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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.

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 cm3. 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.

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). METHODS:: 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. RESULTS:: 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). CONCLUSIONS:: Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

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.

Overall survival of patients with brain metastases has improved in the past decade.1,2 Such improvement can often be offset by the late toxicities of whole-brain radiotherapy (WBRT), for which the likelihood and severity of cognitive decline continues to worsen with time.3 Multiple randomized trials have now shown that using radiosurgery as an upfront single modality and without WBRT does not affect overall survival in select patients.4,5 However, there are patients who will experience early or multiple distant brain failures, and these patients will likely need WBRT earlier in the course of their disease. As a result, an increasing emphasis is being placed on prognostic factors that may distinguish populations that benefit more from upfront radiosurgery from those that may benefit from upfront WBRT. Recent data from the scientific literature have suggested that the natural history of brain metastases can depend on the histological subtype of the primary cancer. Some histologies such as renal cell carcinoma have proved more radioresistant.6 Even for tumors of the same primary histology, such as invasive ductal carcinoma of the breast, there can be variability in the natural history of brain metastases depending on the Her2 receptor status of the individual patient’s cancer.7 It has been suggested that patients with melanoma and triple-negative breast cancers may have higher rates of distant brain failure after radiosurgery.8,9 Within lung cancer, there are several known differences between the various histological subtypes with regard to the natural history of the disease. Small cell lung cancer (SCLC) has a high rate of metastatic brain disease, and prophylactic cranial irradiation has in fact resulted in survival benefits both in limited- and extensive-stage disease.10,11 Adenocarcinoma appears to have a survival advantage over squamous cell carcinoma (SCC) within the non-small cell subtypes in the setting of locally advanced disease.12 It has been previously unknown, however, whether biological differences in various subtypes of lung cancer affect the biological behavior of brain metastases. Objectives To this end, we present a single-institution retrospective review of patients with lung cancer and first diagnosis of brain metastases treated with Gamma Knife radiosurgery (GKRS) and without previous therapeutic WBRT. Our analysis focuses on variations of clinical outcomes caused by histological differences of the primary cancer. Furthermore, we evaluate factors that may predict survival, distant brain failure, and neurological death.

BACKGROUND It has been well established that Gamma Knife radiosurgery (GKS) is an effective treatment for brain arteriovenous malformations (AVMs). OBJECTIVE To evaluate complete obliteration rates for magnetic resonance imaging (MRI)-based GKS treatment planning performed with and without angiography and to conduct a preliminary assessment of the utility of using pulsed arterial spin labeling (PASL) magnetic resonance (MR) perfusion imaging to confirm complete obliteration. METHODS Forty-six patients were identified who had undergone GKS without embolization with a minimum follow-up of 2 years. One group was planned with integrated stereotactic angiography and MR (spoiled gradient recalled) images obtained on the day of GKS. A second technique avoided the risk of arteriography by using only axial MR images. Beginning in 2007, PASL MR perfusion imaging was routinely performed as a portion of the follow-up MRI to assess the restoration of normal blood flow of the nidus and surrounding area. RESULTS The overall obliteration rate for the angiography/MRI group was 88.0% (29 of 33). Patients in the MRI-only group had an obliteration rate of 61.5% (8 of 13), with P=.092 with the Fisher exact test, which is not statistically significant. A Kaplan-Meier analysis was also not statistically significant (log rank test, P=.474). Four of 9 patients with incomplete obliteration on angiography also had shown residual abnormal blood flow on PASL imaging. CONCLUSION This retrospective analysis shows that treatment planning technique used in GKS does not play a role in the eventual obliteration of treated AVMs. PASL may have potential in the evaluation of AVM obliteration.

Introduction The goal of this study was to determine if clinically relevant endpoints were changed by improved MRI resolution during radiosurgical treatment planning. Methods and Materials 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. Results 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

Introduction: 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. Methods: 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. Results: 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). Conclusions: 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.

Object Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS. Methods Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13–24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival. Results Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume. Conclusions Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

Novel therapeutic options for patients with recurrent primary central nervous system lymphoma (RPCNSL) are needed. Bendamustine, a bifunctional purine analog/alkylating agent, is approved for use in patients with progressive systemic indolent non-Hodgkin's B-cell lymphomas. Limited data suggests that bendamustine may partition into the brain in the setting of a disrupted blood-brain barrier. This report describes the first known experience of patients with RPCNSL treated with bendamustine. Therapy was well-tolerated and best response was noted as stable disease after eight cycles of bendamustine followed by a subsequent local systemic recurrence found at five months follow-up. CNS involvement in this patient remained stable 20 + months post-bendamustine treatment. Based on our observations, further neuropharmacokinetic and efficacy studies with bendamustine may be warranted in this patient population.

