A Review on the Surgical Management of Insular Gliomas.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

Intracranial subsecond dopamine measurements during a "sure bet or gamble" decision-making task in patients with alcohol use disorder suggest diminished dopaminergic signals about relief.

OBJECTIVE: To the authors' knowledge, no data have been reported on dopamine fluctuations on subsecond timescales in humans with alcohol use disorder (AUD). In this study, dopamine release was monitored in 2 patients with and 2 without a history of AUD during a "sure bet or gamble" (SBORG) decision-making task to begin to characterize how subsecond dopamine responses to counterfactual information, related to psychological notions of regret and relief, in AUD may be altered. METHODS: Measurements of extracellular dopamine levels were made once every 100 msec using human voltammetric methods. Measurements were made in the caudate during deep brain stimulation electrode implantation surgeries (for treatment of movement disorders) in patients who did (AUD, n = 2) or did not (non-AUD, n = 2) have a history of AUD. Participants performed an SBORG decision-making task in which they made choices between sure bets and 50%-chance monetary gamble outcomes. RESULTS: Fast changes were found in dopamine levels that appear to be modulated by "what could have been" and by patients' AUD status. Positive counterfactual prediction errors (related to relief) differentiated patients with versus without a history of AUD. CONCLUSIONS: Dopaminergic encoding of counterfactual information appears to differ between patients with and without AUD. The current study has a major limitation of a limited sample size, but these data provide a rare insight into dopaminergic physiology during real-time decision-making in humans with an addiction disorder. The authors hope future work will expand the sample size and determine the generalizability of the current results.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases.

BACKGROUND: Previous series have demonstrated CNS activity for immune checkpoint inhibitors, yet no prior data exists regarding whether this activity can improve outcomes of stereotactic radiosurgery. METHODS: In this single institution retrospective series, the clinical outcomes of 80 consecutive lung cancer patients treated with concurrent immune checkpoint inhibitors and stereotactic radiosurgery were compared to 235 in the historical control cohort in which patients were treated prior to immune checkpoint inhibition being standard upfront therapy. Overall survival was estimated using the Kaplan Meier method. Cumulative incidence of local progression was estimated using a competing risk model. RESULTS: Median overall survival time was improved in patients receiving upfront immunotherapy compared to the historical control group (40 months vs 8 months, p < 0.001). Factors affected overall survival include concurrent immunotherapy (HR 0.23, p < 0.0001) and KPS (HR 0.97, p = 0.0001). Cumulative incidence of local failure in the historical control group was 10% at 1 year, compared to 1.1% at 1 year in the concurrent immunotherapy group (p = 0.025). Factors affected local control included use of concurrent immunotherapy (HR 0.09, p = 0.012), and lowest margin dose delivered to a metastasis (HR 0.8, p = 0.0018). CONCLUSION: Local control and overall survival were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent use of immunotherapy with SRS.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Gamma Knife Stereotactic Radiosurgery favorably changes the clinical course of hemangioblastoma growth in von Hippel-Lindau and sporadic patients.

PURPOSE: This is the first single-institution study of its size to characterize the treatment impact and to address the question of whether hemangioblastoma treatment with Gamma Knife Stereotactic Radiosurgery (GKRS) in both sporadic and VHL patients changes the characteristic saltatory hemangioblastoma growth pattern. METHODS: The authors reviewed a single-institution tumor registry to identify patients who had received GKRS for hemangioblastomas between January 1st, 1999, and December 31st, 2017. RESULTS: 15 patients with 101 lesions met search criteria with a median age of first GKRS of 39.2 years (interquartile range [IQR] of 25.7-57.4 years), including 96 VHL and 5 sporadic lesions. The median time from GKRS to last follow-up was 5.4 years (IQR 2.3-11.5 years). 4 lesions (4%) and 3 patients (20%) experienced a local failure. The 1-year, 3-year, and 5-year freedom from new hemangioblastoma formation rates were 97%, 80%, and 46% respectively. Multivariate analysis revealed a reduction in tumor volume after GKRS. Several variables associated with a greater percent reduction in volume from GKRS to last follow-up: non-cystic status (p = .01), no prior craniotomy (p = .04), and follow-up time from GKRS (p < .0001). CONCLUSIONS: GKRS is a successful long-term treatment option for hemangioblastomas changing the clinical course from saltatory growth to reduction in tumor volume. Non-cystic tumors and those without prior craniotomy were associated with a greater percent reduction in volume from GKRS at last follow-up.

