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John H. Sampson

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Edward F. Chang, Aaron Clark, Justin S. Smith, Mei-Yin Polley, Susan M. Chang, Nicholas M. Barbaro, Andrew T. Parsa, Michael W. McDermott and Mitchel S. Berger

Object

Low-grade gliomas (LGGs) frequently infiltrate highly functional or “eloquent” brain areas. Given the lack of long-term survival data, the prognostic significance of eloquent brain tumor location and the role of functional mapping during resective surgery in presumed eloquent brain regions are unknown.

Methods

We performed a retrospective analysis of 281 cases involving adults who underwent resection of a supratentorial LGG at a brain tumor referral center. Preoperative MR images were evaluated blindly for involvement of eloquent brain areas, including the sensorimotor and language cortices, and specific subcortical structures. For high-risk tumors located in presumed eloquent brain areas, long-term survival estimates were evaluated for patients who underwent intraoperative functional mapping with electrocortical stimulation and for those who did not.

Results

One hundred and seventy-four patients (62%) had high-risk LGGs that were located in presumed eloquent areas. Adjusting for other known prognostic factors, patients with tumors in areas presumed to be eloquent had worse overall and progression-free survival (OS, hazard ratio [HR] 6.1, 95% CI 2.6–14.1; PFS, HR 1.9, 95% CI 1.2–2.9; Cox proportional hazards). Confirmation of tumor overlapping functional areas during intraoperative mapping was strongly associated with shorter survival (OS, HR 9.6, 95% CI 3.6–25.9). In contrast, when mapping revealed that tumor spared true eloquent areas, patients had significantly longer survival, nearly comparable to patients with tumors that clearly involved only noneloquent areas, as demonstrated by preoperative imaging (OS, HR 2.9, 95% CI 1.0–8.5).

Conclusions

Presumed eloquent location of LGGs is an important but modifiable risk factor predicting disease progression and death. Delineation of true functional and nonfunctional areas by intraoperative mapping in high-risk patients to maximize tumor resection can dramatically improve long-term survival.

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Atom Sarkar and E. Antonio Chiocca

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Wael Hassaneen, Nicholas B. Levine, Dima Suki, Abhijit L. Salaskar, Alessandra de Moura Lima, Ian E. McCutcheon, Sujit S. Prabhu, Frederick F. Lang, Franco DeMonte, Ganesh Rao, Jeffrey S. Weinberg, David M. Wildrick, Kenneth D. Aldape and Raymond Sawaya

Object

Multiple craniotomies have been performed for resection of multiple brain metastases in the same surgical session with satisfactory outcomes, but the role of this procedure in the management of multifocal and multicentric glioblastomas is undetermined, although it is not the standard approach at most centers.

Methods

The authors performed a retrospective analysis of data prospectively collected between 1993 and 2008 in 20 patients with multifocal or multicentric glioblastomas (Group A) who underwent resection of all lesions via multiple craniotomies during a single surgical session. Twenty patients who underwent resection of solitary glioblastoma (Group B) were selected to match Group A with respect to the preoperative Karnofsky Performance Scale (KPS) score, tumor functional grade, extent of resection, age at time of surgery, and year of surgery. Clinical and neurosurgical outcomes were evaluated.

Results

In Group A, the median age was 52 years (range 32–78 years); 70% of patients were male; the median preoperative KPS score was 80 (range 50–100); and 9 patients had multicentric glioblastomas and 11 had multifocal glioblastomas. Aggressive resection of all lesions in Group A was achieved via multiple craniotomies in the same session, with a median extent of resection of 100%. Groups A and B were comparable with respect to all the matching variables as well as the amount of tumor necrosis, number of cysts, and the use of intraoperative navigation. The overall median survival duration was 9.7 months in Group A and 10.5 months in Group B (p = 0.34). Group A and Group B (single craniotomy) had complication rates of 30% and 35% and 30-day mortality rates of 5% (1 patient) and 0%, respectively.

Conclusions

Aggressive resection of all lesions in selected patients with multifocal or multicentric glioblastomas resulted in a survival duration comparable with that of patients undergoing surgery for a single lesion, without an associated increase in postoperative morbidity. This finding may indicate that conventional wisdom of a minimal role for surgical treatment in glioblastoma should at least be questioned.

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Andrew E. Sloan

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Kaisorn L. Chaichana, Khan K. Chaichana, Alessandro Olivi, Jon D. Weingart, Richard Bennett, Henry Brem and Alfredo Quiñones-Hinojosa

Object

As the population ages, the incidence of glioblastoma multiforme (GBM) among older patients (age > 65 years) will increase. Older patients, unlike their younger counterparts, are not often offered aggressive surgery because of their age, comorbidities, and potential inability to tolerate surgery. The goal of this study was to identify preoperative factors associated with decreased survival for older patients who underwent resection of a GBM. The identification of these factors may provide insight into which patients would benefit most from aggressive surgery.

Methods

All patients older than 65 years who underwent nonbiopsy resection of an intracranial GBM at a single institution between 1997 and 2007 were retrospectively reviewed. Factors associated with overall survival were assessed using multivariate proportional hazards regression analysis after controlling for peri- and postoperative factors known to be associated with outcome (extent of resection, carmustine wafer implantation, temozolomide chemotherapy, and radiation therapy). Variables with p < 0.05 were considered statistically significant.