Background: Intracranial neoplasms can cause pain similar to trigeminal neuralgia. Literature regarding radiosurgery for this is limited. We present a retrospective review of patients with tumor-related facial pain from benign lesions treated with gamma knife radiosurgery (GKRS) at Wake Forest University. Objectives: The primary objectives were to determine long-term pain relief and predictive factors for pain alleviation. Methods: We reviewed 515 patients treated with GKRS for benign meningioma, vestibular schwannoma or trigeminal schwannoma between August 1999 and August 2010. Twenty-one eligible patients had tumor-related facial pain prior to GKRS. The median marginal tumor dose was 12 Gy. Long-term pain relief data were obtained by chart review and telephone interview. Results: The median follow-up for symptom evaluation was 3.8 years. Seventeen of 21 patients (81%) experienced a Barrow Neurological Institute (BNI) score of I–III at 6 months following GKRS. Kaplan-Meier estimates of freedom from BNI IV–V relapse were 66% at 1 year and 53% at 2 years. No pain relapses occurred after 2 years. Conclusion: GKRS of benign lesions is a noninvasive option for patients with tumor-related facial pain. Pain relief is modest, with the majority of pain relapses occurring within 2 years and approximately one half of patients maintaining relief beyond 2 years.

BACKGROUND AND PURPOSE: MR perfusion imaging can be used to help predict glial tumor grade and disease progression. Our purpose was to evaluate whether perfusion imaging has a diagnostic or therapeutic impact on clinical management planning in patients with glioma. MATERIALS AND METHODS: Standard MR imaging protocols were interpreted by a group of 3 NRs in consensus, with each case being interpreted twice: first, including routine sequences; and second, with the addition of perfusion imaging. A multidisciplinary team of treating physicians assessed tumor status and created hypothetical management plans, on the basis of clinical presentation and routine MR imaging and then routine MR imaging plus perfusion MR imaging. Physicians9 confidence in the tumor status assessment and management plan was measured by using Likert-type items. RESULTS: Fifty-nine consecutive subjects with glial tumors were evaluated; 50 had known pathologic diagnoses. NRs and the treatment team agreed on tumor status in 45/50 cases (κ = 0.81). With the addition of perfusion, confidence in status assessment increased in 20 (40%) for NRs and in 28 (56%) for the treatment team. Of the 59 patient-care episodes, the addition of perfusion was associated with a change in management plan in 5 (8.5%) and an increase in the treatment team9s confidence in their management plan in 34 (57.6%). NRs and the treatment team found perfusion useful in most episodes of care and wanted perfusion included in future MR images for >80% of these subjects. CONCLUSIONS: Perfusion imaging appears to have a significant impact on clinical decision-making and subspecialist physicians9 confidence in management plans for patients with brain tumor.

Purpose: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. Methods and Materials: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. 'Rare toxicities' were characterized as those reported in the scientific literature at an incidence of

Object As a strategy to delay or avoid whole-brain radiotherapy (WBRT) after resection of a brain metastasis, the authors used high-resolution MR imaging and cavity-directed radiosurgery for the detection and treatment of further metastases. Methods Between April 2001 and October 2009, 112 resection cavities in 106 patients with no prior WBRT were treated using radiosurgery directed to the tumor cavity and for any synchronous brain metastases detected on high-resolution MR imaging at the time of radiosurgical planning. A median dose of 17 Gy to the 50% isodose line was prescribed to the gross tumor volume, defined as the rim of enhancement around the resection cavity. Patients were followed up via serial imaging, and new brain metastases were generally treated using additional radiosurgery, with salvage WBRT typically reserved for local treatment failure at a resection cavity, numerous failures, or failures occurring at short time intervals. Local and distant treatment failures were determined based on imaging results. Kaplan-Meier curves were generated to estimate local and distant treatment failure rates, overall survival, neurological cause–specific survival, and time delay to salvage WBRT. Results Radiosurgery was delivered to the resection cavity alone in 57.5% of patients, whereas 24.5% of patients also received treatment for 1 synchronous metastasis, 11.3% also received treatment for 2 synchronous metastases, and 6.6% also received treatment for 3–10 additional lesions. The median overall survival was 10.9 months. Overall survival at 1 year was 46.8%. The local tumor control rate at 1 year was 80.3%. The disease control rate in distant regions of the brain at 1 year was 35.4%, with a median time of 6.9 months to distant failure. Thirty-nine of 106 patients eventually received salvage WBRT, and the median time to salvage WBRT was 12.6 months. Kaplan-Meier estimates showed that the rate of requisite WBRT at 1 year was 45.9%. Neurological cause–specific survival at 1 year was 50.1%. Leptomeningeal failure occurred in 8 patients. One patient had treatment failure within the resection tract. Seven patients required reoperation: 2 for resection cavity recurrence, 3 for radiation necrosis, 1 for hydrocephalus, and 1 for a CSF cutaneous fistula. On multivariate analysis, a preoperative tumor diameter > 3 cm was predictive of local treatment failure. Conclusions Cavity-directed radiosurgery combined with high-resolution MR imaging detection and radiosurgical treatment of synchronous brain metastases is an effective strategy for delaying and even foregoing WBRT in most patients. This technique provides acceptable local disease control, although distant treatment failure remains significant.

