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ABSTRACT: BACKGROUND: Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib. METHODS: Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment. RESULTS: After dosing of oral TMZ only, ECF-TMZ mean-C max and area under the concentration curve(AUC0-∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C max and AUC0-∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C max and AUC0-∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment. CONCLUSIONS: In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.
Cancer Chemotherapy and Pharmacology 05/2013; · 2.83 Impact Factor
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ABSTRACT: Patients with glioblastoma (GB) are known to have poor prognoses, and among these patients, those with poor neurological function have an even poorer prognosis. Consequently, aggressive surgeries and adjuvant therapies are often withheld because of this dismal outlook. The effects of aggressive therapies in this small subset of patients remain unknown. The goal of this study was to evaluate outcomes and factors associated with survival for poor functioning patients who underwent aggressive resection of their GB. Adult patients who underwent surgical resection of an intracranial primary GB at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score of ⩽60 were included. A total of 100 patients with primary GB met the inclusion criteria. The average age (±standard deviation) and KPS score of this cohort were 54±15years and 53±12, respectively. No patient (0%) experienced perioperative mortality, and 0 (0%), 10 (10%), and 3 (3%) of patients incurred a new or increasing language, motor, and visual deficit, respectively. At last follow-up, 88 (88%) patients died with a median survival of 6.6months. The factors associated with improved survival were age <65year (p=0.005), tumor size >2cm (p=0.01), radical tumor resection (p=0.01), and temozolomide (p=0.001). This study identifies a subset of patients with poor functional status who may benefit from aggressive surgical resection.
Journal of Clinical Neuroscience 04/2013; · 1.25 Impact Factor
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ABSTRACT: Recent advances in glioblastoma therapy have led to optimism that more effective therapies will improve outcomes. Immunotherapy is a promising approach that has demonstrated the potential to eradicate cancer cells with cellular-level accuracy while minimizing damage to surrounding healthy tissue. Several vaccination strategies have been evaluated for activity against glioblastoma in clinical trials. These include peptide vaccines, polyvalent dendritic cell vaccines, heat shock protein vaccines and adoptive immunotherapy. In this review, we highlight clinical trials representative of each of these approaches and discuss strategies for integrating these therapies into routine patient care.
Immunotherapy 02/2013; 5(2):155-67. · 1.85 Impact Factor
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Kaisorn L Chaichana,
Courtney Pendleton,
Christopher Jackson,
Juan Carlos Martinez-Gutierrez,
Andrea Diaz-Stransky,
Javier Aguayo,
Alessandro Olivi,
Jon Weingart,
Gary Gallia,
Michael Lim, Henry Brem,
Alfredo Quinones-Hinojosa
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ABSTRACT: OBJECTIVE: The development of venothromboembolisms (VTEs), including deep vein thrombosis (DVT) and pulmonary emboli (PE), is common in brain tumor patients. Their development can be catastrophic. Studies evaluating pre-operative clinical factors that predispose patients to the development of VTE are few and limited. An understanding may help risk stratify patients and guide subsequent therapy aimed at reducing the risk of DVTs/PEs. METHODS: All adult patients who underwent surgery for an intracranial tumor at an academic tertiary care institution between 1998 and 2008 were retrospectively reviewed. Stepwise multivariate logistical regression analysis was used to identify pre-operative factors associated with the development of peri-operative (within 30 days of surgery) DVTs/PEs among patients who underwent surgery of their intracranial tumor. RESULTS: Of the 4293 patients in this study, 126 (3%) patients developed DVT and/or PE in the peri-operative period. The pre-operative factors independently associated with the development of DVTs/PEs were: poorer Karnofsky performance scale (KPS) [odds ratio (OR), 1.040; 95% confidence interval (CI), 1.026-1.052; P<0.0001], high grade glioma (OR, 1.702; 95% CI, 1.176-2.465; P=0.005), older age (OR, 1.033; 95% CI, 1.020-1.046; P<0.0001), hypertension (OR, 1.785; 95% CI, 1.180-2.699; P=0.006), and motor deficit (OR, 1.854; 95% CI, 1.244-2.763; P=0.002). Eighty-six per cent of the patients with DVTs/PEs were treated with either unfractionated or low molecular weight heparin, and 4% of these patients developed intracranial hemorrhage. DISCUSSION: The present study found that poorer functional status, older age, pre-operative motor deficit, high grade glioma, and hypertension each independently increased the risk of developing peri-operative DVTs/PEs. These findings may provide patients and physicians with prognostic information that may guide therapies aimed at minimizing the development of peri-operative DVTs/PEs.