Results

A total of 129 patients with an average age of 73 ± 5 years met the inclusion/exclusion criteria. At last follow-up, all 129 patients had died, with a median survival of 7.9 months. The preoperative factors that were independently associated with decreased survival were Karnofsky Performance Scale (KPS) score less than 80 (p = 0.001), chronic obstructive pulmonary disease (p = 0.01), motor deficit (p = 0.01), language deficit (p = 0.005), cognitive deficit (p = 0.02), and tumor size larger than 4 cm (p = 0.002). Patients with 0–1 (Group 1), 2–3 (Group 2), and 4–6 (Group 3) of these factors had statistically different survival times, where the median survival was 9.2, 5.5, and 4.4 months, respectively. In log-rank analysis, the median survival for Group 1 was significantly longer than that for Group 2 (p = 0.004) and Group 3 (p < 0.0001), while Group 2 had longer survival than Group 3 (p = 0.02).

Conclusions

Older patients with an increasing number of these factors may not benefit as much from aggressive surgery as patients with fewer factors. This may provide insight into identifying which patients older than 65 years of age may benefit from aggressive surgery.

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David W. Roberts, Pablo A. Valdés, Brent T. Harris, Kathryn M. Fontaine, Alexander Hartov, Xiaoyao Fan, Songbai Ji, S. Scott Lollis, Brian W. Pogue, Frederic Leblond, Tor D. Tosteson, Brian C. Wilson and Keith D. Paulsen

Object

The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection.

Methods

In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0–3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E–stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0–IV); 2) tumor burden score (0–III); and 3) necrotic burden score (0–III).

Results

Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of intraoperative fluorescence and histopathological score (χ2 = 58.8, p < 0.001), between fluorescence levels and tumor burden (χ2 = 42.7, p < 0.001), and between fluorescence levels and necrotic burden (χ2 = 30.9, p < 0.001). The corresponding Spearman rank correlation coefficients were 0.51 (p < 0.001) for fluorescence and histopathological score, and 0.49 (p < 0.001) for fluorescence and tumor burden, suggesting a strongly positive relationship for each of these variables.

Conclusions

These results demonstrate a significant relationship between contrast enhancement on preoperative MR imaging and observable intraoperative PpIX fluorescence. The finding that preoperative MR image signatures are predictive of intraoperative PpIX fluorescence is of practical importance for identifying candidates for the procedure. Furthermore, this study provides evidence that a strong relationship exists between tumor aggressiveness and the degree of tissue fluorescence that is observable intraoperatively, and that observable fluorescence has an excellent positive predictive value but a low negative predictive value.

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Kaisorn L. Chaichana, Aditya N. Halthore, Scott L. Parker, Alessandro Olivi, Jon D. Weingart, Henry Brem and Alfredo Quinones-Hinojosa

Object

The median survival duration for patients with glioblastoma is approximately 12 months. Maximizing quality of life (QOL) for patients with glioblastoma is a priority. An important, yet understudied, QOL component is functional independence. The aims of this study were to evaluate functional outcomes over time for patients with glioblastoma, as well as identify factors associated with prolonged functional independence.

Methods

All patients who underwent first-time resection of either a primary (de novo) or secondary (prior lower grade glioma) glioblastoma at a single institution from 1996 to 2006 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score ≥ 80 were included. Kaplan-Meier, log-rank, and multivariate proportional hazards regression analyses were used to identify associations (p < 0.05) with functional independence (KPS score ≥ 60) following glioblastoma resection.

Results

The median follow-up duration time was 10 months (interquartile range [IQR] 5.6–17.0 months). A patient's preoperative (p = 0.02) and immediate postoperative (within 2 months) functional status was associated with prolonged survival (p < 0.0001). Of the 544 patients in this series, 302 (56%) lost their functional independence at a median of 10 months (IQR 6–16 months). Factors independently associated with prolonged functional independence were: preoperative KPS score ≥ 90 (p = 0.004), preoperative seizures (p = 0.002), primary glioblastoma (p < 0.0001), gross-total resection (p < 0.0001), and temozolomide chemotherapy (p < 0.0001). Factors independently associated with decreased functional independence were: older age (p < 0.0001), coexistent coronary artery disease (p = 0.009), and incurring a new postoperative motor deficit (p = 0.009). Furthermore, a decline in functional status was independently associated with tumor recurrence (p = 0.01).

Conclusions

The identification and consideration of these factors associated with prolonged functional outcome (preoperative KPS score ≥ 90, seizures, primary glioblastoma, gross-total resection, temozolomide) and decreased functional outcome (older age, coronary artery disease, new postoperative motor deficit) may help guide treatment strategies aimed at improving QOL for patients with glioblastoma.

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Walter Stummer, Jörg-Christian Tonn, Hubertus Maximilian Mehdorn, Ulf Nestler, Kea Franz, Claudia Goetz, Andrea Bink and Uwe Pichlmeier

Object

Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA–induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery.

Methods

Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function.

Results

More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm3, p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036).

Conclusions

Extended resections performed using a tool such as 5-ALA–derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.

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John A. Boockvar, Apostolos J. Tsiouris, Christoph P. Hofstetter, Ilhami Kovanlikaya, Sherese Fralin, Kartik Kesavabhotla, Stephen M. Seedial, Susan C. Pannullo, Theodore H. Schwartz, Philip Stieg, Robert D. Zimmerman, Jared Knopman, Ronald J. Scheff, Paul Christos, Shankar Vallabhajosula and Howard A. Riina

Object

The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma.

Methods

A total of 30 patients with recurrent malignant glioma were included in the current study.

Results

The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients.

Conclusions

The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.