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

Patients with Parkinson's disease (PD) and essential tremor (ET) tend to lose weight progressively over years. Weight gain following deep brain stimulation (DBS) of the subthalamic nucleus (STN) for treatment of PD has been documented in several studies that were limited by small sample size and exclusive focus on PD patients with STN stimulation. The current study was undertaken to examine weight change in a large sample of movement disorder patients following DBS. A retrospective review was undertaken of 182 patient charts following DBS of the STN, ventralis intermedius nucleus of the thalamus (VIM), and globus pallidus internus (GPi). Weight was collected preoperatively and postoperatively up to 24 months following surgery. Data were adjusted for baseline weight and multivariate linear regression was performed with repeated measures to assess weight change. Statistically significant mean weight gain of 1.8 kg (2.8% increase from baseline, p = 0.0113) was observed at a rate of approximately 1 kg per year up to 24 months following surgery. This gain was not predicted by age, gender, diagnosis, or stimulation target in a multivariate model. Significant mean weight gain of 2.3 kg (p = 0.0124) or 4.2% was observed in our PD patients. Most patients with PD and ET gain weight following DBS, and this gain is not predicted by age, gender, diagnosis, or stimulation target.

The authors present the case of a rare extraventricular, intraparenchymal choroid plexus carcinoma (CPC). This 6-year-old girl presented to the emergency department with a 1-week history of headaches, nausea, and vomiting. Imaging studies revealed an intraaxial cystic and solid mass located in the right frontal lobe with central nodular enhancement and minimally enhancing cyst walls. Gross-total resection was accomplished via craniotomy without complications. The initial pathological diagnosis was atypical teratoid/rhabdoid tumor (AT/RT); however, immunostaining for INI1 protein (using the BAF47/SNF5 antibody) showed retention of nuclear staining in the tumor cells, resulting in a change in the diagnosis to CPC. There was no evidence of recurrence at the last follow-up 2.5 years after treatment, which supports the diagnosis of CPC over AT/RT. This case emphasizes the importance of immunostaining for INI1 protein for distinguishing CPC from AT/RT in cases with atypical or indeterminate features.

Attempts to modulate brain activity for therapeutic purposes by stimulating various cortical and subcortical areas, have been made since the 19th century. Bartholow was one of the first to describe in detail, a case of brain stimulation in 1874 [13]. However, it was not until a century later, when in 1987, Benabid and Pollack proved that chronic high frequency deep brain stimulation (DBS) of thalamus could be used as a safe and effective way of treating the tremor of Parkinson’s disease (PD) [11,19]. A timeline of important milestones in the history of brain stimulation is shown in Fig. 1. In this article we will discuss the currently approved and the experimental uses of DBS. In addition we will give a brief overview of the proposed mechanisms by which DBS is currently thought to modulate brain activity. Sometimes referred to as a ‘brain pacemaker’, DBS involves placement of intracranial electrodes (Fig. 2) which can be connected to a subcutaneously and subclavicularly implanted pulse generator (IPG). The IPG allows noninvasive adjustments of current amplitude, frequency, pulse width and polarity by means of a hand

Stereotactic radiosurgery (GKRS) using the Leksell Gamma Knife is a treatment option for patients with trigeminal pain. We analyzed a database of 326 GKRS procedures performed over 4.6 years at three discrete dose levels commonly described in the published literature. Logistic regression was used to model the logit of response as a function of treatment time. The resulting coefficient was converted to an estimated probability of response for the shortest and longest treatment times in clinical practice. The two estimated probabilities were then compared to yield the estimated difference in the biologically effective dose (BED) between the two doses, using a modified linear-quadratic model for stereotactic radiosurgery. This difference was used to back-calculate a clinical value for T(1/2), resulting in a range of 1.28-1.77 h for T(1/2). The biological model appeared to accurately predict that, given the doses and treatment times used in general clinical practice, there would be no significant difference in clinical outcome.

