at 1 year and 84% at 2 years for patients without MS, and 68% at 1 year and 51% at 2 years for all patients. The nerve length, nerve volume, target distance from the brainstem, and presence of NVC were not predictive of pain recurrence. Patients with a smaller volume of nerve (< 35% of the total nerve volume) that received a high dose (>/= 80% isodose) were less likely to experience recurrence of their TN pain after 1 year (mean time to recurrence: < 35%, 32.2 +/- 4.0 months; > 35%, 17.9 +/- 2.8 months, log-rank test, chi2 = 4.3, p = 0.039). CONCLUSIONS The ratio of dose to nerve volume may predict recurrence of TN pain after GKS. Prospective studies are needed to determine the optimal dose to nerve volume ratio and whether this will result in longer pain-free outcomes.

OBJECTIVE The incidence of brain metastases is increasing with improved systemic therapies, many of which have a limited impact on intracranial disease. Stereotactic radiosurgery (SRS) is a first-line management option for brain metastases. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100%, and to relate these findings to the use of routine surveillance brain imaging. METHODS From a prospective registry, 200 patients with 1237 brain metastases were identified who underwent SRS between December 2012 and May 2015. The median imaging follow-up duration was 7.9 months, and the median margin dose was 18 Gy. The maximal diameter and volume of tumors were measured. Histological analysis included 96 patients with non-small cell lung cancers (NSCLCs), 40 with melanoma, 35 with breast cancer, and 29 with other histologies. RESULTS Almost 50% of brain metastases were NSCLCs and commonly measured less than 6 mm in maximal diameter or 70 mm3 in volume. Thirty-three of 1237 tumors had local progression at a median of 8.8 months. The 1- and 2-year actuarial LC rates were 97% and 93%, respectively. LC of 100% was achieved for all intracranial metastases less than 100 mm3 in volume or 6 mm in diameter. Patients whose tumors at first SRS were less than 10 mm maximal diameter or a volume of 250 mm3 had improved overall survival. CONCLUSIONS SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier initial detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms and the need for resection, and improve overall survival. To identify tumors when they are small, routine surveillance brain imaging should be considered as part of the standard of care for lung, breast, and melanoma metastases. CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort; evidence: Class II.

Leptomeningeal disease (LMD) is well described in patients with brain metastases, presenting symptomatically in approximately 5% of patients. Conventionally, the presence of LMD is an indication for whole brain radiation therapy (WBRT) and not suitable for stereotactic radiosurgery (SRS). The purpose of the study was to evaluate the local control and overall survival of patients who underwent SRS to focal LMD. We reviewed our prospective registry and identified 32 brain metastases patients with LMD, from a total of 465 patients who underwent SRS between 2013 and 2015. Focal LMD was targeted with SRS in 16 patients. The median imaging follow-up time was 7 months. The median volume of LMD was 372 mm3 and the median margin dose was 16 Gy. Five patients underwent prior WBRT. Histology included non-small cell lung (8), breast (5), melanoma (1), gastrointestinal (1) and ovarian cancer (1). Follow-up MR imaging was available for 14 patients. LMD was stable in 5 and partially regressed in 8 patients at follow-up. One patient had progression of LMD with hemorrhage 5 months after SRS. Seven patients developed distant LMD at a median time of 7 months. The median actuarial overall survival from SRS for LMD was 10.0 months. The 6-month and 1-year actuarial overall survival was 60% and 26% respectively. Six patients underwent WBRT after SRS for focal LMD at a median time of 6 months. Overall, focal LMD may be may be treated successfully with radiosurgery, potentially delaying WBRT in some patients.