Epithelioid glioblastoma presenting as aphasia in a young adult with ovarian cancer: A case report.

Our patient's clinical history and preoperative radiographic evaluation suggested central nervous system (CNS) metastatic disease. Ultimately, final pathology revealed epithelioid glioblastoma (eGBM), a newly classified CNS primary tumor. This reinforces the importance of direct tissue sampling and including eGBM on the differential for young patients with histories of systemic cancer presenting with new CNS lesions.

Fluorescence-guided stereotactic biopsy: a proof-of-concept study.

OBJECTIVEAccurate histopathological diagnoses are often necessary for treating neuro-oncology patients. However, stereotactic biopsy (STB), a common method for obtaining suspicious tissue from deep or eloquent brain regions, fails to yield diagnostic tissue in some cases. Failure to obtain diagnostic tissue can delay initiation of treatment and may result in further invasive procedures for patients. In this study, the authors sought to determine if the coupling of in vivo optical imaging with an STB system is an effective method for identification of diagnostic tissue at the time of biopsy.METHODSA minimally invasive fiber optic imaging system was developed by coupling a 0.65-mm-diameter coherent fiber optic fluorescence microendoscope to an STB system. Human U251 glioma cells were transduced for stable expression of blue fluorescent protein (BFP) to produce U251-BFP cells that were utilized for in vitro and in vivo experiments. In vitro, blue fluorescence was confirmed, and tumor cell delineation by fluorescein sodium (FNa) was quantified with fluorescence microscopy. In vivo, transgenic athymic rats implanted with U251-BFP cells (n = 4) were utilized for experiments. Five weeks postimplantation, the rats received 5-10 mg/kg intravenous FNa and underwent craniotomies overlying the tumor implantation site and contralateral normal brain. A clinical STB needle containing our 0.65-mm imaging fiber was passed through each craniotomy and images were collected. Fluorescence images from regions of interest ipsilateral and contralateral to tumor implantation were obtained and quantified.RESULTSLive-cell fluorescence imaging confirmed blue fluorescence from transduced tumor cells and revealed a strong correlation between tumor cells quantified by blue fluorescence and FNa contrast (R2 = 0.91, p < 0.001). Normalized to background, in vivo FNa-mediated fluorescence intensity was significantly greater from tumor regions, verified by blue fluorescence, compared to contralateral brain in all animals (301.7 ± 34.18 relative fluorescence units, p < 0.001). Fluorescence intensity measured from the tumor margin was not significantly greater than that from normal brain (p = 0.89). Biopsies obtained from regions of strong fluorescein contrast were histologically consistent with tumor.CONCLUSIONSThe authors found that in vivo fluorescence imaging with an STB needle containing a submillimeter-diameter fiber optic fluorescence microendoscope provided direct visualization of neoplastic tissue in an animal brain tumor model prior to biopsy. These results were confirmed in vivo with positive control cells and by post hoc histological assessment. In vivo fluorescence guidance may improve the diagnostic yield of stereotactic biopsies.

Overview of dosimetric and biological perspectives on radiosurgery of multiple brain metastases in comparison with whole brain radiotherapy.

PURPOSE: Treatment option of stereotactic radiosurgery versus whole brain radiotherapy for multiple brain metastases (>10) is an ongoing debate. Detailed dosimetric and biological information are presented in this study to investigate the possible clinical outcomes.Materials and Methods: Nine patients with multiple brain metastases (11-25) underwent stereotactic radiosurgery. Whole brain radiotherapy plans are retrospectively designed with the same MR image set and the same structure set for each patient using the standard opposing lateral beams and fractionation (3 Gy × 10).Physical doses and biologically effective doses are calculated for each lesion target and the CNS normal tissues and they are compared between whole brain radiotherapy and stereotactic radiosurgery in the context of clinical efficacy and published toxicities. RESULTS: Tumor biologically effective dose is higher in radiosurgery than in whole brain radiotherapy by factors of 3.2-5.3 in maximum dose and of 2.4-3.1 in mean dose. Biologically effective mean dose in radiosurgery is 1.3-34.3% for normal brain, 0.7-31.6% for brainstem, 0.5-5.7% for chiasm, 0.2-5.7% for optic nerves and 0.6-18.1% for hippocampus of that in whole brain radiotherapy over nine cases presented here. We also presented the dose-volume relationship for normal brain to address the dosimetric concerns in radiosurgery. CONCLUSIONS: Dose-volume metrics presented in this study are essential to understanding the safety and efficacy of whole brain radiotherapy and/or radiosurgery for multiple brain metastases. Whole brain radiotherapy has resulted in higher incidence of radiation-related toxicities than radiosurgery. Even for patients with more than 10 brain metastases, the CNS normal tissues receive significantly lower doses in radiosurgery. Mean normal brain dose in SRS is found to correlate with the total volume of lesions rather than the number of lesions treated.

Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases.