ObjectSalvage treatment of large, symptomatic brain metastases after failure of whole-brain radiotherapy (WBRT) remains challenging. When these lesions require resection, there are few options to lower expected rates of local recurrence at the resection cavity margin. The authors describe their experience in using Gamma Knife surgery (GKS) to target the resection cavity in patients whose tumors had progressed after WBRT.MethodsThe authors retrospectively identified 143 patients in whom GKS had been used to target a brain metastasis resection cavity between 2000 and 2005. Seventy-nine of these patients had undergone WBRT prior to resection and GKS. The median patient age was 53 years, and the median prescribed dose was 18 Gy (range 8–24 Gy), with resection cavities of relatively larger volume (> 15 cm3). The GKS dose was prescribed at the 40 to 95% isodose contour (mode 50%).Local recurrence within 1 cm of the treatment volume occurred in four (5.1%) of 79 cases. The median duration of time to local recurrence was 6.1 months (range 2–13 months). The median duration of time to occurrence of distant metastases following GKS of the resection cavity was 10.8 months (range 2–86 months). Carcinomatous meningitis developed in four (5.1%) of 79 cases. Symptomatic radionecrosis requiring surgical treatment occurred in three (3.8%) of 79 cases. The median duration of survival following GKS of the resection cavity was 69.6 weeks. The median 2- and 5-year survival rates were 20.2 and 6.3%, respectively.Conclusions When metastases progress after WBRT and require resection, GKS targeting the resection cavity is a viable strategy. In 75 (94.9%) of 79 cases, GKS of the resection cavity in patients in whom WBRT had failed appears to have achieved its goal of local disease control.

Object. The goal of this study was to evaluate the outcomes of patients who underwent repeated radiosurgery to treat a residual intracranial arteriovenous malformation (AVM) after an initial radiosurgical treatment failure. Methods. The authors reviewed the cases of 52 patients who underwent repeated radiosurgery for residual AVM at the University of Florida between December 1991 and June 1998. In each case, residual arteriovenous shunting persisted longer than 36 months after the initial treatment; the mean interval between the first and second treatment was 41 months. Each AVM nidus was measured at the time of the original treatment and again at the time of retreatment, and the dosimetric parameters of the two treatments were compared. After retreatment, patients were followed up and their outcomes were evaluated according to a standard posttreatment protocol for radiosurgery for AVMs. The mean original lesion volume was 13.8 cm3 and the mean volume at retreatment was 4.7 cm3, for an average volume reduction of 66% after the initial treatment failure. Only two AVMs (3.8%) failed to demonstrate size reduction after the primary treatment. The median doses on initial and repeated treatment were 12.5 and 15 Gy, respectively. Five patients were lost to follow up and five refused neuroimaging follow up. One patient died of a hemorrhage shortly after retreatment. Of the remaining 41 patients, 24 had evidence of cure, 15 on angiographic studies and nine on magnetic resonance (MR) images. Seventeen had evidence of treatment failure, 10 on angiographic studies and seven on MR images. By angiographic criteria alone, the cure rate after retreatment was 60%, whereas according to angiographic and MR imaging results, the cure rate was 59%. Conclusions. Although initial radiosurgical treatment failed to obliterate the AVM in these 52 patients, it did produce a substantial therapeutic effect (volume reduction). This size reduction commonly allowed higher doses to be delivered during radiosurgical retreatment. The results show rates of angiographically confirmed cure comparable to primary treatment and a low incidence of complications, indicating that salvage radiosurgical retreatment is a safe and effective therapy in cases of failed AVM radiosurgery.

Influenza is a common RNA virus that causes yearly epidemics with an illness typically presenting with fever, myalgias, constitutional symptoms, and upper and/or lower respiratory tract symptoms. Patients with malignancies receiving chemotherapy are at increased risk for influenza-related illness1,2 and have been shown to have higher complication and mortality rates.3–5 The Centers for Disease Control (CDC) recommends annual influenza vaccination for all persons older than 6 months.6 The CDC endorses the practice of influenza vaccination for patients with malignancies, although little concrete evidence exists to suggest that patients with malignancies and/or those undergoing active chemotherapy mount a sufficient immunologic response to achieve clinical protection. In the general population, influenza vaccination results in prevention of infection in ∼70%–90% of healthy young adults.7,8 Serologic response is high, with seroconversion rates of 75%–80% and seroprotection rates of around 95% based on hemagglutinin inhibition (HI) titer assessment.9,10 Studies have demonstrated reduced immunogenicity in elderly populations, with seroconversion rates of 23%–51% and seroprotection rates of 68%–97%,11 as well as other groups including patients with end-stage renal disease,12 renal transplants,13,14 liver transplants,15 and lung transplants,16 HIV populations,17 and others. Investigation of influenza vaccine efficacy in patients with malignancies has been limited. Cancer patients are vaccinated at rates well below 50%. Lack of awareness of the current recommendations, fear of side effects, and concerns about vaccine efficacy have been cited as the primary reasons for not offering vaccination.18 Studies have demonstrated seroconversion and seroprotection rates similar to healthy adults following vaccination of patients with lung cancer19 as well as those with a variety of solid tumors.20 In patients with hematologic malignancies, seroconversion rates have been reported to be lower (21%).21 Some studies have evaluated the efficacy of single vaccination, while others have suggested additional efficacy using a multidose regimen.22 The efficacy of influenza vaccination has not been evaluated in patients with central nervous system (CNS) malignancies. Nevertheless, this is a potentially robust population for study given the immunosuppressive effects of gliomas and its associated treatment,23 variable degrees of therapy-induced lymphopenia and neutropenia, and the inclusion of glucocorticoids into pharmocotherapeutic regimens. The current study pilots an investigation into influenza vaccine immunogenicity in a group of patients with CNS malignancy.

