[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Nov 2015 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: OBJECT Irreversible electroporation (IRE) is a novel nonthermal ablation technique that has been used for the treatment of solid cancers. However, it has not been evaluated for use in brain tumors. Here, the authors report on the safety and feasibility of using the NanoKnife IRE system for the treatment of spontaneous intracranial gliomas in dogs. METHODS Client-owned dogs with a telencephalic glioma shown on MRI were eligible. Dog-specific treatment plans were generated by using MRI-based tissue segmentation, volumetric meshing, and finite element modeling. After biopsy confirmation of glioma, IRE treatment was delivered stereotactically with the NanoKnife system using pulse parameters and electrode configurations derived from therapeutic plans. The primary end point was an evaluation of safety over the 14 days immediately after treatment. Follow-up was continued for 12 months or until death with serial physical, neurological, laboratory, and MRI examinations. RESULTS Seven dogs with glioma were treated. The mean age of the dogs was 9.3 ± 1.6 years, and the mean pretreatment tumor volume was 1.9 ± 1.4 cm(3). The median preoperative Karnofsky Performance Scale score was 70 (range 30-75). Severe posttreatment toxicity was observed in 2 of the 7 dogs; one developed fatal (Grade 5) aspiration pneumonia, and the other developed treatment-associated cerebral edema, which resulted in transient neurological deterioration. Results of posttreatment diagnostic imaging, tumor biopsies, and neurological examinations indicated that tumor ablation was achieved without significant direct neurotoxicity in 6 of the 7 dogs. The median 14-day post-IRE Karnofsky Performance Scale score of the 6 dogs that survived to discharge was 80 (range 60-90), and this score was improved over the pretreatment value in every case. Objective tumor responses were seen in 4 (80%) of 5 dogs with quantifiable target lesions. The median survival was 119 days (range 1 to > 940 days). CONCLUSION With the incorporation of additional therapeutic planning procedures, the NanoKnife system is a novel technology capable of controlled IRE ablation of telencephalic gliomas.
No preview · Article · Jul 2015 · Journal of Neurosurgery
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Feb 2014 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: To estimate the hazard for Neurologic (CNS) and Non-Neurologic (Non-CNS) death associated with patient, treatment and systemic disease status in patients receiving SRS following WBRT failure using a competing risk model.
No preview · Article · Oct 2013 · International Journal of Radiation OncologyBiologyPhysics
[Show abstract][Hide abstract] ABSTRACT: Primary central nervous system lymphoproliferative disorders comprise a heterogenous group of intracranial disease, predominantly of the high-grade non-Hodgkin's lymphoma type. We report a 56-year-old woman who developed new-onset grand mal seizures and was found to have two small uniformly enhancing dural-based lesions, which were radiologically concerning for meningiomas. Biopsy demonstrated findings consistent with benign, reactive lymphoid tissue. The patient's seizures resolved post-operatively. To our knowledge, this is the first reported patient with intracranial pseudolymphoma presenting as grand mal seizures. This case highlights this rare differential consideration in a patient with symptomatic dural-based lesion.
No preview · Article · Sep 2013 · Journal of Clinical Neuroscience
[Show abstract][Hide abstract] ABSTRACT: We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS) to determine if tumor histology predicts patient outcomes.
To determine if histology predicts outcomes METHODS:: Between 7/1/2000 and 12/31/2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. 44 squamous cell carcinomas (SCC), 31 small cell carcinomas (SCLC), and 138 adenocarcinoma (ACA) patients were included in our study. 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole brain radiation therapy (WBRT) prior to their GK, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of two lesions were treated per patient with median marginal dose of 20 Gy.
Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC (p=0.008). 1 year local control was 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (p=0.027). 1 year distant failure was 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (p=0.057). Likelihood of dying from neurologic death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (p=0.027). Median time to WBRT was 11 months for SCC, and 24 months for ACA (p=0.04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (HR 6.46, p=0.025) and distant failure (HR 3.32, p=0.0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR 2.552, p=0.01) and worsened overall survival (HR 1.77, p<0.0121).
