Parney, Ian F.

AbstractPleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

Abstract BACKGROUND: Patients with pleomorphic xanthoastrocytoma (PXA) routinely undergo multiple procedures to ensure recurrence-free survival and are resultantly at increased risk of experiencing perioperative complications (regional, medical, and/or neurological), a combination of which has not been recorded in previous studies. OBJECTIVE: To determine perioperative outcomes in a cohort of patients (adult and pediatric) with intracranial PXA. METHODS: We retrospectively identified 39 patients who underwent surgery at our institution for intracranial PXA between 1994 and 2011. Demographic factors were recorded along with Karnofsky Performance Status (KPS), complications, and mortality. RESULTS: Mean patient age was 31 years at the most recent surgery. A majority of patients (24; 62%) had multiple surgeries with a mean of 2 operations per patient. Eleven PXAs (28%) were malignant (grade III or IV). Perioperative complications included permanent neurological worsening in 4 patients (10%), regional complications in 4 (10%), and medical complications in 3 (8%). Preoperative KPS was ≥70 in 34 of 38 patients (89%). Long-term postoperative KPS was ≥70 in 36 of 37 patients (97%), suggesting good functional outcomes. There was no perioperative mortality, but 7 patients (18%) died of tumor progression. Patients with malignant PXAs trended toward higher risk of regional complications (3 of 11 patients [27%]; P = .06), received adjuvant therapy more often (10 of 11 patients [91%]; P < .001), had higher mortality from tumor progression (7 of 11 patients [64%]; P < .001), and were significantly larger (mean, 6.05 ± 0.73 cm standard error of the mean; n = 7; P < .01). CONCLUSION: Both pediatric and adult PXAs may be resected with good functional outcomes. Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality. Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy.

Accumulating pre-clinical data suggests that matrix metalloproteinase (MMP) expression plays a critical role in the pathophysiology of secondary brain injury. We conducted a prospective multimodal monitoring study in order to characterize the temporal MMP response after severe traumatic brain injury (TBI) in eight critically ill humans and its relationship with outcomes. High-cutoff, cerebral microdialysis ( n =8); external ventricular drainage ( n =3); and arterial and jugular venous bulb catheters were used to collect microdialysate, cerebrospinal fluid, and arterial and jugular bulb blood over 6 days. Levels of MMP-8 and -9 were initially high in microdialysate and then gradually declined over time. After these MMPs decreased, a spike in the microdialysate levels of MMP-2 and -3 occurred, followed by a gradual rise in the microdialysate concentration of MMP-7. Use of generalized estimating equations suggested that MMP-8 concentration in microdialysate was associated with mortality ( p =0.019) and neurological outcome at hospital discharge ( p =0.013). Moreover, the mean microdialysate concentration of MMP-8 was 2.4-fold higher among those who died after severe TBI than in those who survived. Mean microdialysate levels of MMP-8 also rose with increasing intracranial pressure (ICP), whereas those of MMP-7 decreased with increasing cerebral perfusion pressure (CPP). Significant changes in the mean microdialysate concentrations of MMP-1, -2, -3, and -9 and MMP-1, -2, -3, -7, and -9 also occurred with increases in microdialysate glucose and the lactate/pyruvate ratio, respectively. These results imply that monitoring of MMPs following severe TBI in humans is feasible, and that their expression may be associated with clinical outcomes, ICP, CPP, and cerebral metabolism.