Purpose: To report initial clinical experience with a novel high-precision stereotactic radiotherapy system. Methods and Materials: Sixty patients ranging in age from 2 to 82 years received a total of 1426 treatments with the University of Florida frameless stereotactic radiotherapy system. Of the total, 39 (65%) were treated with stereotactic radiotherapy (SRT) alone, and 21 (35%) received SRT as a component of radiotherapy. Pathologic diagnoses included meningiomas (15 patients), low-grade astrocytomas (11 patients), germinomas (9 patients), and craniopharyngiomas (5 patients). The technique was used as means of dose escalation in 11 patients (18%) with aggressive tumors. Treatment reproducibility was measured by comparing bite plate positioning registered by infrared light-emitting diodes (IRLEDs) with the stereotactic radiosurgery reference system, and with measurements from each treatment arc for the 1426 daily treatments (5808 positions). We chose 0.3 mm vector translation error and 0.3° rotation about each axis as the maximum tolerated misalignment before treating each arc. Results: With a mean follow-up of 11 months, 3 patients had recurrence of malignant disease. Acute side effects were minimal. Of 11 patients with low grade astrocytomas, 4 (36%) had cerebral edema and increased enhancement on MR scans in the first year, and 2 required steroids. All had resolution and marked tumor involution on follow-up imaging. Bite plate reproducibility was as follows. Translational errors: anterior-posterior, 0.01 ± 0.10; lateral, 0.02 ± 0.07; axial, 0.01 ± 0.10. Rotational errors (degrees): anterior-posterior, 0.00 ± 0.03; lateral, 0.00 ± 0.06; axial, 0.01 ± 0.04. No patient treatment was delivered beyond the maximum tolerated misalignment. Daily treatment was delivered in approximately 15 min per patient. Conclusion: Our initial experience with stereotactic radiotherapy using the infrared camera guidance system was good. Patient selection and treatment strategies are evolving rapidly. Treatment accuracy was the best reported, and the treatment approach was practical.

✓ Glossopharyngeal neuralgia (GPN) is a rare condition in which patients present with intractable deep throat pain. Similar to trigeminal neuralgia (TN), treatment with microvascular decompression (MVD) has been successful in both. Because gamma knife surgery (GKS) has also been shown to be effective in treating TN, it seemed reasonable to apply it to GPN. The authors present the first report of GKS-treated GPN in a patient who presented with severe, poorly controlled GPN and who refused MVD.

✓ Glossopharyngeal neuralgia (GPN) is a rare condition in which patients present with intractable deep throat pain. Similar to trigeminal neuralgia (TN), treatment with microvascular decompression (MVD) has been successful in both. Because gamma knife surgery (GKS) has also been shown to be effective in treating TN, it seemed reasonable to apply it to GPN. The authors present the first report of GKS-treated GPN in a patient who presented with severe, poorly controlled GPN and who refused MVD.

This study describes 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 using a dose-escalation protocol with an additional dog receiving sham treatment. Animals were allowed to recover following N-TIRE ablation and the effects of treatment were monitored with clinical and magnetic resonance imaging examinations. Brains were subjected to histopathologic and ultrastructural assessment along with Bcl-2, caspase-3, and caspase-9 immunohistochemical staining following sacrifice 72 h post-treatment. Adverse clinical effects of N-TIRE 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. Lesion size correlated to the intensity of the applied electrical field. N-TIRE-induced lesions were characterized by parenchymal necrosis and hemorrhage; however, large blood vessels were preserved. A transition zone containing parenchymal edema, perivascular inflammatory cuffs, and reactive gliosis was interspersed between the necrotic focus and normal neuropil. Apoptotic labeling indices were not different between the 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 while selectively preserving major vascular structures. This work was supported in part by the Wallace Coulter and National Science Foundations (NSF-CBET 0933335). The authors thank Dr. Bernard Jortner, Dr. Elankumaran Subbiah, Ms. Jennifer Rudd, and Mrs. Barbara Wheeler for technical assistance with the ultrastructural and immunohistochemical studies. Angiodynamics, Inc. (USA) provided the NanoKnife pulse generator and electrodes used in this study. Published version