Neurological Research 12/2012; · 1.52 Impact Factor
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ABSTRACT: OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ-pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5-9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.
Journal of Neuro-Oncology 12/2012; · 3.21 Impact Factor
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ABSTRACT: Laser speckle contrast imaging (LSCI) is a contrast agent free imaging technique suited for longitudinal assessment of vascular remodeling that accompanies brain tumor growth. We report the use of LSCI to monitor vascular changes in a rodent glioma model. Ten rats are inoculated with 9L gliosarcoma cells, and the angiogenic response is monitored five times over two weeks through a thinned skull imaging window. We are able to visualize neovascularization and measure the number of vessels per unit area to assess quantitatively the microvessel density (MVD). Spatial spread of MVD reveals regions of high MVD that may correspond to tumor location. Whole-field average MVD values increase with time in the tumor group but are fairly stable in the control groups. Statistical analysis shows significant differences in MVD values between the tumor group and both saline-receiving and unperturbed control groups over the two-week period (p<0.05). In conclusion, LSCI is suitable for investigation of tumor angiogenesis in rodent models. In addition, the statistical difference (p<0.02) between MVD values of the tumor (24.40±1.41) and control groups (15.40±1.60) on the 14th day after inoculation suggests a potential use of LSCI in the clinic in distinguishing tumor environments from normal vasculature.
Journal of Biomedical Optics 12/2012; 17(12):126017. · 3.16 Impact Factor
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ABSTRACT: OBJECTIVE To examine whether being uninsured is associated with higher in-hospital postoperative mortality when undergoing surgery in the United States for a brain tumor. DESIGN Retrospective cohort study using the Nationwide Inpatient Sample, January 1, 1999, through December 31, 2008. SETTING The Nationwide Inpatient Sample contains all inpatient records from a stratified sample of 20% of hospitals in 37 states. PATIENTS A total of 28 581 patients, aged 18 to 65 years, who underwent craniotomy for a brain tumor. Three groups were studied: Medicaid recipients and privately insured and uninsured patients. MAIN OUTCOME MEASURE The main outcome measure was in-hospital postoperative death. Associations between this outcome and insurance status were examined within the full cohort and within the subset of patients with no comorbidity using Cox proportional hazards models. These models were stratified by hospital to control for any clustering effects that could arise from differing access to care. RESULTS In the unadjusted analysis, the mortality rate for privately insured patients was 1.3% (95% CI, 1.1%-1.4%) compared with 2.6% for uninsured patients (95% CI, 1.9%-3.3%; P < .001) and 2.3% for Medicaid recipients (95% CI, 1.8%-2.8%; P < .001). After adjusting for patient characteristics and stratifying by hospital in patients with no comorbidity, uninsured patients still had a higher risk of experiencing in-hospital death (hazard ratio, 2.62; 95% CI, 1.11-6.14; P = .03) compared with privately insured patients. In this adjusted analysis, the disparity was not conclusively present in Medicaid recipients (hazard ratio, 2.03; 95% CI, 0.97-4.23; P = .06). CONCLUSIONS Uninsured patients who underwent craniotomy for a brain tumor experienced the highest in-hospital mortality. Differences in overall health do not fully account for this disparity.
Archives of surgery (Chicago, Ill.: 1960) 11/2012; 147(11):1017-24. · 4.32 Impact Factor
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ABSTRACT: Object Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival. Methods The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis. Results Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423-4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525-0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388-0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238-0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05). Conclusions Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.
Journal of Neurosurgery 10/2012; · 2.96 Impact Factor
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ABSTRACT: SF188/V+ is a highly vascular human glioma model that is based on transfection of vascular endothelial growth factor (VEGF) cDNA into SF188/V- cells. This study aims to assess its growth and vascularity properties in vivo in a rat model. Thirty-two adult rats were inoculated with SF188/V+ tumor cells, and, for comparison, five were inoculated with SF188/V- tumor cells. Several conventional magnetic resonance imaging (MRI) sequences were acquired, and several quantitative structural (T(2) and T(1)), functional [isotropic apparent diffusion coefficient (ADC) and blood flow], and molecular [protein and peptide-based amide proton transfer (APT)] MRI parameters were mapped on a 4.7 T animal scanner. In rats inoculated with SF188/V+ tumor cells, conventional T(2)-weighted images showed a highly heterogeneous tumor mass, and post-contrast T(1)-weighted images showed a heterogeneous, strong enhancement of the mass. There were moderate increases in T(2), T(1), and ADC, and large increases in blood flow and APT in the tumor, compared to contralateral brain tissue. Microscopic examination revealed prominent vascularity and hemorrhage in the VEGF-secreting xenografts as compared to controls, and immunohistochemical staining confirmed increased expression of VEGF in tumor xenografts. Our results indicate that the SF188/V+ glioma model exhibits some MRI and histopathology features that closely resemble human glioblastoma.