Histologic subtype of lung cancer appears to predict for outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to describe the neuropathologic features of normal canine brain ablated with non-thermal irreversible electroporation (N-TIRE). The parietal cerebral cortices of four dogs were treated with N-TIRE in a dose-escalation protocol, with an additional dog receiving sham treatment. Dogs were recovered following N-TIRE ablations and the effects of treatment monitored with clinical and MRI examinations. Brains were subjected to histopathologic, ultrastructural, and Bcl-2, caspase-3, and caspase-9 immunohistochemical examinations following sacrifice 72 hours post-treatment. Adverse clinical effects from N-TIRE treatment were only observed in the dog treated at the upper energy tier. MRI and neuropathologic examinations indicated that N-TIRE ablation resulted in focal regions of severe cytoarchitectural and blood-brain-barrier disruption, with lesion size correlated to the applied electrical field. N-TIRE lesions consisted of parenchymal necrosis and hemorrhage; however, large blood vessels were preserved. A transition zone of parenchymal edema, perivascular inflammatory cuffs, and reactive gliosis was interspersed between the necrotic focus and normal neuropil. Apoptotic labeling indices were not different between N-TIRE treated and control brains. This study identified N-TIRE pulse parameters that can be used to safely create circumscribed foci of brain necrosis, with selective preservation of major vascular structures.
Full-text · Article · Jun 2013 · Journal of veterinary science (Suwŏn-si, Korea)
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study sought to assess clinical outcomes in patients receiving gamma knife radiosurgery (GK) for treatment of brain metastases from melanoma and evaluate for potential predictive factors.
We reviewed 188 GK procedures in 129 consecutive patients that were treated for brain metastases from melanoma. The population consisted of 84 males and 45 females with a median age of 57 years. Fifty-five patients (43%) had a single metastasis. Seventy-one patients (55%) received chemotherapy, 58 patients (45%) received biologic agents, and 36 patients (28%) received prior whole brain radiation therapy (WBRT). The median marginal dose was 18.8 Gy (range 12 to 24 Gy).
Actuarial survival was 52%, 26%, and 13% at 6, 12, and 24 months, respectively. The median survival time was 6.7 months. Local tumor control was 95%, 81% 53% at 6, 12, and 24 months, respectively. The median time to LBF was 25.2 months. Freedom from distant brain failure was 40%, 29%, and 10% at 6, 12, and 24 months, and the median time to DBF was 4.6 months. At the time of data analysis, 108 patients (84%) had died. Fifty-eight patients (52%) died from neurologic death. The median time to neurologic death from GK treatment was 7.9 months. Multivariate analysis revealed that hemorrhage of metastases prior to GK (P = .02) and LBF (P = .03) were the dominant predictors of neurologic death.
GK achieves excellent local control and may improve outcomes as a component of a multidisciplinary treatment strategy. Distant brain failure and neurologic demise remain problematic and prospective trials are necessary.
Full-text · Article · Feb 2013 · World Neurosurgery
[Show abstract][Hide abstract] ABSTRACT: Objective:
We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT).
Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and χ test was used for comparison of cohorts.
For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97).
Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.