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward.

In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes?

PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS). A limitation in the application of BMV is it cannot be applied until time of first BM failure after SRS. We developed initial BM velocity (iBMV), a new metric that accounts for the number of BM at first SRS and the time since initial cancer diagnosis. MATERIALS/METHODS: We reviewed patients with BM treated at our institution with upfront SRS without WBRT. iBMV was calculated as the number of BM at initial SRS divided by time (years) from initial cancer diagnosis to first SRS. We performed a linear regression to correlate BMV as a continuous variable and with low, intermediate, and high BMV risk groups. Kaplan-Meier estimation of OS was calculated from time of first SRS to death. iBMV was not calculated for patients who presented with BM at initial cancer diagnosis. RESULTS: 994 patients were treated with upfront SRS without WBRT between 2000 and 2017. Median OS was 8.5 mos. 595 (60%) patients developed BM after cancer diagnosis and median time to first SRS from time of initial diagnosis was 2.2 years. Median iBMV was 0.79 BM/year. iBMV correlated with BMV (ß = 1.57 p = 0.021) and independently predicted for mortality [Cox proportional hazard ratio (HR) 1.11, p = 0.036] after accounting for histology, number of initial brain metastases (HR 1.03, p = 0.32), time from cancer diagnosis to SRS (HR 0.98, p = 0.157) in a multivariate model. CONCLUSION: iBMV correlates with BMV and OS. With further validation, iBMV could serve as a metric to risk stratify patients for WBRT or SRS at time of first BM presentation.

Glioblastoma radiomics: can genomic and molecular characteristics correlate with imaging response patterns?

PURPOSE: For glioblastoma (GBM), imaging response (IR) or pseudoprogression (PSP) is frequently observed after chemoradiation and may connote a favorable prognosis. With tumors categorized by the Cancer Genome Atlas Project (mesenchymal, classical, neural, and proneural) and by methylguanine-methyltransferase (MGMT) methylation status, we attempted to determine if certain genomic or molecular subtypes of GBM were specifically associated with IR or PSP. METHODS: Patients with GBM treated at two institutions were reviewed. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Mantel-cox test determined effect of IR and PSP on OS and PFS. Fisher's exact test was utilized to correlate IR and PSP with genomic subtypes and MGMT status. RESULTS: Eighty-two patients with GBM were reviewed. The median OS and PFS were 17.9 months and 8.9 months. IR was observed in 28 (40%) and was associated with improved OS (median 29.4 vs 14.5 months p < 0.01) and PFS (median 17.7 vs 5.5 months, p < 0.01). PSP was observed in 14 (19.2%) and trended towards improved PFS (15.0 vs 7.7 months p = 0.08). Tumors with a proneural component had a higher rate of IR compared to those without a proneural component (IR 60% vs 28%; p = 0.03). MGMT methylation was associated with IR (58% vs 24%, p = 0.032), but not PSP (34%, p = 0.10). CONCLUSION: IR is associated with improved OS and PFS. The proneural subtype and MGMT methylated tumors had higher rates of IR.

Gamma Knife Stereotactic Radiosurgery for the Treatment of Brain Metastases from Primary Tumors of the Urinary Bladder.

BACKGROUND/AIMS: Brain metastases from bladder cancer are rare and published outcomes data are sparse. To date, no institutions have reported a series of patients with brain metastases from bladder cancer treated with stereotactic radiosurgery (SRS). Our aim was to identify patients with brain metastases from bladder primaries treated with SRS with or without surgical resection and report the clinical outcomes. METHODS: Patients meeting eligibility criteria at our institution between 2000 and 2017 were included. The clinical variables of interest, including overall survival (OS), local recurrence, V12, distant brain failure (DBF), and initial brain metastases velocity, were calculated. Cox proportional hazards analysis was performed to identify predictors of time-to-event outcomes. RESULTS: A total of 14 patients were included. The median OS from the time of treatment was 2.1 months. Factors predictive of OS include intracranial resection (HR 0.21, p = 0.03). The cumulative incidence of local failure was 21% at 6 months and 30% at 12 months. The cumulative incidence of DBF at 6 and 12 months was 23 and 31%, respectively. CONCLUSIONS: The prognosis in this patient population remains guarded. Factors associated with improved survival include intracranial resection. Future, prospective work is needed to further define optimal management.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Surgical Considerations in the Optimal Management of Patients with Malignant Brain Tumors.

