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This paper has two main purposes: (1) to report a rare case of paediatric gliosarcoma that invaded the surrounding orbit and (2) to demonstrate chlorpromazine injection as a potential treatment option for blind, painful eye caused by tumour invasion. A 12-year-old man who presented with headaches was found to have glioblastoma multiforme and it was excised and treated with radiation and chemotherapy. Seven months later, the tumour recurred as gliosarcoma, a rare variant of glioblastoma multiforme containing distinct gliomatous and sarcomatous components. In spite of treatment, the tumour progressed and eventually invaded into the right orbit. He subsequently developed a proptotic, blind, painful eye and was treated with retrobulbar chlorpromazine injection, which provided immediate symptomatic relief., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Brain metastasis (BM) affects up to one-third of adults with cancer and carries a historically bleak prognosis. Despite advances in stereotactic radiosurgery (SRS), rates of in-field recurrence (IFR) after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. Laser interstitial thermal therapy (LITT) is an emerging option in this setting, but its ability to prevent a neurologic death is unknown. In this study, we investigate the causes of death among patients with BM who undergo LITT for IFR after SRS. We conducted a single institution retrospective case series of patients with BM who underwent LITT for IFR after SRS. Clinical and demographic data were collected via chart review. The primary endpoint was cause of death. Between 2010 and 2018, 70 patients with BM underwent LITT for IFR after SRS. Median follow-up after LITT was 12.0 months. At analysis, 49 patients died; a cause was determined in 44. Death was neurologic in 20 patients and non-neurologic in 24. The 24-month cumulative incidence of neurologic and non-neurologic death was 35.1% and 38.6%, respectively. Etiologies of neurologic death included local recurrence (n = 7), recovery failure (n = 7), distant progression (n = 5), and other (n = 1). Among our patient population, LITT provided the ability to stabilize neurologic disease in up to 2/3 of patients. For IFR after SRS, LITT may represent a reasonable treatment strategy for select patients. Additional work is necessary to determine the extent to which LITT can prevent neurologic death after recurrence of BM.

Objective: The role of repeat resection for recurrent glioblastoma multiforme (rGBM) is unclear. This large comparative cohort study assessed overall survival (OS), survival since recurrence (SSR), quality of life, and complications in reoperated versus non-reoperated patients for rGBM., Patients and Methods: All patients with rGBM between 2005 and 2015, who were discussed by our institution's multi-disciplinary team, and who either did or did not undergo reoperation, were prospectively followed up with data collected and compared. Survival and prognostic factors were analysed using Kaplan-Meier and Cox regression methods., Results: 312 patients (reoperated, n = 145; non-reoperated, n = 167) were analysed. Median SSR was 10.8 months and 6.9 months in the reoperated and non-reoperated groups respectively (Log-rank test: p = 0.02). Median OS was 24.1 months and 20.4 months in the reoperated and non-reoperated groups, respectively (Log-rank test: p = 0.04). Quality of life as measured by Short Form 36 scores were 59 versus 54 at baseline and 62 versus 51 at four-month follow-up for re-operated and non-reoperated groups, respectively (p < 0.05). Age < 60 years, Karnofsky Performance Status (KPS) ≥ 80, recurrence ≥ 9 months from initial diagnosis, methylguanine methyltransferase (MGMT) promoter methylation, and extent of resection (EOR) > 80 %, each were significant predictors of SSR and OS. Complication rates were 5.5 % and 6.2 % following repeat resection and primary resection, respectively (p > 0.05)., Conclusion: This is the first large prospective comparative cohort study of rGBM and demonstrates that repeat resection confers a small but significant benefit in survival and quality of life over non-operative treatment. Best prognosis is associated with: younger age, KPS ≥ 80, late recurrence, MGMT promoter methylation and EOR > 80 %., (Copyright © 2019. Published by Elsevier B.V.)

Intracranial metastases are the most frequent brain tumor with recurrence rates after treatment of around 40-60%. Age is still considered a determinant of treatment and prognosis in this pathology. Recent studies analyzing the impact of metastasectomy in elderly patients focused on reporting perioperative mortality and morbidity rates but not on the evaluation of oncological outcome parameters. Aim of this study is to determine risk factors for in-brain local recurrence after brain surgery in this sub-population. From October 2009 until September 2016 all patients aged 65 years and above with histopathologically confirmed metastasis after surgical resection were retrospectively studied. Clinical, radiological and perioperative information was collected and statistically analysed. Follow-up consisted of clinical and radiological assessment every 3-months following surgery. 78 patients were included, of these 50% were female (39 patients). Median age was 71 years (66-83). Early postoperative-MRI verified a complete surgical resection in 41 patients (52.6%) and showed a tumor-remnant in 15 patients (19.2%). In 22 patients the MRI result was inconclusive (28.2%). None of the patients experienced severe complications due to surgery. The median postoperative NIHSS was adequate 1 ± 1.4 (0-6), nonetheless, insignificantly improved in comparison to the preoperative NIHSS (p = 0.16). A total of 20 patients (25.6%) presented local recurrence. The only statistically significant factor for development of local in-brain recurrence after resection of cerebral metastases in patients above 65 years of age was a tumor-remnant in the early postoperative MRI (p = 0.00005). Median overall survival was 13 months. Local in-brain recurrence after surgical resection of a cerebral metastasis in patients above 65 years of age was 25.6%. In our analysis, tumor-remnant in early postoperative MRI is the only risk factor for local in-brain recurrence. Oncological parameters in the present cohort do not seem to differ from recent phase III studies with non-geriatric patients. Nevertheless, controlled studies on the impact of metastasectomy in elderly patients delivering high quality reliable data are required.

