Orin Bloch

Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article.

OBJECT Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. METHODS Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, ≤ 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. RESULTS Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence.

K+ waves in brain cortex visualized using a long-wavelength K+-sensing fluorescent indicator

We synthesized a water-soluble, long-wavelength K+ sensor, TAC-Red, consisting of triazacryptand coupled to 3,6-bis(dimethylamino)xanthylium, whose fluorescence increased 14-fold at 0–50 mM K+ with K+-to-Na+ selectivity >30. We visualized K+ waves in TAC-Red–stained brain cortex in mice during spreading depression, with velocity 4.4 ± 0.5 mm/min, and K+ release and reuptake half-times (t1/2) of 12 ± 2 and 32 ± 4 s, respectively. Aquaporin-4 (AQP4) deletion slowed K+ reuptake about twofold, suggesting AQP4-dependent K+ uptake by astroglia.

Gliomas Promote Immunosuppression through Induction of B7-H1 Expression in Tumor-Associated Macrophages

Purpose: Gliomas are known to induce local and systemic immunosuppression, inhibiting T-cell–mediated cytotoxic responses to tumor growth. Tumor-associated macrophages are a significant component of the immune infiltrate in gliomas and may express immunosuppressive surface ligands, such as B7-H1. Experimental Design: Tumor and peripheral blood samples from patients with glioblastoma (GBM) were analyzed by flow cytometry to evaluate the expression of B7-H1 in circulating and tumor-infiltrating macrophages. Human monocytes from healthy patients were stimulated with conditioned media from glioma cells to evaluate B7-H1 expression. Production of interleukin (IL)-10 by stimulated monocytes was measured by ELISA, and stimulation with IL-10 alone was evaluated for the ability to induce B7-H1 expression. The effect of inhibiting IL-10 and its receptor on glioma-induced B7-H1 expression in monocytes was evaluated. Results: Circulating monocytes in patients with GBM had significantly increased expression of B7-H1 compared with healthy control patients. Tumor-associated macrophages from matched GBM tissue had even greater B7-H1 expression. Treatment of normal monocytes with glioma-conditioned media could significantly increase B7-H1 expression. Stimulation of monocytes with conditioned media resulted in substantial production of IL-10 and upregulation of the IL-10 receptor. Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T-cell apoptosis when cocultured with stimulated monocytes. Inhibition of IL-10 and the IL-10 receptor could knock down the effect of glioma media on B7-H1 by more than 50%. Conclusions: Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype. Clin Cancer Res; 19(12); 3165–75. ©2013 AACR.

Aquaporin‐4 gene deletion in mice increases focal edema associated with staphylococcal brain abscess

Brain abscess is associated with local vasogenic edema, which leads to increased intracranial pressure and significant morbidity. Aquaporin‐4 (AQP4) is a water channel expressed in astroglia at the blood–brain and brain–CSF barriers. To investigate the role of AQP4 in brain abscess‐associated edema, live Staphylococcus aureus (105 colony‐forming units) was injected into the striatum to create a focal abscess. Wild‐type and AQP4‐deficient mice had comparable immune responses as measured by brain abscess volume (∼ 3.7 mm3 at 3 days), bacterial count and cytokine levels in brain homogenates. Blood–brain barrier permeability was increased comparably in both groups as assessed by extravasation of Evans blue dye. However, at 3 days the AQP4 null mice had significantly higher intracranial pressure (mean ± SEM 27 ± 2 vs. 17 ± 2 mmHg; p < 0.001) and brain water content (81.0 ± 0.3 vs. 79.3 ± 0.5 % water by weight in the abscess‐containing hemisphere; p < 0.01) than wild‐type mice. Reactive astrogliosis was found throughout the abscess‐containing hemisphere; however, only a subset of astrocytes in the peri‐abscess region of wild‐type mice had increased AQP4 immunoreactivity. Our findings demonstrate a protective effect of AQP4 on brain swelling in bacterial abscess, suggesting that AQP4 induction may reduce vasogenic edema associated with cerebral infection.

Accelerated Progression of Kaolin-Induced Hydrocephalus in Aquaporin-4-Deficient Mice

Hydrocephalus is caused by an imbalance in cerebrospinal fluid (CSF) production and absorption, resulting in excess ventricular fluid accumulation and neurologic impairment. Current therapy for hydrocephalus involves surgical diversion of excess ventricular fluid. The water-transporting protein aquaporin-4 (AQP4) is expressed at the brain-CSF and blood-brain barriers. Here, we provide evidence for AQP4-facilitated CSF absorption in hydrocephalus by a transparenchymal pathway into the cerebral vasculature. A mouse model of obstructive hydrocephalus was created by injecting kaolin (2.5 mg/mouse) into the cisterna magna. Intracranial pressure (ICP) was ~5mm Hg and ventricular size < 0.3 mm3 in control mice. Lateral ventricle volume increased to 3.7 ± 0.5 and 5.1 ±0.5 mm3 in AQP4 null mice at 3 and 5 days after injection, respectively, significantly greater than 2.6 ± 0.3 and 3.5 ± 0.5 mm3 in wildtype mice (P < 0.005). The corresponding ICP was 22 ± 2 mm Hg at 3 days in AQP4 null mice, significantly greater than 14 ± 1 mm Hg in wildtype mice (P < 0.005). Brain parenchymal water content increased by 2% to 3% by 3 days, corresponding to ~50 μL of fluid, indicating backflow of CSF from the ventricle into the parenchymal extracellular space. A multi-compartment model of hydrocephalus based on experimental data from wildtype mice accurately reproduced the greater severity of hydrocephalus in AQP4 null mice, and predicted a much reduced severity if AQP4 expression/function were increased. Our results indicate a significant role for AQP4-mediated transparenchymal CSF absorption in hydrocephalus and provide a rational basis for evaluation of AQP4 induction as a nonsurgical therapy for hydrocephalus.