Journal of Neuro-Oncology 09/2012; · 3.21 Impact Factor
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ABSTRACT: An important question in the sequencing of anti-cancer therapies in patients with glioblastoma (GBM) is whether concurrent anti-angiogenesis therapies improve or impair brain concentrations of concomitantly administered cytotoxic therapies. The purpose of this study is to assess the intratumoral disposition of temozolomide (TMZ) via microdialysis before and after bevacizumab in an intracranial GBM xenograft model.
Microdialysis probes were placed within tumor and contralateral brain in athymic rats bearing U87 intracerebral gliomas. TMZ (50 mg/kg oral) was administered 10 days thereafter. Extracellular fluid (ECF) was collected for 6 h. BEV was administered (10 mg/kg IV), and TMZ was re-dosed (50 mg/kg oral) 36 h thereafter with additional ECF collection. All ECF samples were assessed for TMZ concentration with liquid chromatography-tandem mass spectrometry.
Tumor TMZ mean area under the concentration-time curve (AUC(0-∞)) was 3.35 μg h/mL pre-BEV. Post-BEV, tumor mean TMZ AUC(0-∞) was 3.98 μg h/mL. In non-tumor brain, mean TMZ AUC(0-∞) pre-BEV was 3.22 μg h/mL and post-BEV was 3.34 μg h/mL.
There were no statistically significant changes in TMZ pharmacokinetics before or after BEV in the athymic rat U87 intracranial glioma model. BEV and TMZ are being investigated as a combination therapy in several ongoing studies for patients with glioma. These data reassuringly suggest that BEV does not significantly change the ECF tumor concentrations of TMZ in either tumor-bearing or normal brain when dosed 36 h prior to TMZ.
Cancer Chemotherapy and Pharmacology 05/2012; 70(1):129-39. · 2.83 Impact Factor
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ABSTRACT: The poor prognosis for patients with glioblastoma (GB) heightens the importance of maintaining function throughout treatment. Hyperglycemia has been linked to poor neurological outcomes following stroke, traumatic brain and spinal cord injury. We hypothesized this may also be true following the resection of GB. We assessed associations with post-operative function with the goal of identifying modifiable factors in the peri-operative period with a particular focus on blood glucose levels. Independent associations with worse post-operative function included: patient age, pre-operative motor deficit, deep tumor location, post-operative motor deficit, and elevated mean peri-operative glucose. Interestingly, controlling for associated factors including dexamethasone dosing, patients with elevated peri-operative glucose levels were nearly twice as likely to have new post-operative neurological deficits. These results suggest, together with the broad literature supporting a role for hyperglycemia in neurological injury, that this may represent a modifiable factor in the peri-operative care of these patients.
Journal of Clinical Neuroscience 05/2012; 19(7):996-1000. · 1.25 Impact Factor
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ABSTRACT: Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed with preliminary in vivo studies. The impact of TMZ release kinetics was investigated by conducting in vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.
Biomaterials 05/2012; 33(23):5768-75. · 7.40 Impact Factor
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ABSTRACT: OBJECTIVE: Seizures are common among patients with meningiomas and are a significant cause of morbidity and poor quality of life. The factors associated with the onset of seizures as well as factors associated with seizure control remains poorly understood. METHODS: Adult patients who underwent primary resection of a supratentorial World Health Organization grade I meningioma at a single institution between 1996 and 2006 were retrospectively reviewed. Multivariate logistical regression analyses were used to identify associations with preoperative seizures, and multivariate proportional hazards regression analyses were used to identify associations with prolonged seizure control after surgical resection. RESULTS: Of the 626 patients in this series, 84 (13%) presented with seizures. The factors independently associated with preoperative seizures were Karnofsky performance score ≤80 (P< 0.0001), absence of headaches (P = 0.0006), and vasogenic edema (P = 0.007). At 48 months postoperatively, 90% were Engel class I, 3% were class II, 0 were class III, and 7% were class IV. The factors independently associated with decreased seizure control after surgical resection were uncontrolled preoperative seizures (P = 0.04), parasagittal tumors (P = 0.03), and tumors along the sphenoid wing (P = 0.05). The association between seizure recurrence and tumor recurrence trended toward but did not achieve statistical significance (P = 0.11). CONCLUSIONS: With the widespread availability of various neuroimaging modalities, there will be increased detection of intracranial meningiomas. The identification and consideration of factors associated with seizure onset and prolonged seizure control may help guide treatment strategies aimed at improving the quality of life for patients with meningiomas.