In patients with gliomas, changes in hemispheric specialization for language determined by magnetoencephalography (MEG) were analyzed to elucidate the impact of treatment and tumor recurrence on language networks. Demonstration of reorganization of language networks in these patients has significant implications on the prevention of postoperative functional loss and recovery. Whole-brain activity during an auditory verb generation task was estimated from MEG recordings in a group of 73 patients with recurrent gliomas. Hemisphere of language dominance was estimated using the language laterality index (LI), a measure derived from the task. The initial scan was performed prior to resection; patients subsequently underwent surgery and adjuvant treatment. A second scan was performed upon recurrence prior to repeat resection. The relationship between the shift in LI between scans and demographics, anatomic location, pathology, and adjuvant treatment was analyzed. Laterality shifts were observed between scans; the median percent change was 29.1% across all patients. Laterality shift magnitude and relative direction were associated with the initial position of language dominance; patients with increased lateralization experienced greater shifts than those presenting more bilateral representation. A change in LI from left or right to bilateral (or vice versa) occurred in 23.3% of patients; complete switch occurred in 5.5% of patients. Patients with tumors within the language-dominant hemisphere experienced significantly greater shifts than those with contralateral tumors. The majority of patients with glioma experience shifts in language network organization over time which correlate with the relative position of language lateralization and tumor location., (© 2018 Wiley Periodicals, Inc.)

Background: To avoid permanent neurologic deficits and preserve brain function in and near the eloquent area, intraoperative electrical stimulation mapping (IESM) is necessary. However, little is known about how these subcortical regions are involved in calculation processing function in patients with glioma., Case Description: We report the case of a 56-year-old, right-handed woman working at a primary school as a teacher who had recurrent left parietal glioma. She underwent initial surgical resection for a low-grade glioma present in the left parietal lobe 14 months before recurrence. The latest magnetic resonance imaging results revealed an enhancing lesion in the cavity of the initial resection with an infiltrating tumor in the parietal lobe. Preserving language function and calculation processing was critical; therefore, she underwent awake surgery using IESM. Thus, the calculation site was elicited by subcortical electrical stimulation at the bottom of the tumor cavity during second resection. At the same point, she could speak normally but could not calculate repeatedly when stimulated. Therefore, we stopped tumor resection. After diagnosing anaplastic astrocytoma, she underwent radiation therapy and chemotherapy. She resumed her normal life as a teacher with preserved language and calculation processing. Eventually, 31 months later, she died from disease progression., Conclusions: In this report, IESM performed during awake surgery in a subcortical site demonstrated a crucial role played by the dominant parietal lobe in calculation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Surgery precedes both radiotherapy and chemotherapy as the first-line therapy for glioma. However, despite multimodal treatment, most glioma patients die from local recurrence in the resection margin. Glioma surgery is inherently lesional, and the response of brain tissue to surgery includes hemostasis, angiogenesis, reactive gliosis and inflammation. Unfortunately, these processes are also associated with tumorigenic side-effects. An increasing amount of evidence indicates that the response to a surgery-related brain injury is hijacked by residual glioma cells and participates in the local regeneration of tumor tissues at the resection margin. Inducing therapeutic hypothermia in the brain has long been used to treat the secondary damage, such as neuroinflammation and edema, that are caused by accidental traumatic brain injuries. There is compelling evidence to suggest that inducing therapeutic hypothermia at the resection margin would delay the local recurrence of glioma by (i) limiting cell proliferation, (ii) disrupting the pathological connection between inflammation and glioma recurrence, and (iii) limiting the consequences of the functional heterogeneity and complexity inherent to the tumor ecosystem. While the global whole-body cooling methods that are currently used to treat stroke in clinical practice may not adequately treat the resection margin, the future lies in implantable focal microcooling devices similar to those under development for the treatment of epilepsy. Preclinical and clinical strategies to evaluate focal hypothermia must be implemented to prevent glioma recurrence in the resection margin. Placing the resection margin in a state of hibernation may potentially provide such a long-awaited therapeutic breakthrough.

Background: Surgical resection is a universal component of glioma therapy. Little is known about the postoperative microenvironment due to limited preclinical models. Thus, we sought to develop a glioma resection and recurrence model in syngeneic immune-competent mice to understand how surgical resection influences tumor biology and the local microenvironment., Methods: We genetically engineered cells from a murine glioma mouse model to express fluorescent and bioluminescent reporters. Established allografts were resected using image-guided microsurgery. Postoperative tumor recurrence was monitored by serial imaging, and the peritumoral microenvironment was characterized by histopathology and immunohistochemistry. Coculture techniques were used to explore how astrocyte injury influences tumor aggressiveness in vitro. Transcriptome and secretome alterations in injured astrocytes was examined by RNA-seq and Luminex., Results: We found that image-guided resection achieved >90% reduction in tumor volume but failed to prevent both local and distant tumor recurrence. Immunostaining for glial fibrillary acidic protein and nestin showed that resection-induced injury led to temporal and spatial alterations in reactive astrocytes within the peritumoral microenvironment. In vitro, we found that astrocyte injury induced transcriptome and secretome alterations and promoted tumor proliferation, as well as migration., Conclusions: This study demonstrates a unique syngeneic model of glioma resection and recurrence in immune-competent mice. Furthermore, this model provided insights into the pattern of postsurgical tumor recurrence and changes in the peritumoral microenvironment, as well as the impact of injured astrocytes on glioma growth and invasion. A better understanding of the postsurgical tumor microenvironment will allow development of targeted anticancer agents that improve surgery-mediated effects on tumor biology., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