Object The object of this study was to assess outcomes after surgery for recurrent intracranial glioma. Methods The authors retrospectively reviewed cases involving adult patients with intracranial glioma patients undergoing initial surgery (biopsy or resection) and one or more additional surgeries at their institution. Results A total of 323 operations were performed in 131 patients. The median survival was 76 months after first surgery, 36 months after second, 24 months after third, and 26.5 months after 4 or more surgeries. The overall complication rate was 12.8% after first surgery, 27.0% after second (OR 2.52, p = 0.0068), 22.0% after third (OR 1.92, not statistically significant [NS]), and 22.2% after 4 or more (OR 1.95, NS). Neurological complications occurred in 4.8% of patients at first surgery, 12.1% at second (OR 2.7, p = 0.0437), 8.2% at third (OR 1.75, NS), and 11.1% at 4 or more surgeries (OR 2.4583, NS). Regional complications occurred in 6.2% after first surgery, 9.9% after second surgery (OR 2.30, p = 0.095), 13.7% after third surgery (OR 3.31, p = 0.015), and 22.2% after 4 or more surgeries (OR 5.95, p = 0.056). Systemic complications occurred in 3.2% after first surgery, in 7.3% after second surgery (OR 2.3, p = 0.NS), in 4.1% after third surgery (OR 1.3, NS), and 0% after 4 or more surgeries. Reduction in Karnofsky Performance Status score occurred in 0% after first surgery, 8.1% after second surgery (OR 3.13, p = 0.0018), 10.2% after third surgery (OR 5.52, p < 0.0001), and 11.1% after 4 or more surgeries (OR 1.037, NS). Conclusions Postoperative survival is relatively prolonged but complication risk increases in patients with glioma who undergo multiple cranial surgeries. The largest increase in neurological risk occurs between the first and second surgery. In contrast, regional complication risk increases consistently with each surgery. The risk of systemic complications is not significantly altered with increasing surgeries. However, these complications only result in a modestly increased risk of functional decline after 2 or more surgeries. These findings may help counsel patients considering multiple glioma surgeries.

Object Carcinoid tumors are rare and have generally been regarded as indolent neoplasms. Systemic disease is often incurable; however, patients may live years with this disease. Furthermore, metastatic brain lesions are extremely uncommon. As such, few series have examined outcomes and prognostic factors in those with brain involvement. Methods The authors performed a retrospective review of patients who underwent primary treatment at Mayo Clinic in Rochester, Minnesota, for metastatic carcinoid tumors to the brain between 1986 and 2011. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier statistics. Cox proportional hazards were used to determine predictors of survival. Results Fifteen patients underwent primary treatment for metastatic carcinoid tumors to the brain between 1986 and 2011. Their mean age was 58 ± 12 years. Eighty percent (n = 12) of patients underwent surgery, whereas 2 received stereotactic radiosurgery and 1 had whole-brain radiation therapy (WBRT) as the primary treatment. The median follow-up duration was 19 months (maximum 124 months). Systemic disease progression occurred in 73% and was the leading cause of death in known cases, while intracranial disease recurred in 40%. The median PFS and OS were 21 and 19 months, respectively. The use of adjuvant WBRT correlated with improved PFS (HR 0.15, CI 0.0074–0.95, p = 0.044). Those who underwent surgery as primary modalities trended toward longer progression-free intervals (p = 0.095), although this did not reach significance. Conclusions Metastatic carcinoid disease to the brain appears to have a worse prognosis than that of other extracranial metastases. Although there was a trend toward a survival advantage in patients who underwent surgery and WBRT, further study is needed to establish definitive treatment recommendations.

Object Optimum management for elderly patients with newly diagnosed glioblastoma (GBM) in the temozolomide (TMZ) era is not well defined. The object of this study was to clarify outcomes in this population. Methods The authors retrospectively reviewed 105 consecutive cases involving elderly patients (age ≥ 65 years) with newly diagnosed GBM who were treated at the Mayo Clinic between 2003 and 2008. Results The patients' median age was 74 years (range 66–87 years), and the median Karnofsky Performance Status (KPS) score was 80 (range 40–90). Half of the patients underwent biopsy and half underwent resection. Patients with deep-seated lesions (19 patients [18%]) or multifocal lesions (34 patients [32%]) were more likely to have biopsy than resection (p = 0.0001 and 0.0009, respectively). New persistent neurological deficits developed in 7 patients (6.7%). Postoperative hemorrhage occurred in 6 patients (5.7%), all of whom underwent biopsy. Complete follow-up data regarding adjuvant treatment was available in 84 patients. Forty-one (49%) were treated with chemotherapy (mostly TMZ) and radiation therapy (RT), and 23 (27%) with RT alone. Nineteen (23%) received only palliative care after surgery (more common with biopsy, p = 0.03). Chemotherapy complications occurred in 28.6% (Grade 3 or 4 hematological complications in 11.9%). The median values for progression-free survival (PFS) and overall survival (OS) were 3.5 and 5.5 months. In a multivariate analysis, younger age (p = 0.03, risk ratio [RR] 0.34, 95% CI 0.13–0.89), single lesion (p = 0.02, RR 0.51, 95% CI 0.30–0.89), resection (p = 0.04, RR 0.54, 95% CI 0.31–0.94), and adjuvant treatment (p = 0.0001, RR 0.24, 95% CI 0.11–0.49) were associated with better OS. Only adjuvant treatment was significantly associated with prolonged PFS (p = 0.0007, RR 0.27, 95% CI 0.13–0.57). With combined therapy with resection, RT, and chemotherapy, the median PFS and OS were 8 and 12.5 months, respectively. Conclusions The prognosis for GBM worsens with increasing age in elderly patients. With important risks, resection and adjuvant treatment are associated with prolonged survival. Although selection bias cannot be excluded in this retrospective study, advanced age alone should not necessarily preclude optimal resection followed by adjuvant radiochemotherapy.

