Is Visible Aminolevulinic Acid-Induced Fluorescence an Independent Biomarker for Prognosis in Histologically Confirmed (World Health Organization 2016) Low-Grade Gliomas?

Neurosurgery, Volume 84, Issue 6, June 2019, Pages 1214–1224

Approximately 20% of low-grade gliomas (LGG) display visible protoporphyrin fluorescence during surgery after 5-aminolevulinic acid (5-ALA) administration.

OBJECTIVE: To determine if fluorescence represents a prognostic marker in LGG.

METHODS: Seventy-four consecutive patients with LGG (World Health Organization 2016) were operated on with 5-ALA. Fluorescent tissue was specifically biopsied. Tumor size, age, Karnofsky index, contrast-enhancement, fluorescence, and molecular factors (IDH1/IDH2-mutations, Ki67/MIB1 Index, 1p19q codeletions, ATRX, EGFR, p53 expression, and O6-methylguanine DNA methyltransferase promotor methylation), were related to progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS).

RESULTS: Sixteen of seventy-four LGGs (21.6%) fluoresced. Fluorescence was partially related to weak enhancement on magnetic resonance imaging and increased (positron emission tomography)PET-FET uptake, but not to Karnofsky Performance Score, tumor size, or age. Regarding molecular markers, only EGFR expression differed marginally (fluorescing vs nonfluorescing: 19% vs 5%; P = .057). Median follow-up was 46.4 mo (95% confidence interval [CI]: 41.8-51.1). PFS, MTFS, and OS were shorter in fluorescing tumors (PFS: median 9.8 mo, 95% CI: 1.00-27.7 vs 45.8, 31.9-59.7, MTFS: 43.0 [27.5-58.5] vs 64.6 [57.7- 71.5], median not reached, P = .015; OS: 51.6, [34.8-68.3] vs [68.2, 62.7-73.8], P = .002). IDH mutations significantly predicted PFS, MTFS, and OS. In multivariate analysis IDH status and fluorescence both independently predictedMTFS and OS. PFSwas not independently predicted by fluorescence.

CONCLUSION: This is the first report investigating the role of ALA-induced fluorescence in histologically confirmed LGG. Fluorescence appeared to be a marker for inherent malignant transformation and OS, independently of known prognostic markers. Fluorescence in LGG might be taken into account when deciding on adjuvant therapies.

Accurate Delineation of Glioma Infiltration by Advanced PET/MR Neuro-Imaging (FRONTIER Study)

f1-largeNeurosurgery 79:535–540, 2016

Glioma imaging, used for diagnostics, treatment planning, and followup, is currently based on standard magnetic resonance imaging (MRI) modalities (T1 contrast-enhancement for gadolinium-enhancing gliomas and T2 fluid-attenuated inversion recovery hyperintensity for nonenhancing gliomas). The diagnostic accuracy of these techniques for the delineation of gliomas is suboptimal.

OBJECTIVE: To assess the diagnostic accuracy of advanced neuroimaging compared with standard MRI modalities for the detection of diffuse glioma infiltration within the brain.

METHODS: A monocenter, prospective, diagnostic observational study in adult patients with a newly diagnosed, diffuse infiltrative glioma undergoing resective glioma surgery. Forty patients will be recruited in 3 years. Advanced neuroimaging will be added to the standard preoperative MRI. Serial neuronavigated biopsies in and around the glioma boundaries, obtained immediately preceding resective surgery, will provide histopathologic and molecular characteristics of the regions of interest, enabling comparison with quantitative measurements in the imaging modalities at the same biopsy sites.

DISCUSSION: In this clinical study, we determine the diagnostic accuracy of advanced imaging in addition to standard MRI to delineate glioma. The results of our study can be valuable for the development of an improved standard imaging protocol for glioma treatment.

EXPECTED OUTCOME: We hypothesize that a combination of positron emission tomography, MR spectroscopy, and standard MRI will have a superior accuracy for glioma delineation compared with standard MRI alone. In addition, we anticipate that advanced imaging will correlate with the histopathologic and molecular characteristics of glioma.

Epidural Cortical Stimulation of the Left Dorsolateral Prefrontal Cortex for Refractory Major Depressive Disorder

Neurosurgery 69:1015–1029, 2011 DOI: 10.1227/NEU.0b013e318229cfcd

A significant number of patients with major depressive disorder are unresponsive to conventional therapies. For these patients, neuromodulation approaches are being investigated.