OBJECT To avoid iatrogenic injury during the removal of intrinsic cerebral neoplasms such as gliomas, direct electrical stimulation (DES) is used to identify cortical and subcortical white matter pathways critical for language, motor, and sensory function. When a patient undergoes more than 1 brain tumor resection as in the case of tumor recurrence, the use of DES provides an unusual opportunity to examine brain plasticity in the setting of neurological disease. METHODS The authors examined 561 consecutive cases in which patients underwent DES mapping during surgery forglioma resection. "Positive" and "negative" sites-discrete cortical regions where electrical stimulation did (positive) or did not (negative) produce transient sensory, motor, or language disturbance-were identified prior to tumor resection and documented by intraoperative photography for categorization into functional maps. In this group of 561 patients, 18 were identified who underwent repeat surgery in which 1 or more stimulation sites overlapped with those tested during the initial surgery. The authors compared intraoperative sensory, motor, or language mapping results between initial and repeat surgeries, and evaluated the clinical outcomes for these patients. RESULTS A total of 117 sites were tested for sensory (7 sites, 6.0%), motor (9 sites, 7.7%), or language (101 sites, 86.3%) function during both initial and repeat surgeries. The mean interval between surgical procedures was 4.1 years. During initial surgeries, 95 (81.2%) of 117 sites were found to be negative and 22 (18.8%) of 117 sites were found to be positive. During repeat surgeries, 103 (88.0%) of 117 sites were negative and 14 (12.0%) of 117 were positive. Of the 95 sites that were negative at the initial surgery, 94 (98.9%) were also negative at the repeat surgery, while 1 (1.1%) site was found to be positive. Of the 22 sites that were initially positive, 13 (59.1%) remained positive at repeat surgery, while 9 (40.9%) had become negative for function. Overall, 6 (33.3%) of 18 patients exhibited loss of function at 1 or more motor or language sites between surgeries. Loss of function at these sites was not associated with neurological impairment at the time of repeat surgery, suggesting that neurological function was preserved through neural circuit reorganization or activation of latent functional pathways. CONCLUSIONS The adult central nervous system reorganizes motor and language areas in patients with glioma. Ultimately, adult neural plasticity may help to preserve motor and language function in the presence of evolving structural lesions. The insight gained from this subset of patients has implications for our understanding of brain plasticity in clinical settings.

Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre-operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression-free survival (PFS). Pre-operative serum GFAP level of ≥0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor.

Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.

Glioblastoma, the most aggressive of the gliomas, has a high recurrence and mortality rate. The nature of this poor prognosis resides in the molecular heterogeneity and phenotypic features of this tumor. Despite research advances in understanding the molecular biology, it has been difficult to translate this knowledge into effective treatment. Nearly all will have tumor recurrence, yet to date very few therapies have established efficacy as salvage regimens. This challenge is further complicated by imaging confounders and to an even greater degree by the ever increasing molecular heterogeneity that is thought to be both sporadic and treatment-induced. The development of novel clinical trial designs to support the development and testing of novel treatment regimens and drug delivery strategies underscore the need for more precise techniques in imaging and better surrogate markers to help determine treatment response. This review summarizes recent approaches to treat patients with recurrent glioblastoma and considers future perspectives.

Introduction: Nutritional status is a major clinical parameter in multiple cancers. Indeed, nutritional status is a prognostic factor and a predictor of response and toxicity to treatments in breast and lung cancers for instance. To our knowledge, in patients suffering from malignant primary brain tumors, nutritional status has been poorly investigated., Methods: Nutritional status of 26 glioblastoma patients relapsing after a first line of treatment was studied. The body mass index (BMI), the prognostic inflammatory and nutritional index (PINI) and the instant nutritional score (INS) were assessed., Results: The BMI was abnormal in 12 patients, two were malnourished while 10 were overweight. The BMI was not correlated to age of patients. Overweight status did not impact patient survival but it was associated with reduced performance status. The PINI was abnormal in three patients. Finally, the INS was abnormal in 24 patients, noted 2 (n=22) or 4 (n=4)., Conclusions/discussion: Our results were not in favor of systematic nutritional support in patients with recurrent glioblastoma after a first line of treatment. Being overweight does not influence prognosis but may influence performance status. Steroid therapy and chemotherapy (inducing sodium and water retention and lymphopenia) weaken the relevance of BMI and INS for nutritional assessment in patients with recurrent glioblastoma. Further studies using additional nutritional tests in larger, independent and prospective cohorts of patients are warranted to obtain more details., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The breach rhythm is sometimes considered the consequence of reduced resistance between the cortex and the scalp electrode in the region of a skull defect. On the other hand, the electroencephalographic (EEG) changes after craniotomy were attributed to an activation of EEG activity by meningocortical adhesions with admixed gliosis. We report changes of the breach rhythm in a patient with astrocytoma, which give further evidence that the breach rhythm is not merely the result of physical changes in the area of a skull defect. In our patient, the breach rhythm was no longer detectable before a new tumor progression took place, showed up again, and at the end changed into localized slowing before the deterioration of the patient's general medical condition. This case suggests that in patients with brain tumors, the loss or attenuation in frequency of an established breach rhythm might be considered as an indication of a new tumor progression.