Irreversible Electroporation (IRE) is a new focal tissue ablation technique that has shown great promise as a treatment for a variety of soft-tissue neoplasms. The therapy uses pulsed electric fields to destabilize cell membranes and achieve tissue death in a non-thermal manner. The procedure is minimally invasive and is performed through small electrodes inserted into the tissue with treatment duration of about 1 min. In this chapter we describe the first systematic in vivo studies of IRE in canine brain tissue. We confirmed that the procedure can be applied safely in the brain and was well tolerated clinically in normal dogs. The necrotic lesions created with IRE were sub-millimeter in resolution, sharply delineated from normal brain, and spared the major blood vessels. In addition, our preliminary results in a rodent study indicate that IRE transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner with implications for enhanced delivery of cytotoxic agents to regions with infiltrative tumor cells. Finally, we present representative case examples demonstrating therapeutic planning aspects, clinical applications, and results of IRE ablation of spontaneous malignant intracranial gliomas in canine patients. Our group has demonstrated that IRE ablation can be performed safely, and is effective at reducing the tumor volume and associated intracranial hypertension, and allows for improvement in tumor-associated neurologic dysfunction. Our work illustrates the potential benefits of IRE for in vivo ablation of neoplastic brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal.

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. Methods 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). Results 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. Conclusions 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.

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.

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.

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.

Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS.Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13-24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival.Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume.Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

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.

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.

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.

Brain tumors constitute the most common intracranial tumor. Management of brain metastases has become increasingly complex as patients with brain metastases are living longer and more treatment options develop. The goal of this paper is to review the role of stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery, in isolation and in combination, in the contemporary treatment of brain metastases. Surgery and SRS both offer management options that may help to optimize therapy in selected patients. WBRT is another option but can lead to late toxicity and suboptimal local control in longer term survivors. Improved prognostic indices will be critical for selecting the best therapies. Further prospective trials are necessary to continue to elucidate factors that will help triage patients to the proper brain-directed therapy for their cancer.

Epilepsy is a common chronic neurologic disorder affecting 0.5 to 1 percent of the population. (Hauser, 1993 4131) More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. (Kwan et al. 2000; Sillanpaa et al. 2006; Sander et al. 1993) Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. (Brodie et al. 1996) Treatment options for these patients include new anti-epileptic drugs (AEDs), which may lead to seizure freedom in 7 percent of patients (Fisher et al. 1993) and resective surgery which is associated with longterm seizure freedom in 60-80% of patients.(Engel et al. 2003 ;Lee et al. 2005) Surgery for patients whose epilepsy has proven refractory to AEDs provides a high likelihood of reduction in seizure frequency, is generally safe, and is recommended for selected patients with refractory partial seizures. In spite of improvements in surgical technique, approximately 4 percent of patients will suffer death or permanent neurologic disability ( A global survey on epilepsy surgery, 1980-1990: a report by the Commission on Neurosurgery of Epilepsy, the International League Against Epilepsy 1997). Moreover, more than onethird of patients will not be candidates for surgical resection (Kwan et al. 2000). For patients who are not candidates for resective surgery, there are limited options. 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. The interest in neuromodulation for neurological disorders is driven by a desire to discover less invasive surgical treatments, as well as new treatments for patients whose medical conditions remain refractory to existing modalities. Vagal nerve stimulation (VNS) is one example of neuromodulation that was developed in the 1980s, and which is now routinely available. (Ben-Menachem et al. 2002) VNS, as an adjunct to medical management, may yield up to a 50 percent reduction in seizure frequency (A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. 1995) although most of these patients will not be seizurefree. Deep brain stimulation (DBS) is another example of neuromodulation. Given the significant experience and success of DBS for movement disorders (Krack et al. 2003) combined with its reversibility, programmability, and low risk of morbidity, there has been

Atypical meningiomas have poor local control with emerging literature indicating the use of radiosurgery in treatment. The purpose of this study was to evaluate clinical outcomes including local control and failure pattern after Gamma Knife radiosurgery (GKRS) and factors that may affect these outcomes. Between 1999 and 2008, 24 patients were treated with GKRS as either primary or salvage treatment for pathologically proven atypical meningiomas. Treatment failures were determined by serial magnetic resonance imaging. A median marginal dose of 14 Gy was used (range 10.5–18 Gy). Overall local control rates at 1, 2, and 5 years were 75, 51, and 44%, respectively. With median follow-up time of 42.5 months, 14 of 24 patients experienced a treatment failure at time of last follow-up. Eight recurrences were in-field, four were marginal failures, and two were distant failures. Wilcoxon analysis revealed that the conformality index (CI) was a significant predictor of local recurrence (P = 0.04). CI did not predict for distant recurrences (P = 0.16). On multivariate analysis evaluating factors predicting progression free survival, dose >14 Gy was found to be statistically significant (P = 0.01). There appears to be a dose response using GKRS beyond 14 Gy but given the suboptimal local control rates in this study, higher doses may still be needed to obtain better local control.