Aquaporins: role in cerebral edema and brain water balance.

The regulation of water balance in the brain is crucial. A disruption in this equilibrium causes an increase in brain water content that significantly contributes to the pathophysiology of traumatic brain injury, hydrocephalus, and a variety of neurological disorders. The discovery of the aquaporin (AQP) family of membrane water channels has provided important new insights into the physiology and pathology of brain water homeostasis. A number of recent studies are described in the review that demonstrated the important role of AQP1 and AQP4 in brain water balance and cerebral edema. Phenotypic analyses of AQP deficient mice have allowed us to explore the role of these membrane water channels in the mechanisms of cytotoxic edema, vasogenic edema, and CSF production. These studies indicate that AQP4 plays significant role in the development of cytotoxic edema and the absorption of excess brain water resulting from vasogenic edema. They also have demonstrated the role of AQP1 in CSF production and maintenance of steady-state ICP. The ability to modulate water flux through AQP deletion has provided new insights into brain water homeostasis and suggested a number of new research directions. However, these efforts have not yet translated to the treatment human clinical diseases. These advances will require the development of AQP inhibitors and activators to establish the benefit modulating the function of these water channels.

Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial

BACKGROUND Outcomes for patients with recurrent glioblastoma multiforme (GBM) are poor and may be improved by immunotherapy. We investigated the safety and efficacy of an autologous heat-shock protein peptide complex-96 (HSPPC-96) vaccine for patients with recurrent GBM. METHODS In this open-label, single-arm, phase II study, adult patients with surgically resectable recurrent GBM were given vaccine after gross total resection. The primary endpoint was overall survival at 6 months. Secondary endpoints included overall survival, progression-free survival, safety, and immune profiling. Outcome analyses were performed in the intention-to-treat and efficacy populations. RESULTS Between October 3, 2007 and October 24, 2011, 41 patients underwent gross total resection of recurrent GBM and received a median of 6 doses of HSPPC-96 vaccine. Following treatment, 90.2% of patients were alive at 6 months (95% confidence interval [CI]: 75.9-96.8) and 29.3% were alive at 12 months (95% CI: 16.6-45.7). Median overall survival was 42.6 weeks (95% CI: 34.7-50.5). Twenty-seven (66%) patients were lymphopenic prior to therapy, and patients with lymphocyte counts below the cohort median demonstrated decreased overall survival (hazard ratio: 4.0; 95% CI: 1.4-11.8; P = .012). There were no treatment-related deaths. There were 37 serious (grades 3-5) adverse events reported, with 17 attributable to surgical resection and a single grade 3 constitutional event related to the vaccine. CONCLUSION The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation.

Intracranial hemangiopericytoma: Clinical experience and treatment considerations in a modern series of 40 adult patients

Intracranial hemangiopericytoma (HPC) is a malignant meningothelial tumor. Because of its rarity, few guidelines exist for optimal management.

A systematic review of intracranial chondrosarcoma and survival

Most data regarding survival in patients with chondrosarcoma are limited to case studies and small series performed at single institutions. A systematic review was performed to study the relationship between potential prognostic factors and survival. The survival rates were analyzed according to modality of treatment, treatment history, histological subtype, and histological grade. A total of 560 patients with intracranial chondrosarcoma were analyzed. Median follow-up time was 60 months. The 5-year mortality among all patients was 11.5% with median survival of 24 months. Mortality at 5 years was significantly greater for patients with tumors of higher grade, or of the mesenchymal subtype, or who had received surgical resection alone. The results of our systematic review provide useful data in predicting survival among intracranial chondrosarcoma patients.

Cranial Chondrosarcoma and Recurrence

The literature regarding recurrences in patients with cranial chondrosarcoma is limited to small series performed at single institutions, raising the question if these data precisely reflect the true recurrence of this tumor for guiding the clinician in the management of these patients. An extensive systematic review of the English literature was performed. The patients were stratified according to treatment modality, treatment history, histological subtype, and histological grade, and the recurrence rates were analyzed. A total of 560 patients treated for cranial chondrosarcoma were included. Five-year recurrence rate among all patients was 22% with median follow-up of 60 months and median disease-free interval of 16 months. Tumor recurrence was more common in patients who only received surgery or had mesenchymal subtype tumors. Our systematic review closely reflects the actuarial recurrence rate and provides predictive factors in the recurrence of cranial chondrosarcoma.