Objective: Navigated transcranial magnetic stimulation (nTMS) has been repeatedly shown to be comparably accurate to direct cortical stimulation (DCS) for rolandic region mapping. However, there are no data on its use for recurrent gliomas in which scarring and radiotherapy can impair nTMS. We therefore evaluated the accuracy of nTMS versus DCS and functional MRI (fMRI) in recurrent gliomas compared to initially operated tumors., Methods: We examined 8 patients with recurrent gliomas and 23 patients with initially operated lesions in or adjacent to the precentral gyrus by preoperative nTMS., Results: Preoperative motor mapping correlated well with intraoperative DCS in recurrent gliomas (6.2±6.0mm), as well as in newly diagnosed tumor patients (5.7±4.6mm) with no significant difference. Compared to fMRI, the difference was larger for upper (recurrent: 8.5±7.2mm; new: 9.8±8.6mm) and lower (recurrent: 17.1±10.6mm; new: 13.8±13.0mm) extremities, with no significant differences., Conclusions: When comparing nTMS with DCS and fMRI, nTMS is as accurate in recurrent gliomas as it is prior to the first operation. It should be considered a helpful modality in recurrent glioma patients as well., Significance: nTMS is also applicable in recurrent tumors., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

High grade gliomas (HGG) frequently recur regardless of treatment. Radiological detection of progressive disease (PD) is challenging due to the possibility of therapy-related MRI changes including: pseudoprogression (PP) and radiation necrosis (RN). Both may mimic PD. We undertook a literature review to examine existing data regarding imaging modalities and their ability to distinguish between PP, RN and PD. The review revealed 26 articles comparing the value of imaging modalities used to differentiate PP, RN and PD. Overall, conventional MRI and (18)fluorine-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) were more sensitive, while thallium single photon emission CT (SPECT) was more specific in differentiating PD from PP and RN. However, further prospective studies comparing the clinical utility of MRI, PET, and SPECT are needed to establish the most reliable diagnostic tool for the differentiation of PP, RN and PD in HGG., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Object: To define the role of Gamma Knife radiosurgery (GKRS) for the treatment of patients with hemangioblastomas., Methods: Between 1992 and 2009, 26 hemangioblastomas in 14 patients (9 female and 5 male) were treated with GKRS. Mean age of patients at the time of treatment was 45.1 years (range 25-61). von Hippel-Lindau disease was established in 7 patients, and 7 patients had sporadic hemangioblastomas. Twenty-one tumors were solid, 4 were cystic, and 1 had both components. Four patients were treated with upfront radiosurgery, and 10 were treated following a resection. Mean tumor volume was 1.65 cm3 (range 0.08-9.02, median 1.1 cm3). Mean dose to the tumor margin was 18 Gy (range 10-25, median 18). Patients were assessed clinically and radiologically at 6- to 12-month intervals following GKRS. The median follow-up was 3 years (range 0.5-12 years). Kaplan-Meier analysis was used to assess factors predictive of tumor progression, and factors predictive in univariate analysis (P < 0.10) were entered into Cox multivariate regression analysis., Results: On follow-up, 4 tumors were stable in volume (15%), 14 decreased (54%), and 8 increased (31%). Local tumor control rates at 1, 5, and 10 years was 89%, 74%, and 50%, respectively. There was a trend toward tumor progression in sporadic patients (P = 0.10), women (P = 0.09), and larger tumors (P = 0.10). In patients with multiple hemangioblastomas as compared to those with only a solitary hemangioblastoma, the radiosurgically treated lesion was 7.9 times more likely to progress after GKRS treatment (P = 0.018). This remained the only significant predictor in multivarialble analysis. At the last clinical follow-up, seven patients showed no change or improvement in their symptoms and seven deteriorated., Conclusion: Stereotactic radiosurgery offers a reasonable rate of tumor control and preservation of neurologic function in patients with hemangioblastomas. Patients with multiple hemangioblastomas are less likely to exhibit long-term tumor control of treated lesions following radiosurgery., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We present a 22-year-old woman with an ectopic recurrence of a craniopharyngioma. The patient presented first with a visual field deficit, and a craniopharyngioma was removed via an interhemispheric transcallosal approach. Magnetic resonance imaging (MRI) performed at 1 month, and then at 1 year after surgery showed complete removal of the lesion. However, at 4 years, MRI showed the presence of a small tumor in the right medial frontal lobe attached to the falx and along the previous surgical route. We present possible explanations for the ectopic recurrence and literature review.

We present an application of a previously developed agent-based glioma model (Chen et al 2009 Biosystems 95 234-42) for predicting spatio-temporal tumor progression using a patient-specific MRI lattice derived from apparent diffusion coefficient (ADC) data. Agents representing collections of migrating glioma cells are initialized based upon voxels at the outer border of the tumor identified on T1-weighted (Gd+) MRI at an initial time point. These simulated migratory cells exhibit a specific biologically inspired spatial search paradigm, representing a weighting of the differential contribution from haptotactic permission and biomechanical resistance on the migration decision process. ADC data from 9 months after the initial tumor resection were used to select the best search paradigm for the simulation, which was initiated using data from 6 months after the initial operation. Using this search paradigm, 100 simulations were performed to derive a probabilistic map of tumor invasion locations. The simulation was able to successfully predict a recurrence in the dorsal/posterior aspect long before it was depicted on T1-weighted MRI, 18 months after the initial operation.