Abstract Heat shock protein (HSP) 90 is a molecular chaperone that modulates stability of several client proteins, many of which are key regulators of signaling pathways in glioblastoma multiforme (GBM). The potential for targeting multiple effectors makes HSP90 an appealing therapeutic target for GBM. The biological activity of HSP990, a novel HSP90 inhibitor (Novartis Pharmaceuticals) as single agent was evaluated in a panel of short-term explant cultures derived from primary GBM xenografts (n=10). HSP990 treatment resulted in a dose-dependent growth inhibition in the all xenograft lines, with an IC50 ranging from 5 to 30 nM. A 72 h exposure to HSP990 (10–30 nM) resulted in a dose-dependent decrease in the HSP90 client proteins Akt, Cdc2 and Cdc25C, a decrease in associated post-translational modifications p-Akt (S473), p-CDC2 (Y15), p-CDC25 (S216), and increased expression of HSP70. Additionally, a dose-dependent increase in HSP990-induced apoptosis (Annexin-V positivity), was observed within 24–72 hours of drug treatment. GBM tumors harbor a subpopulation of glioma stem cells that grow as neurospheres in neurobasal media and are considered important for tumor maintenance and progression. The effects of HSP990 were tested in neurospheres derived from 4 of the xenografts tested above (GBM12, GBM39, GB59, GBM12TMZ). These cultures demonstrated potential for tri-lineage differentiation upon serum challenge and had robust secondary neurosphere formation, demonstrating two hallmark features of cancer stem cells. In a bulk-culture neurosphere formation assay, co-incubation with 5 to 10 nM HSP990 was highly effective at suppressing neurosphere formation in all 4 xenograft lines. Notably, in GBM12 neurosphere cultures maintained in either serum-free media or challenged with serum, 30 nM HSP990 was equally effective at promoting up-regulation of HSP70, but exhibited less effect on Akt or Cdc2 in serum-free cultures as compared to cultures supplemented with serum. Incubation of serum-free neurosphere cultures with 5 nM HSP990 (5 days) resulted in increased glioneuronal differentiation exhibiting elevated GFAP, Oct-4 and beta-tubulin expression compared to untreated controls. To test ‘self renewal’ GBM12 neurospheres were treated with HSP990 (10, 30 nM) for 7 days followed by dissociation and plating equal numbers of viable cells at low density in fresh drug-free neurobasal media. Interestingly, HSP990 treatment did not affect the number of secondary neurospheres (surviving fraction: control = 1.00, 10 nM = 1.30, 30 nM = 1.05). Treatment of GBM12TMZ flank tumor xenografts with weekly HSP990 (13 mg/kg P.O.) resulted in a modest 9 day delay in tumor re-growth (40.3 and 49.3 respectively) compared to placebo treatment. In conclusion, HSP990 (a) had anti-proliferative, pro-apoptotic effect on differentiated serum-supplemented xenograft cultures (b) a pro-differentiation effect on serum-free GBM stem cell cultures (c) markedly suppressed neurosphere formation with prolonged drug exposure but not with more limited drug exposure (d) inhibited GBM growth in vivo. Thus, HSP990 may inhibit GBM growth both through direct growth inhibition and through pro-differentiation effects on GBM stem-like cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B100.