OBJECT: The efficacy and safety of treatment with whole-brain radiotherapy (WBRT) or with stereotactic radiosurgery (SRS) for multiple brain metastases (> 10) are topics of ongoing debate. This study presents detailed dosimetric and biological information to investigate the possible clinical outcomes of these 2 modalities. METHODS: Five patients with multiple brain metastases (n = 11-23) underwent SRS. Whole-brain radiotherapy plans were retrospectively designed with the same MR image set and the same structure set for each patient, using the standard opposing lateral beams and fractionation (3 Gy × 10). Physical radiation doses and biologically effective doses (BEDs) in WBRT and SRS were calculated for each lesion target and for the normal brain tissues for comparison of the 2 modalities in the context of clinical efficacy and published toxicities. RESULTS: The BEDs targeted to the tumor were higher in SRS than in WBRT by factors ranging from 2.4- to 3.0- fold for the mean dose and from 3.2- to 5.3-fold for the maximum dose. In the 5 patients, mean BEDs in SRS (calculated as percentages of BEDs in WBRT) were 1.3%-34.3% for normal brain tissue, 0.7%-31.6% for the brainstem, 0.5%-5.7% for the chiasm, 0.2%-5.7% for optic nerves, and 0.6%-18.1% for the hippocampus. CONCLUSIONS: The dose-volume metrics presented in this study were essential to understanding the safety and efficacy of WBRT and SRS for multiple brain metastases. Whole-brain radiotherapy results in a higher incidence of radiation-related toxicities than SRS. Even in patients with > 10 brain metastases, the normal CNS tissues receive significantly lower doses in SRS. The mean normal brain dose in SRS correlated with the total volume of the lesions rather than with the number of lesions treated.

Dose-volume effects on brainstem dose tolerance in radiosurgery.

OBJECT: Dose-volume data concerning the brainstem in stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN) were analyzed in relation to associated complications. The authors present their set of data and compare it with currently cited information on brainstem dose tolerance associated with conventional fractionated radiation therapy and hypofractionated radiation treatment of other diseases. METHODS: Stereotactic radiosurgery for TN delivers a much higher radiation dose to the brainstem in a single fraction than doses delivered by any other procedures. A literature survey of articles on radiosurgery for TN revealed no incidences of severe toxicity, unlike other high-dose procedures involving the brainstem. Published data on brainstem dose tolerance were investigated and compared with dose-volume data in TN radiosurgery. The authors also performed a biological modeling study of dose-volume data involving the brainstem in cases of TN treated with the Gamma Knife, CyberKnife, and linear accelerator-based systems. RESULTS: The brainstem may receive a maximum dose as high as 45 Gy during radiosurgery for TN. The major complication after TN radiosurgery is mild to moderate facial numbness, and few other severe toxic responses to radiation are observed. The biologically effective dose of 45 Gy in a single fraction is much higher than any brainstem dose tolerance currently cited in conventional fractionation or in single or hypofractionated radiation treatments. However, in TN radiosurgery, the dose falloff is so steep and the delivery so accurate that brainstem volumes of 0.1-0.5 cm(3) or larger receive lower planned and delivered doses than those in other radiation-related procedures. Current models are suggestive, but an extensive analysis of detailed dose-volume clinical data is needed. CONCLUSIONS: Patients whose TN is treated with radiosurgery are a valuable population in which to demonstrate the dose-volume effects of an extreme hypofractionated radiation treatment on the brainstem. The result of TN radiosurgery suggests that a very small volume of the brainstem can tolerate a drastically high dose without suffering a severe clinical injury. The authors believe that the steep dose gradient in TN radiosurgery plays a key role in the low toxicity experienced by the brainstem.

Long-term follow-up after gene therapy for canavan disease.

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

Glycerol rhizotomy versus gamma knife radiosurgery for the treatment of trigeminal neuralgia: an analysis of patients treated at one institution.