In a consecutive series of 26 previously operated patients diagnosed with cerebral glioma, magnetic resonance spectroscopy (MRS), 2-((18)F) fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and perfusion MRI (MRP), were performed at follow-up to distinguish recurrence from radiation necrosis, and to identify tumour upgrading. Discrepancy between techniques was observed in 9 cases. The positive predictive value (PPV) and the negative predictive value (NPV) of each technique to detect the presence of high grade glioma was: MRI, PPV=50%; MRS, PPV=91.6%, NPV=100%; FDG-PET, PPV=75%, NPV=61.1%; MRP, PPV=100%, NPV=100%. In the selected group of nine cases studied to differentiate viable tumour from radiation necrosis, MRS and MRP reached a PPV and a NPV of 100%, whereas for FDG-PET, PPV and NPV were 66.6% and 60%, respectively. To distinguish between viable high-grade glioma and radiation necrosis, gadolinium-enhanced MRI gives a high false-positive rate, while MRS and MRP are superior to FDG-PET in discriminating tumour recurrence, grade increase and radiation necrosis., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Objective: To describe initial experience with resting-state correlation mapping as a potential aid for presurgical planning of brain tumor resection., Methods: Resting-state blood oxygenation-dependent functional magnetic resonance imaging (fMRI) scans were acquired in 17 healthy young adults and 4 patients with brain tumors invading sensorimotor cortex. Conventional fMRI motor mapping (finger-tapping protocol) was also performed in the patients. Intraoperatively, motor hand area was mapped using cortical stimulation., Results: Robust and consistent delineation of sensorimotor cortex was obtained using the resting-state blood oxygenation-dependent data. Resting-state functional mapping localized sensorimotor areas consistent with cortical stimulation mapping and in all patients performed as well as or better than task-based fMRI., Conclusion: Resting-state correlation mapping is a promising tool for reliable functional localization of eloquent cortex. This method compares well with "gold standard" cortical stimulation mapping and offers several advantages compared with conventional motor mapping fMRI.

Objective: Primary malignant odontogenic tumors in the suprasellar region have rarely been reported., Clinical Presentation: A partially cystic tumor that originated from the stalk and showed rapid enlargement was observed in a 56-year-old woman., Intervention: Gross total removal of the tumor was performed with sacrifice of the stalk. The tumor was a malignant epithelial type with odontogenic features, whereas findings consistent with craniopharyngioma were absent. The tumor recurred 14 months after surgery., Conclusion: The present unusual tumor may represent a novel member of malignant tumors of the suprasellar region. Given the common embryological origin of craniopharyngiomas to odontogenic lesions, a possible correlation with craniopharyngioma was suggested.

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.

Background: Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. Perillyl alcohol has shown to have both chemopreventive and chemotherapeutic activities in preclinical studies. The underlying action mechanism(s) of POH has yet to be delineated but may involve effects on the TGF-beta and/or the Ras signaling pathways. The intranasal delivery allows drugs that do not cross the BBB to enter the CNS; moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects., Methods: We are conducting a phase I/II study to evaluate the antitumoral activity of POH intranasal delivery in a 4x daily schedule in patients with recurrent MG. The objective was to determine PFS at 6 months and the safety for POH in adult patients who failed conventional treatment. Assessments were performed every 27 days. Thirty-seven patients with progressive disease after prior surgery, radiotherapy, and at least temozolomide-based chemotherapy were enrolled, 29 of whom had GBM, 5 who had anaplastic astrocytoma, and 3 had AO., Results: One patient (3.4%) with GBM and 1 patient (33.3%) with AO achieved partial response; 13 patients (44.8%) with GBM, 3 patients (60%) with AA, and 1 (33.3%) with AO achieved stable disease; 15 (51.7%) patients with GBM, 2 (40%) patients with AA, and 1 (33.3%) with AO showed progressive disease. Progression-free survival (partial response and stable disease) was 48.2% for patients with GBM, 60% for patients with AA, and 66.6% for patients with AO., Conclusions: There were no toxicity events. Perillyl alcohol is well tolerated and regression of tumor size in some patients is suggestive of antitumor activity. This work discusses POH intranasal delivery as a potential adjuvant therapeutic strategy for patients with malignant gliomas.

We report on a young woman operated for a ganglioglioma involving the right auditory cortex (AC), presenting with auditory seizures. Despite a normal pre-operative examination, a specific post-operative disorder affecting the perception of a human voice occurred. The patient was unable to recognise the tone of familiar voices while she recognised the expressed content. A temporal lobectomy for recurrence was performed two years later. The patient recovered from the voice perception deficit. This report shows that (1) a discrete site within the AC is specifically involved in the perception of tone of the human voice (2) functional compensation is possible.