Background: Gamma Knife radiosurgery (GKRS) has been reported to be an effective modality to treat trigeminal neuralgia. Objective: To determine predictive factors for the successful treatment of trigeminal neuralgia with GKRS. Methods: Between 1999 and 2008, 777 GKRS procedures for patients with trigeminal neuralgia were performed at our institution. Evaluable follow-up data were obtained for 448 patients. Median follow-up time was 20.9 months (range, 3–86 months). The mean maximum prescribed dose was 88 Gy (range, 80–97 Gy). Dosimetric variables recorded included dorsal root entry zone dose, pons maximum dose, dose to the petrous dural ridge, and cisternal nerve length. Results: By 3 months after GKRS, 86% of patients achieved Barrow Neurologic Institute I to III pain scores, with 43% of patients achieving a Barrow Neurologic Institute I pain score. Twenty-six percent of patients reported posttreatment facial numbness; 28% of patients reported a post-GKRS procedure for relapsed pain, and median time to next procedure was 4.4 years. Multivariate analysis revealed that the development of postsurgical numbness (odds ratio [OR], 2.76; P = .006) was the dominant factor predictive of efficacy. Longer cisternal nerve length (OR, 0.85; P = .005), prior radiofrequency ablation (OR, 0.35; P = .028), and diabetes mellitus (OR, 0.38; P = .013) predicted decreased efficacy. The mean dose delivered to the dorsal root entry zone dose in patients who developed facial numbness (57.6 Gy) was more than the mean dose (47.3 Gy) given to patients who did not develop numbness (P = .02). Conclusion: The development of post-GKRS facial numbness is a dominant factor that predicts for efficacy of GKRS. History of diabetes mellitus or previous radio-frequency ablation may portend worsened outcome.

Irreversible electroporation (IRE) is a new non-thermal focal tissue ablation technique that uses low-energy electric pulses to destabilize cell membranes, thus achieving tissue death [1]. The procedure is minimally invasive and is performed through small electrodes inserted into the tissue with pulse delivery of about one minute. The pulses create an electric field that induces an increase in the resting transmembrane potential (TMP) of the cells [1]. Depending on the magnitude of the induced TMP, the electric pulses can have no effect, transiently increase membrane permeability, or cause cell death [1]. Our group has confirmed the safety of the procedure in brain with three experimental dogs [2]. We also treated a canine patient with IRE and radiation therapy for a non-resectable, high-grade glioma, resulting in complete remission of the tumor at four months [3].Copyright © 2011 by ASME

Purpose Radiosurgery has been successfully used in selected cases to avoid repeat whole-brain irradiation (WBI) in patients with multiple brain metastases of most solid tumor histological findings. Few data are available for the use of radiosurgery for small-cell lung cancer (SCLC). Methods and Materials Between November 1999 and June 2009, 51 patients with SCLC and previous WBI and new brain metastases were treated with GammaKnife stereotactic radiosurgery (GKSRS). A median dose of 18 Gy (range, 10–24 Gy) was prescribed to the margin of each metastasis. Patients were followed with serial imaging. Patient electronic records were reviewed to determine disease-related factors and clinical outcomes after GKSRS. Local and distant brain failure rates, overall survival, and likelihood of neurologic death were determined based on imaging results. The Kaplan-Meier method was used to determine survival and local and distant brain control. Cox proportional hazard regression was performed to determine strength of association between disease-related factors and survival. Results Median survival time for the entire cohort was 5.9 months. Local control rates at 1 and 2 years were 57% and 34%, respectively. Distant brain failure rates at 1 and 2 years were 58% and 75%, respectively. Fifty-three percent of patients ultimately died of neurologic death. On multivariate analysis, patients with stable (hazard ratio [HR] = 2.89) or progressive (HR = 6.98) extracranial disease (ECD) had worse overall survival than patients without evidence of ECD ( p = 0.00002). Concurrent chemotherapy improved local control (HR = 89; p = 0.006). Conclusions GKSRS represents a feasible salvage option in patients with SCLC and brain metastases for whom previous WBI has failed. The status of patients' ECD is a dominant factor predictive of overall survival. Local control may be inferior to that seen with other cancer histological results, although the use of concurrent chemotherapy may help to improve this.