No preview · Article · Dec 2012 · American journal of clinical oncology
[Show abstract][Hide abstract] ABSTRACT: The blood-brain-barrier (BBB) presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE) is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd) uptake as a surrogate marker for BBB disruption. The study was performed in a Good Laboratory Practices (GLP) compliant facility and had Institutional Animal Care and Use Committee (IACUC) approval. IRE ablations were performed in vivo in normal rat brain (n = 21) with 1-mm electrodes (0.45 mm diameter) separated by an edge-to-edge distance of 4 mm. We used an ECM830 pulse generator to deliver ninety 50-μs pulse treatments (0, 200, 400, 600, 800, and 1000 V/cm) at 1 Hz. The effects of applied electric fields and timing of Gd administration (-5, +5, +15, and +30 min) was assessed by systematically characterizing IRE-induced regions of cell death and BBB disruption with 7.0-T magnetic resonance imaging (MRI) and histopathologic evaluations. Statistical analysis on the effect of applied electric field and Gd timing was conducted via Fit of Least Squares with α = 0.05 and linear regression analysis. The focal nature of IRE treatment was confirmed with 3D MRI reconstructions with linear correlations between volume of ablation and electric field. Our results also demonstrated that IRE is an ablation technique that kills brain tissue in a focal manner depicted by MRI (n = 16) and transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner as seen with Evan's Blue (n = 5) and Gd administration.
[Show abstract][Hide abstract] ABSTRACT: IRE-induced BBB disruption as seen in the T1W+Gd MRI. The lesion was achieved with ninety 50-μs pulses at 1000 V/cm with Gd administration 5 min pre-IRE at a repetition rate of one pulse per second.
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to determine if clinically relevant endpoints were changed by improved MRI resolution during radiosurgical treatment planning.
Between 2003 and 2008, 200 consecutive patients with brain metastases treated with Gamma Knife radiosurgery (GKRS) using either 1.5 T or 3.0 T MRI for radiosurgical treatment planning were retrospectively analysed. The number of previously undetected metastases at time of radiosurgery, distant brain failures, time delay to whole brain radiotherapy (WBRT), overall survival and likelihood of neurological death were determined.
Additional metastases were detected in 31.3% and 24.5% of patients at time of radiosurgery with 3.0 T and 1.5 T MRI, respectively (P = 0.27). Patients with multiple metastases at diagnostic scan were more likely to have additional metastases detected by 3.0 T MRI (P < 0.1). Median time to distant brain failure was 4.87 months and 5.43 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.44). Median time to WBRT was 5.8 months and 5.3 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.87). Median survival was 6.4 months for the 3.0 T cohort, and 6.1 months for the 1.5 T cohort (P = 0.71). Likelihood of neurological death was 25.3% and 16.7% for the 3.0 and 1.5 T populations, respectively (P = 0.26).
The 3.0 T MRI-based treatment planning for GKRS did not appear to affect the likelihood of distant brain failure, the need for WBRT or the likelihood of neurological death in this series.
No preview · Article · Oct 2012 · Journal of Medical Imaging and Radiation Oncology
[Show abstract][Hide abstract] ABSTRACT: We investigate the variance in patterns of failure after Gamma Knife™ radiosurgery (GKRS) for patients with brain metastases based on the subtype of the primary breast cancer. Between 2000 and 2010, 154 breast cancer patients were treated with GKRS for brain metastases. Tumor subtypes were approximated based on hormone receptor (HR) and HER2 status of the primary cancer: Luminal A/B (HR+/HER2(−)); HER2 (HER2+/HR(−)); Luminal HER2 (HR+/HER2+), Basal (HR(−)/HER2(−)), and then based on HER2 status alone. The median follow-up period was 54 months. Kaplan–Meier method was used to estimate survival times. Multivariable analysis was performed using Cox regression models. Median number of lesions treated was two (range 1–15) with a median dose of 20 Gy (range 9–24 Gy). Median overall survival (OS) was 7, 9, 11 and 22 months for Basal, Luminal A/B, HER2, and Luminal HER2, respectively (p = 0.001), and was 17 and 8 months for HER2+ and HER(−) patients, respectively (p < 0.001). Breast cancer subtype did not predict time to local failure (p = 0.554), but did predict distant brain failure rate (76, 47, 47, 36 % at 1 year for Basal, Luminal A/B, HER2, and Luminal HER2 respectively, p < 0.001). An increased proportion of HER2+ patients experienced neurologic death (46 vs 31 %, p = 0.066). Multivariate analysis revealed that HER2+ patients (p = 0.007) independently predicted for improved survival. Women with basal subtype have high rates of distant brain failure and worsened survival. Our data suggest that differences in biologic behavior of brain metastasis occur across breast cancer subtypes.