Currently, surgical resection is one of only a few options for treating brain cancer. Unfortunately, postoperative tumour recurrence remains almost inevitable despite additional radiation or chemotherapy treatment following resection. Clinical observations and a growing body of experimental evidence have led to speculation that there is a population of persistent brain tumour stem cells (BTSCs)--or brain tumour initiating cells--that are difficult to completely remove surgically. Furthermore, residual BTSCs following surgery may actually be more resistant to subsequent radiation and/or chemotherapies. It remains to be determined if brain surgeries render the postoperative tissue microenvironment more favourable for the survival and growth of BTSCs, and therefore the recurrence of brain tumours.We hypothesise that BTSC-based tumour recurrence may develop within a specific niche of the aberrant tumour microenvironment. Even when the gross appearance of the primary tumour seems confined, BTSCs (albeit accounting only for a small population of tumour cells) may microscopically enter the stroma, hampering curative surgeries. This article discusses the theory that surgical resection of brain tumours generates niches recruiting BTSCs to the surgical wounds, stimulating the proliferation and invasiveness of BTSCs, and leading to tumour recurrence. Postoperative brains are marked with active wound repair in peritumoural margins, which is likely to be accompanied by increased inflammatory paracrine production, angiogenesis and reactive astrogliosis. The postoperative BTSC niche concept is consistent with the observation that brain tumour recurrence usually occurs in tissues that are proximal to the resection margin. In this article, we intend to reflect recent advances that may lead to novel strategies to eliminate postoperative brain tumour recurrence.

Background: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, may have activity in recurrent malignant gliomas. At recurrence some patients appear to develop nonenhancing infiltrating disease rather than enhancing tumor., Methods: We retrospectively reviewed 55 consecutive patients with recurrent malignant gliomas who received bevacizumab and chemotherapy to determine efficacy, toxicity, and patterns of recurrence. Using a blinded, standardized imaging review and quantitative volumetric analysis, the recurrence patterns of patients treated with bevacizumab were compared to recurrence patterns of 19 patients treated with chemotherapy alone., Results: A total of 2.3% of patients had a complete response, 31.8% partial response, 29.5% minimal response, and 29.5% had stable disease. Median time to radiographic progression was 19.3 weeks. Six-month progression-free survival (PFS) was 42% for patients with glioblastoma and 32% for patients with anaplastic glioma. In 23 patients who progressed on their initial therapy, bevacizumab was continued and the concurrent chemotherapy agent changed. In no case did the change produce a radiographic response, but two patients had prolonged PFS of 20 and 31 weeks. Recurrence pattern analysis identified a significant increase in the volume of infiltrative tumor relative to enhancing tumor in bevacizumab responders., Conclusions: Combination therapy with bevacizumab and chemotherapy is well-tolerated and active against recurrent malignant gliomas. At recurrence, continuing bevacizumab and changing the chemotherapy agent provided long-term disease control only in a small subset of patients. Bevacizumab may alter the recurrence pattern of malignant gliomas by suppressing enhancing tumor recurrence more effectively than it suppresses nonenhancing, infiltrative tumor growth.

A 21-year-old man presented with extraneural metastases to the peritoneum, pleura, bone marrow, lymph nodes, and other organs from a pulvinar high grade glioma. He had undergone a shunt operation and three tumor removals during a 6-year period. He also received radiotherapy and adjuvant chemotherapy with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride and interferon-beta. Two and a half years after the last surgery, extraneural metastasis to the peritoneal cavity was discovered. He died 13 months after the occurrence of extraneural metastases and 10 years after the initial diagnosis. Autopsy revealed tumor masses in the peritoneum, pleura, bone marrow, lymph nodes, and other organs, but no recurrent tumor of the primary lesion or metastases to other areas in the central nervous system. Systemic metastases from primary intracranial tumors are rare, but are likely to become more frequent as the prognosis of patients with brain tumors improves and the duration of survival lengthens.

Developmental venous anomalies (DVAs) are often associated with intracranial cavernous malformations (CMs). The frequency of this association and the observation of de novo CMs located near a known, preexisting DVA raise speculations as to the possible etiopathogenetic relationship between the two. In this article, the authors review the recent literature dealing with the potential etiopathogenetic, prognostic, and therapeutic implications of the association between DVAs and CMs.

Glioma is the most common malignant disease in the brain, and recurrence is the main cause of death from this disease. Tumor recurrence involves multiple steps, and requires the accumulation of the altered expression of many different proteins. Identification of the recurrence associated protein profile in glioma cell lines will be helpful in clarifying the molecular mechanisms underlying glioma recurrence. In this report, two glioma cell lines with distinct tumor forming ability in vitro and in vivo were chosen and the different protein expression patterns were analyzed by proteomics method. To confirm the utility of this method, we validated the differential expression of one protein, cathepsin D, by immunohistochemistry analysis. Forty-six proteins appeared differently between two cell lines and 18 of them were identified. These 18 are involved in cell proliferation, DNA replication, protein synthesis, invasion, angiogenesis and neurotrophic factor. All of these molecules are important in tumor growth, and a subset of them may be related to glioma recurrence. These findings may contribute to the discovery of new diagnostic markers and therapeutic targets of glioma.

Despite the implementation of increasingly aggressive surgery, chemotherapy, and fractionated radiotherapy for the treatment of glioblastoma multiforme (GBM), most therapeutic regimens have resulted in only modest improvements in patient survival. Gamma knife surgery (GKS) has become an indispensable tool in the primary and adjuvant management of many intracranial pathologies, including meningiomas, pituitary tumors, and arteriovenous malformations. Although it would seem that radiosurgical techniques, which produce steep radiation dose fall-off around the target, would not be well suited to treat these infiltrative lesions, a limited number of institutional series suggest that GKS might provide a survival benefit when used as part of the comprehensive management of GBM. This may largely be attributed to the observation that tumors typically recur within a 2-cm margin of the tumor resection cavity. Despite these encouraging results, enthusiasm for radiosurgery as a primary treatment for GBM is significantly tempered by the failure of the only randomized trial that has been conducted to yield any benefit for patients with GBM who were treated with radiosurgery. In this paper, the authors review the pathophysiological mechanisms of GKS and its applications for GBM management.