OBJECTIVE: To determine whether epidural cortical stimulation at the left dorsolateral prefrontal cortex is safe and efficacious for major depressive disorder through a safety and feasibility study.

METHODS: Twelve patients were recruited in this randomized, single-blind, shamcontrolled study with a 104-week follow-up period. The main outcome measures were Hamilton Depression Rating Scale-28 (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Function (GAF), and Quality of Life Enjoyment and Satisfaction (QLES) questionnaire. An electrode was implanted over Brodmann area 9/46 in the left hemisphere. The electrode provided long-term stimulation to this target via its connections to an implanted neurostimulator in the chest.

RESULTS: During the sham-controlled phase, there was no statistical difference between sham and active stimulation, although a trend toward efficacy was seen with the active stimulation group. In the open-label phase, we observed a significant improvement in outcome scores for the HDRS, MADRS, and GAF but not the QLES (HDRS: df = 7, F = 7.72, P < .001; MADRS: df = 7, F = 8.2, P < .001; GAF: df = 5, F = 16.87, P < .001; QLES: df = 5, F = 1.32, P . .2; repeated measures ANOVA). With regard to the HDRS, 6 patients had ≥40% improvement, 5 patients had ≥ 50% improvement, and 4 subjects achieved remission (HDRS , 10) at some point during the study.

CONCLUSION: Epidural cortical stimulation of the left dorsolateral prefrontal cortex appears to be a safe and potentially efficacious neuromodulation approach for treatment- refractory major depressive disorder.

Molecular imaging of gliomas with PET: Opportunities and limitations

Neuro-Oncology 13(8):806–819, 2011. doi:10.1093/neuonc/nor054

Neuroimaging enables the noninvasive evaluation of glioma and is considered to be one of the key factors for individualized therapy and patient management, since accurate diagnosis and demarcation of viable tumor tissue is required for treatment planning as well as assessment of treatment response. Conventional imaging techniques like MRI and CT reveal morphological information but are of limited value for the assessment of more specific and reproducible information about biology and activity of the tumor. Molecular imaging with PET is increasingly implemented in neuro-oncology, since it provides additional metabolic information of the tumor, both for patient management as well as for evaluation of newly developed therapeutics.Different molecular processes have been proposed to be useful, like glucose consumption, expression of amino acid transporters, proliferation rate, membrane biosynthesis, and hypoxia. Thus, PET might help neuro-oncologists gain further insights into tumor biology by “true molecular imaging” as well as understand treatment-related phenomena. This review describes the method of PET acquisition as well as the tracers used to image biological processes in gliomas. Furthermore, it considers the clinical impact of PET on the use of currently available radiotracers, which were shown to be potentially valuable for discrimination between neoplastic and nonneoplastic tissue, as well as on tumor grading, determinination of treatment response, and providing an outlook toward further developments.

Agraphia after awake surgery for brain tumor: new insights into the anatomo-functional network of writing

Surgical Neurology. Volume 72, Issue 3, Pages 223-241 (September 2009)

Background

Controversy still exists about neural basis underlying writing and its relation with the sites subserving oral language. Our objective is to study functional areas involved in writing network, based on the observations of different postoperative writing disorders in a population of patients without preoperative agraphia.

Methods

We analyzed the postoperative agraphia profiles in 15 patients who underwent surgery for cerebral LGGs in functional language areas, using electrical mapping under local anesthesia. These profiles were then correlated to the sites of the lesions, shown by preoperative cerebral imaging.

Results

Our findings showed that (1) spoken language and writing functions could be dissociated, and that (2) writing is subserved, at least partially, by a network of 5 areas located in the dominant hemisphere for language: the superior parietal region, the supramarginalis gyrus, the second and third frontal convolutions, the supplementary motor area, and the insula. Each of these areas seems to have a different role in writing, which will be detailed in this article. However, among the patients, only those with lesions of the supplementary motor area did not recover from agraphia in the postoperative period (in 50% of cases).

Conclusions

On the basis of these results, and in the light of the recent literature, we discuss the relevance of each area in this anatomo-functional network as well as the clinical implications of such better knowledge of the neural basis of writing, especially for brain surgery and functional rehabilitation.