Thalidomide and procarbazine have demonstrated single agent activity against malignant gliomas (MG). We evaluated the combination of thalidomide and procarbazine with a single arm phase II trial in adults with recurrent or progressive MG. Procarbazine was given at a dose of 250 mg/m(2)/d × 5day q 28 days. Thalidomide was administered at a dose of 200 mg/day continuously. Intrapatient dose escalation of thalidomide was attempted (increase by 100 mg/day weekly as tolerated) to a maximum of 800 mg/day. The primary outcome was tumor response, assessed by MRI and CT. Secondary outcomes were progression free survival (PFS), overall survival (OS) and toxicity. In addition, quality of life questionnaires were performed at baseline and prior to each odd cycle in all treated patients. Eighteen patients (median age of 50) were accrued and received a total of 36 cycles (median 2) of therapy. The median maximum thalidomide dose achieved was 400 mg (range 0-800). No complete or partial responses were seen. One patient (6%) experienced stable disease, fourteen (78%) progressed as best response and three (17%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5-2.5). Seventeen patients have died (one patient lost to follow-up after progression); median survival from enrollment was 7.6 months (95% CI, 3.5-9.4). Grade 3/4 drug related toxicity was minimal. Quality of life diminished over time. The combination of thalidomide and procarbazine demonstrated no efficacy in this trial.

Dystonia is a painful, disabling disease whose cause in many cases remains unknown. It has historically been treated with a variety methodologies including baclofen pumps, Botox injection, peripheral denervation, and stereotactic surgery. Deep brain stimulation (DBS) is emerging as a viable treatment option for selected patients with dystonia. Results of DBS for dystonia appear to be more consistently superior in patients with primary versus secondary forms of the disorder. Patients with secondary dystonia, due to a variety of causes, may still be candidates for DBS surgery, although the results may not be as consistently good. The procedure is relatively safe with a small likelihood of morbidity and mortality. A randomized trial is needed to determine who are the best patients and when it is best to proceed with surgery.

Background Irreversible electroporation (IRE) is a new minimally invasive technique to kill undesirable tissue in a non-thermal manner. In order to maximize the benefits from an IRE procedure, the pulse parameters and electrode configuration must be optimized to achieve complete coverage of the targeted tissue while preventing thermal damage due to excessive Joule heating. Methods We developed numerical simulations of typical protocols based on a previously published computed tomographic (CT) guided in vivo procedure. These models were adapted to assess the effects of temperature, electroporation, pulse duration, and repetition rate on the volumes of tissue undergoing IRE alone or in superposition with thermal damage. Results Nine different combinations of voltage and pulse frequency were investigated, five of which resulted in IRE alone while four produced IRE in superposition with thermal damage. Conclusions The parametric study evaluated the influence of pulse frequency and applied voltage on treatment volumes, and refined a proposed method to delineate IRE from thermal damage. We confirm that determining an IRE treatment protocol requires incorporating all the physical effects of electroporation, and that these effects may have significant implications in treatment planning and outcome assessment. The goal of the manuscript is to provide the reader with the numerical methods to assess multiple-pulse electroporation treatment protocols in order to isolate IRE from thermal damage and capitalize on the benefits of a non-thermal mode of tissue ablation.

Object Nonthermal irreversible electroporation (NTIRE) is a novel, minimally invasive technique to treat cancer, which is unique because of its nonthermal mechanism of tumor ablation. This paper evaluates the safety of an NTIRE procedure to lesion normal canine brain tissue. Methods The NTIRE procedure involved placing electrodes into a targeted area of brain in 3 dogs and delivering a series of short and intense electric pulses. The voltages of the pulses applied were varied between dogs. Another dog was used as a sham control. One additional dog was treated at an extreme voltage to determine the upper safety limits of the procedure. Ultrasonography was used at the time of the procedure to determine if the lesions could be visualized intraoperatively. The volumes of ablated tissue were then estimated on postprocedure MR imaging. Histological brain sections were then analyzed to evaluate the lesions produced. Results The animals tolerated the procedure with no apparent complications except for the animal that was treated at the upper voltage limit. The lesion volume appeared to decrease with decreasing voltage of applied pulses. Histological examination revealed cell death within the treated volume with a submillimeter transition zone between necrotic and normal brain. Conclusions The authors' results reveal that NTIRE at selected voltages can be safely administered in normal canine brain and that the volume of ablated tissue correlates with the voltage of the applied pulses. This preliminary study is the first step toward using NTIRE as a brain cancer treatment.

Objectives To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy. Results All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.