Neurenteric cyst represents a rare cystic lesion of the central nervous system, and is generally thought to result from failure of separation of neuro-ectodermal and endodermal elements during week 3 of embryogenesis. Although recurrences have been reported, only one case of craniospinal dissemination has previously been reported. We describe a unique intracranial neurenteric cyst with recurrence and dissemination to the spinal cord.

Object: The purpose of this study was to assess the differences in spatial extent and metabolic activity in a comparison of a radiosurgical target defined by conventional strategies that utilize the enhancing lesion and a metabolic lesion defined by proton magnetic resonance spectroscopy (MRS) imaging. The authors evaluated whether these differences manifest themselves in the clinical outcome of patients and assessed the value of incorporating 1H-MRS imaging-derived spatial information into the treatment planning process for gamma knife surgery (GKS)., Methods: Twenty-six patients harboring Grade IV gliomas who had previously been treated with external-beam radiation therapy were evaluated by comparing the radiosurgically treated lesion volume with the volume of metabolically active tumor defined on 1H-MRS imaging. The cohort was evenly divided into two groups based on the percentage of overlap between the radiosurgical target and the metabolic lesion volumes. Patients with a percentage of overlap greater than 50% with respect to the metabolic lesion volume were classified as low risk and those with an overlap less than 50% were classified as high risk. Kaplan-Meier estimators were calculated using time to progression and survival as dependent variables. The metabolite levels within the metabolic lesion were significantly greater than those within the radiosurgical target (p < or = 0.001). The median survival was 15.7 months for patients in the low-risk group and 10.4 months for those in the high-risk group. This difference was statistically significant (p < 0.01)., Conclusions: Analysis of the results of this study indicates that patients undergoing GKS may benefit from the inclusion of 1H-MRS imaging in the treatment planning process.

Cognitive function, with survival and response on brain imaging, is increasingly regarded as an important outcome measure in patients with brain tumours. This measure provides us with information on a patient's clinical situation and adverse treatment effects. Radiotherapy has been regarded as the main cause of cognitive decline in these patients, because children with brain tumours can develop intellectual deterioration caused by radiotherapy. In long-term surviving patients, radiotherapy may indeed lead to cognitive deficits, or even dementia. Recent studies, however, have made clear that focal radiotherapy in patients with glioma is not the main reason for cognitive deficits. The tumour itself and other medical treatments contribute largely to the cognitive deficits. Cognitive function is now also recognised as an independent prognostic factor in the survival of glioma patients. Additionally, cognitive deterioration can be the first indicator of progressive disease after treatment.

Purpose: In follow-up examinations of irradiated brain metastases conventional contrast-enhanced morphological MR imaging is often unable to distinguish between transient radiation effects, radionecrosis,and tumor recurrence. To evaluate changes of relative cerebral blood flow (rCBF) in irradiated brain metastases arterial spin-labeling techniques (ASL) were applied and compared to the outcome of (1)H MR spectroscopy and spectroscopic imaging ((1)H MRS, SI)., Patients and Methods: In 2 patients follow-up examinations of irradiated brain metastases were performed on a 1.5-T tomograph (average single dose: 20 Gy/80% isodose). Relative CBF values of gray matter (GM), white matter (WM),and metastases (Met) were measured by means of the ASL techniques ITS-FAIR and Q2TIPS. (1)H MRS was performed with PRESS 1500/135., Results: In both patients with initially hyperperfused metastases (Met/GM >1) the reduction of rCBF after stereotactic radiosurgery indicated response to treatment--even if the contrast-enhancing region increased--while increasing rCBF values indicated tumor progression. The findings were confirmed by (1)H MRS, SI and subsequent follow-up., Conclusion: The ASL techniques ITS-FAIR and Q2TIPS are able to monitor changes of rCBF in irradiated brain metastases. The two cases imply a possible role for ASL-MR perfusion imaging and (1)H MR spectroscopy in differentiating radiation effects from tumor progression.

Purpose: To improve differential diagnosis of residual or recurrent tumor vs. tissue necrosis in the course of radiation therapy of neurosurgically-treated brain tumors by application of fast (1)H-MR spectroscopic imaging in combination with single-voxel spectroscopy (SVS)., Methods: 54 patients after with malignant brain tumor (44 cases of glioblastoma, 10 other high-grade gliomas) were examined post-surgically in a total of 140 proton MRS examinations in the course of radiotherapy and in follow-up controls. Fast SI acquisition was performed as single-slice or double-slice TSI sequence with 32 x 32 phase encodings within 11 or 15 minutes, respectively. SVS with TR/TE 2000/272 ms yielded relative metabolite ratios, and in 15 patients the time courses of the absolute concentrations of brain metabolites were also determined., Results: In the group of 44 patients that could be tracked by MRS until therapy completion, TSI localized in 23 patients a persistent or newly arisen distinct choline accumulation indicating residual or recurrent tumor after radiation therapy. In all these cases MRS diagnosis was confirmed histologically or by short-term follow-up. However, in 6 of 15 patients showing a normal choline pattern in the TSI acquisition, tumor recurrence appeared within three months. SVS provided early recognition of recurrent tumor when detecting characteristic alterations of metabolite concentrations oin therapy follow-up., Conclusion: TSI and SVS represent complementary MRS techniques and are able to diagnose tumor recurrence early and unambiguously in cases where focal choline accumulation is detected.