BACKGROUND: Medically refractory trigeminal neuralgia (TN) has been treated with a variety of minimally invasive techniques, all of which have been compared with microvascular decompression. For patients not considered good surgical candidates, percutaneous retrogasserian glycerol rhizotomy (GR) and gamma knife (GK) radiosurgery are two minimally invasive techniques in common practice worldwide and used routinely at Jefferson Hospital for Neuroscience. Using a common pain scale outcomes questionnaire, we sought to analyze efficacies and morbidities of both treatments. METHODS AND MATERIALS: Between June 1994 and December 2002, 79 patients were treated with GR and 109 patients underwent GK for the treatment of TN. GR was performed with fluoroscopic guidance as an overnight inpatient procedure. GK was performed using a single 4-mm shot positioned at the root exit zone of the trigeminal nerve. Radiation doses of 70-90 Gy prescribed to the 100% isodose line were used. Treatment outcomes including pain response, pain recurrence, treatment failure, treatment-related side effects, and overall patient satisfaction with GK and GR were compared using a common outcomes scale. Using the Barrow Neurologic Institute pain scale, patients were asked to define their level of pain both before and after treatment: I, no pain and no pain medication required; I, occasional pain not requiring medication; IIIa, no pain and pain medication used; IIIb, some pain adequately controlled with medication; IV, some pain not adequately controlled with medication; and V, severe pain with no relief with medication. We used posttreatment scores of I, II, IIIa, and IIIb to identify treatment success, whereas scores of IV and V were considered treatment failure. Results were compiled from respondents and analyzed using SAS software. Statistical comparisons used log-rank test, univariate and multivariate logistic regression, Fisher's exact test, and Wilcoxon test with significance established at p < 0.05. RESULTS: There were 63 evaluable GK patients and 36 evaluable GR patients. The median follow-up time was 34 and 29 months for the GR and GK groups, respectively. The median age was 69 and 70 years and the median number of years with TN pain was 6 and 7 years in the GR and GK groups, respectively. Thirty-one GR (86%) and 58 GK (92%) patients achieved a successful treatment outcome (p = 0.49). The median time to pain relief was < or = 24 h in the GR group and 3 weeks in the GK group (p < 0.001, ordinal logistic regression). Nineteen GR and 26 GK patients experienced pain recurrence or pain never relieved (p = 0.30). The median time to pain recurrence was 5 and 8 months in the GR and GK groups, respectively (p = 0.22). At last follow-up, however, a statistically significant greater number of GR vs. GK patients had failed treatment. Twelve or 33% of GR patients, whereas 8 or 13% of GK patients, had BNI scores of 4 or 5 (p = 0.019, Fisher's exact test). When both initial and late treatment failures were combined, the overall rate of treatment failures was 39% in the GR group and 24% in the GK group (p = 0.023, log-rank). More GR patients developed facial numbness and facial numbness morbidity than GK patients: 19 GR (54%) and 17 GK patients (30%) developed new facial numbness and 12 GR and 7 GK patients reported either somewhat or very bothersome facial numbness (p = 0.018). On multivariate analysis, only treatment with GK and severity of pain before treatment significantly predicted treatment response. GK patients were more likely to have a lower pain score at last follow-up than were GR patients (p = 0.005, OR = 4.3), and patients with pretreatment pain scores of 5 were more likely to have lower posttreatment pain scores than patients with pretreatment pain scores of 4 and lower (p = 0.003, OR = 4.0). CONCLUSION: Despite greater facial numbness morbidity and a higher failure rate, GR provided more immediate pain relief than GK. GR therefore should be considered in patients with disabling trigeminal pain requiring urgent pain relief. For all other patients, GK provides better long-term pain relief with less treatment-related morbidity, and should therefore be considered the preferred treatment for patients with medically refractory trigeminal neuralgia who are not suitable candidates for microvascular nerve decompression.

Fractionated stereotactic radiotherapy for the treatment of optic nerve sheath meningiomas: preliminary observations of 33 optic nerves in 30 patients with historical comparison to observation with or without prior surgery.

OBJECTIVE: We investigated the safety and efficacy of stereotactic radiotherapy as an alternative therapy to surgical resection for optic nerve sheath meningiomas (ONSMs). METHODS: Thirty patients and 33 optic nerves with ONSMs were treated with conventional fractionated stereotactic radiotherapy treatment (CF-SRT) between July 1996 and May 2001 with the use of a 6-MeV LINAC designed for and dedicated to radiosurgery. The LINAC technique involved daily CF-SRT involving a relocatable frame, an average of three isocenters, and high-radiation dose conformality established by noncoplanar arc beam shaping and differential beam weighting. The patients who were treated with CF-SRT were followed clinically with serial visual fields and radiographically with both magnetic resonance imaging and functional (111)In-octreotide single-photon emission computed tomography. The results of treatment were compared with a historical control group of ONSM patients who were either observed or treated surgically and then observed. RESULTS: Our study population comprised 18 women and 12 men with a median age of 44 years (age range, 20-76 yr). The median isosurface radiation dose was 51 Gy (dose range, 50-54.0 Gy), and the median clinical follow-up time was 89 weeks (range, 9-284 wk). Of 22 optic nerves with vision before CF-SRT, 20 nerves (92%) demonstrated preserved vision, and 42% manifested improvement in visual acuity and/or visual field at follow-up. Comparison of our patients with a historical control group revealed preserved vision in only 16% of patients in a comparable period of observation, along with a 150% greater probability of visual improvement. Four patients (13%) had posttreatment morbidities, including visual loss (two patients), optic neuritis (one patient), and transient orbital pain (one patient). On magnetic resonance imaging studies, there was no evidence of tumor progression or recurrence in all patients, including tumor volume reductions noted in four patients. All six patients monitored with (111)In-octreotide scintigraphy demonstrated significant decreases in tumor activity after CF-SRT. CONCLUSION: To date, this article describes the largest reported series of ONSMs. Although longer follow-up is necessary, we think that CF-SRT represents a safe alternative to surgery and offers a higher likelihood of preserved or improved vision in patients with ONSM. Our analysis suggests that CF-SRT is also preferable to observation. Functional (111)In-octreotide single-photon emission computed tomographic scintigraphy provides a useful technique for the assessment of tumor control that complements serial posttreatment magnetic resonance imaging in patients with ONSMs.