No preview · Article · Sep 2012 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Epilepsy is a common chronic neurologic disorder affecting approximately 1% of the world population. More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Effective treatment options for these patients can be limited. The cellular mechanisms underlying seizure activity are incompletely understood, though we here describe multiple lines of evidence supporting the likely contribution of astroglia to epilepsy, with focus on individual astrocytes and their network functions. Of the emerging therapeutic modalities for epilepsy, one of the most intriguing is the field of neuromodulation. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. Current modalities consist of vagal nerve stimulation, open and closed-loop stimulation, and transcranial magnetic stimulation. Due to their unique properties, we here present astrocytes as likely important targets for the developing field of neuromodulation in the treatment of epilepsy.
Preview · Article · Aug 2012 · Frontiers in Computational Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Background: Radiation-induced meningiomas present a unique clinical dilemma given the fact that patients with these tumors have often received a prior full course of radiotherapy. As such, traditional radiotherapy is limited by lifetime tissue tolerances to radiation, leaving surgery and radiosurgery as attractive treatment options. Objectives: To ascertain the safety and efficacy of Gamma Knife radiosurgery as a treatment for radiation-induced meningiomas. Methods: A retrospective chart review was conducted to identify patients who received Gamma Knife radiosurgery for a meningioma and met the criteria for this being a radiation-induced tumor. Serial imaging was used to determine the outcome of treatment and clinical notes used to assess for toxicity. Results: We present our series of 12 patients with radiation-induced meningiomas treated with Gamma Knife stereotactic radiosurgery over a 12-year period at our institution. With a median follow-up of 35 months, local control was 100%. Two patients experienced distant brain failure (>2 cm from previous radiosurgical volume). Two patients experienced posttreatment toxicity related to treatment-related edema. A review of data collected from the scientific literature suggests that tumor volume predicts for treatment failure of radiosurgery. Conclusions: Gamma Knife radiosurgery is both a safe and effective treatment for radiation-induced meningiomas.
Full-text · Article · Aug 2012 · Stereotactic and Functional Neurosurgery
[Show abstract][Hide abstract] ABSTRACT: Gamma Knife radiosurgery (GKRS) has been established as a safe and effective treatment option for trigeminal neuralgia. Some patients have contraindications to magnetic resonance imaging (MRI), the standard stereotactic imaging used for GKRS treatment planning. Computerized tomography (CT) imaging may be used as an alternative in this scenario. We sought to evaluate the outcomes of our patients treated using this technique.
Between August 2001 and November 2009, 19 patients with trigeminal neuralgia were treated with GKRS using CT-only planning. The course of the trigeminal nerve was determined based upon anatomical landmarks when the nerve was not directly visualized on the treatment-planning CT. Median dose used was 90 Gy (range 85-90 Gy). Follow-up data based on Barrow Neurological Institute (BNI) pain score and toxicity were obtained using electronic medical records and by telephone interview.
With median follow-up time of 18 months (range 4-36 months), improvement in quality of life after GKRS was reported in 17 of 19 patients. Freedom from BNI IV-V pain relapse was 82% at 24 months. By 3 months post-GKRS, 50% of patients were able to discontinue medications completely. Three patients reported numbness after GKRS; none of these patients described bothersome numbness. Use of contrast did not affect treatment outcome (P = 0.31).
Stereotactic CT-only treatment planning of GKRS for the treatment of trigeminal neuralgia is feasible and safe. Further studies are necessary to determine if the long-term durability of pain relief is comparable to that of MRI-based GKRS planning.
No preview · Article · Aug 2012 · Journal of Medical Imaging and Radiation Oncology