Investigating intracranial tumors, different MR-related methods permit not only morphological visualization of lesions but also give insights into their metabolism, resulting in information about the biological qualities of the respective tumor. Magnetic resonance protocols are selected based on the type and timing of onset of clinical signs. Combined information from imaging studies and spectroscopy facilitates the differential diagnosis between blastomatous and non-blastomatous lesions before and after therapy.

Background and Purpose: The radiologic assessment of suspicious brain lesions after stereotactic radiotherapy of brain tumors is difficult. The purpose of our study was to define parameters from single-voxel proton MR spectroscopy that provide a probability measure for differentiating neoplastic from radiation-induced, nonneoplastic lesions., Methods: Seventy-two lesions in 56 patients were examined using a combined MR imaging and MR spectroscopy protocol (point-resolved spectroscopy, TE = 135 ms). Signal intensities of cholines, creatines, N-acetyl aspartate, and the presence of lactate and lipid resonances were correlated to final diagnoses established by clinical and MR imaging follow-up, positron emission tomography studies, or biopsy/surgery. Statistical analysis was performed using the t test, linear discriminant analysis, and k nearest-neighbor method., Results: Significantly increased signal intensity ratios I(tCho)/I(tCr) (P <.0001) and I(tCho)/I(NAA) (P <.0001) were observed in neoplastic (n = 34) compared with nonneoplastic lesions (n = 32) and contralateral normal brain (n = 33). Analysis of I(tCho)/I(tCr) and I(tCho)/I(NAA) data yielded correct retrospective classification as neoplastic and nonneoplastic in 82% and 81% of the lesions, respectively. Neither I(NAA)/I(tCr) nor signal intensitities of lactate or lipids were useful for differential diagnosis., Conclusion: Metabolic information provided by proton MR spectroscopy is useful for the differentiation of neoplastic and nonneoplastic brain lesions after stereotactic radiotherapy of brain tumors.

The authors determined the tolerance, response rate, and duration of recurrent anaplastic oligodendroglioma in 30 patients to temozolomide given orally at 150 to 200 mg/m2 on days 1 through 5 in cycles of 28 days. Nine patients responded: 7 of 27 patients (26%) treated with temozolomide after prior PCV chemotherapy and 2 of 3 chemotherapy-naive patients (both complete response). Median time to progression in responding patients was 13 months. Temozolomide shows promise and has an acceptable safety profile in recurrent anaplastic oligodendroglial tumors. Patients not responding to PCV may respond to temozolomide.

Background and Purpose: The diagnosis of brain tumors after high-dose radiation therapy is frequently limited by the lack of metabolic discrimination available with conventional imaging methods. The purpose of this study was to use proton MR spectroscopy to investigate serial changes in recurrent malignant gliomas after gamma knife radiosurgery to characterize tissue response to high-dose radiation., Methods: Eighteen patients with recurrent gliomas were studied with MR imaging and 3D proton MR spectroscopic imaging at the time of radiosurgery and at regular time points thereafter. Choline (Cho) and N-acetyl aspartate levels were calculated on a voxel-by-voxel basis and compared with levels found in normal tissue and with levels observed at previous time points. The results of the spectral analysis were then compared with the radiologic findings. Statistical comparisons were precluded by the small sample sizes involved., Results: Response within the gamma knife target was observed as a reduction of Cho levels and an increase in lactate/lipid levels, typically within 6 months of treatment. Increases in Cho correlated with poor radiologic response and suggested tumor recurrence, confirmed histologically in six cases. The development of a spectral abnormality preceded a coincident increase in contrast enhancement by 1 to 2 months in nine cases., Conclusion: Proton MR spectroscopic imaging provided diagnostic and monitoring information before and after radiosurgery. Evaluation of metabolic changes with proton MR spectroscopy and structural changes with MR imaging improved tissue discrimination and provided correlation with histologic findings.

The purpose of this study was to assess the use of positron emission tomography (PET) as a stereotactic planning modality for gamma knife radiosurgery (GKS). The authors developed and validated a technique for fiducial marker imaging, importation, and handling of PET data for integration into GammaPlan planning software. The clinical feasibility in applying this approach to a selected group of patients presenting with recurrent glial tumors or metastases was evaluated. Positron emission tomography data can be integrated into GammaPlan, allowing a high spatial accuracy, as validated using a phantom. Positron emission tomography data were successfully combined with magnetic resonance (MR) images to define the target volume for the radiosurgical treatment of patients with recurrent glioma or metastasis. This approach may contribute to optimizing target selection for infiltrating or ill-defined brain lesions. Because PET is also useful for the pretreatment and follow-up evaluation, the use of stereotactic PET in these patients can enable an accurate comparison of PET-based metabolic data with MR-based anatomical data. This could give a better understanding of the metabolic changes following radiosurgery. The ability to use PET data in GKS represents a crucial step toward further developments in radiosurgery, as this approach provides additional information that may open new perspectives for the optimization of the treatment of brain tumors.