OPINION STATEMENT: Advances in technology are revolutionizing medicine and the limits of what we can offer to our patients. In neurosurgery, technology continues to reduce morbidity, increase surgical accuracy, facilitate tissue acquisition, and promote novel techniques for prolonging survival in patients with neuro-oncologic disease. Surgery has been the backbone of glioma diagnosis and treatment by providing adequate, high quality material for precise histologic diagnosis, and genomic characterization in the setting of significant intratumoral heterogeneity, thus allowing personalized treatment selection in the clinic. The ability to obtain and accurately measure the maximal extent of resection in glioma surgery also remains a central role of the neurosurgeon in managing this cancer. To meet these goals, today's operating room has transformed from the traditional operating table and anesthesia machine to include neuronavigation instrumentation, intraoperative computed tomography, and magnetic resonance imaging scanners, advanced surgical microscopes fitted with fluorescent light filters, and electrocorticography machines. While surgeons, oncologists, and radiation oncologists all play unique critical roles in the care of patients with malignant gliomas, familiarity with developing techniques in complimentary subspecialties can enhance coordination of patient care, research productivity, professional interactions, and patient confidence and comfort with the physician team. Herein, we provide a summary of the advances in the field of neurosurgical oncology which allow more precise and optimal surgical resection for patients with malignant gliomas.

Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design.

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %,C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size.

Clinical and economic outcomes of patients with brain metastases based on symptoms: an argument for routine brain screening of those treated with upfront radiosurgery.

BACKGROUND: Insurers have started to deny reimbursement for routine brain surveillance with magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases in favor of symptom-prompted imaging. The authors investigated the clinical and economic impact of symptomatic versus asymptomatic metastases and related these findings to the use of routine brain surveillance. METHODS: Between January 2000 and December 2010, 442 patients underwent upfront SRS for brain metastases. In total, 127 asymptomatic patients and 315 symptomatic patients were included. Medical records were used to determine the presenting symptoms, distant and local brain failure, retreatment, and need for hospital and rehabilitative care. Cost-of-care estimates were based on Medicare payment rates as of January 2013. RESULTS: Symptomatic patients had an increased hazard for all-cause mortality (hazard ratio, 1.448) and were more likely to experience neurologic death (42% vs 20%; P < .0001). Relative to asymptomatic patients, symptomatic patients required more craniotomies (43% vs 5%; P < .0001), had more prolonged hospitalization (2 vs 0 days; P < .0001), were more likely to have Radiation Therapy Oncology Group grade 3 and 4 post-treatment symptoms (24% vs 5%; P < .0001), and required $11,957 more on average to manage per patient. Accounting for all-cause mortality rates and the probability of diagnosis at each follow-up period, the authors estimated that insurers would save an average $1326 per patient by covering routine surveillance MRI after SRS to detect asymptomatic metastases. CONCLUSIONS: Patients who presented with symptomatic brain metastases had worse clinical outcomes and cost more to manage than asymptomatic patients. The current findings argue that routine brain surveillance after radiosurgery has clinical benefits and reduces the cost of care.

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma.

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.

Risk factors for leptomeningeal carcinomatosis in patients with brain metastases who have previously undergone stereotactic radiosurgery.

Our objective was to explore the hypothesis that the risk of leptomeningeal dissemination (LMD) in patients who underwent stereotactic radiosurgery (SRS) for brain metastases is influenced by the site of the primary cancer, the addition of whole brain radiation therapy (WBRT), surgical resection, and control over their systemic disease. We conducted a retrospective cohort analysis of 805 patients who were treated with SRS for brain metastases between 1999 and 2012 at the Wake Forest Baptist Medical Center, and excluded all patients with evidence of LMD before SRS. The primary outcome was LMD. Forty-nine of 795 patients developed LMD with a cumulative incidence of 6.2% (95% Confidence Interval (CI), 4.7-8.0). Median time from SRS to LMD was 7.4 months (Interquartile Range (IQR), 3.3-15.4). A colorectal primary site (Hazard Ratio (HR), 4.5; 95% CI 2.5-8.0; p < 0.0001), distant brain failure (HR, 2.0; 95% CI 1.2-3.2; p = 0.007), breast primary site (HR, 1.6; 95% CI 1.0-2.7; p = 0.05), the number of intracranial metastases at time of initial SRS (HR, 1.1; 95% CI 1.0-1.2; p = 0.02), and age (by 5-year interval) (HR, 0.9; 95% CI 0.8, 0.9; p = 0.0006) were independent factors associated with LMD. There was no evidence that surgical resection before SRS altered the risk of LMD (HR, 1.1; 95 % CI 0.6-2.0, p = 0.78). In patients who underwent SRS for brain metastases, a colorectal or breast primary site, distant brain failure, younger age, and an increased number of intracranial metastases were independently associated with LMD. Given its relative rarity as an outcome, multi-institutional prospective studies will likely be necessary to validate and quantify these relationships.

Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: is there a volume threshold for toxicity?

Gamma Knife Radiosurgery (GKRS) has been reported in the treatment of brainstem metastases while dose volume toxicity thresholds remain mostly undefined. A retrospective review of 52 brainstem metastases in 44 patients treated with GKRS was completed. A median dose of 18 Gy (range 10-22 Gy) was prescribed to the tumor margin (median 50 % isodose). 25 patients had undergone previous whole brain radiation therapy. Toxicity was graded by the LENT-SOMA scale. Mean and median follow-up was 10 and 6 months. Only 3 of the 44 patients are living. Multiple brain metastases were treated in 75 % of patients. Median size of lesions was 0.134 cc, (range 0.013-6.600 cc). Overall survival rate at 1 year was 32 % (95 % CI 51.0-20.1 %) with a median survival time of 6 months (95 % CI 5.0-16.5). Local control rate at 6 months and 1 year was 88 % (95 % CI 70-95 %) and 74 % (95 % CI 52-87 %). Cause of death was neurologic in 17 patients, non-neurologic in 20 patients, and unknown in four. Four patients experienced treatment related toxicities. Univariate analysis of tumor volume revealed that volume greater than 1.0 cc predicted for toxicity. A strategy of using lower marginal doses with GKRS to brain stem metastases appears to lead to a lower local control rate than seen with lesions treated within the standard dose range in other locations. Tumor size greater than 1.0 cc predicted for treatment-related toxicity.

Single-institution retrospective series of gamma knife radiosurgery in the treatment of multiple sclerosis-related trigeminal neuralgia: factors that predict efficacy.

BACKGROUND: Gamma knife radiosurgery (GKRS) has been reported as a treatment option for multiple sclerosis (MS)-related trigeminal neuralgia. OBJECTIVE: To report the outcomes of a single-institution retrospective series of MS-related trigeminal neuralgia. METHODS: Between 2002 and 2010, 35 patients with MS-related trigeminal neuralgia were treated with GKRS. The median maximum dose was 90 Gy. Data were analyzed to determine the response to GKRS and factors that may predict for efficacy. RESULTS: Of the 35 patients, 88% experienced a Barrow Neurological Institute (BNI) pain score of I-III at 3 months after GKRS. Kaplan-Meier estimates of 1-, 2- and 5-year freedom from BNI IV-V pain relapse were 57, 57 and 52%, respectively. Numbness was experienced by 39% of patients after GKRS, though no patients reported bothersome numbness. Several differences were noted between how the MS-related variant responded to GKRS and what has previously been reported for idiopathic trigeminal neuralgia. These include the observations that development of post-GKRS numbness did not predict for treatment response (p = 0.62) and that dorsal root entry zone dose did not predict for freedom from pain relapse (odds ratio 1.01, p = 0.1). Active smoking predicted for freedom from pain relapse (odds ratio 67.4, p = 0.04). CONCLUSION: GKRS is a viable noninvasive treatment option for MS-related trigeminal neuralgia.

Sub-second and multi-second dopamine dynamics underlie variability in human time perception.

Timing behaviour and the perception of time are fundamental to cognitive and emotional processes in humans. In non-human model organisms, the neuromodulator dopamine has been associated with variations in timing behaviour, but the connection between variations in dopamine levels and the human experience of time has not been directly assessed. Here, we report how dopamine levels in human striatum, measured with sub-second temporal resolution during awake deep brain stimulation surgery, relate to participants' perceptual judgements of time intervals. Fast, phasic, dopaminergic signals were associated with underestimation of temporal intervals, whereas slower, tonic, decreases in dopamine were associated with poorer temporal precision. Our findings suggest a delicate and complex role for the dynamics and tone of dopaminergic signals in the conscious experience of time in humans.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression.

OBJECTIVE: Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. METHODS: A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. RESULTS: The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. CONCLUSIONS: The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.