World Neurosurgery 03/2012; · 0.68 Impact Factor
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ABSTRACT: Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma.
Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis.
OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5.
OncoGel is safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.
Journal of neurosurgery. Spine 01/2012; 16(1):93-101. · 1.61 Impact Factor
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ABSTRACT: BACKGROUND: In his 1938 monograph, Cushing tabulated 313 meningioma cases treated throughout his career at the Johns Hopkins and the Peter Bent Brigham Hospitals. Of these, 18 patients were treated at the Johns Hopkins Hospital. Cushing provided basic demographic, perioperative, and outcomes data in his tables, but the operative details for many of his early meningioma cases have not been previously described. METHODS: After institutional review board approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical files for the Johns Hopkins Hospital from the period 1896 to 1912 were reviewed. Cases diagnosed as endothelioma or dural endothelioma were selected for further analysis. RESULTS: Of the 14 patients with available records, 1 were male. The mean age was 34.4 years. Nine patients (64.3%) died during their inpatient stay. Cushing used staged resections in an attempt to minimize blood loss, morbidity, and mortality, albeit with limited success. CONCLUSIONS: The operative details demonstrate Cushing's early attention to hemostasis, and use of staged resections in patients with large, highly vascular meningiomas. Cushing's first 18 cases of meningiomas, treated while a young attending physician at the Johns Hopkins Hospital, are not the most elegant operations in his lengthy series, but serve as an illustration of his ability to transform clinical challenges into opportunities for improvement.
World Neurosurgery 11/2011; · 0.68 Impact Factor
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ABSTRACT: Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods.
Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect.
Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post-tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5-9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors.
Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.
Journal of Neurosurgery 09/2011; 115(6):1139-46. · 2.96 Impact Factor
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ABSTRACT: Peak incidence of glioblastoma multiforme (GBM) occurs in individuals aged 65 years and older. The goal was to evaluate the efficacy of carmustine wafers in prolonging survival for older GBM patients.
One hundred and thirty-three consecutive patients aged 65 years and older who underwent surgery for an intracranial primary (de novo) GBM from 1997-2007 were retrospectively reviewed. Among these 133 patients, 45 patients with carmustine wafer implantation were matched with 45 patients without implantation. These groups were matched for factors consistently shown to be associated with survival (age, Karnofsky performance scale, extent of resection, radiation therapy, and temozolomide). Survival was expressed as estimated Kaplan-Meier plots, and log-rank analysis was used to compare survival curves. Variables with P<0.05 were considered statistically significant.
The mean (±standard deviation) age of the cohort was 73±5 years, and the median survival of the entire cohort was 5.9 months. Among patients with and without carmustine wafers, there were no significant differences in pre- and peri-operative variables. However, patients with carmustine wafers demonstrated prolonged survival as compared to patients without wafers. The median survival for patients with carmustine wafers was 8.7 months, while median survival for patients without wafers was 5.5 months (P=0.007). Likewise, in subgroup analysis, patients older than 70 years (P=0.0003) and 75 years (P=0.04) who had carmustine wafers had significantly longer survival than matched patients without wafers.
Older patients with GBM may benefit from carmustine wafers. The survival for older patients who received carmustine wafers is significantly longer than matched patients who did not receive carmustine wafers.
Neurological Research 09/2011; 33(7):759-64. · 1.52 Impact Factor
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Betty Tyler,
Scott Wadsworth,
Violette Recinos,
Vivek Mehta,
Ananth Vellimana,
Khan Li,
Joel Rosenblatt,
Hiep Do,
Gary L Gallia,
I-Mei Siu,
Robert T Wicks,
Michelle A Rudek,
Ming Zhao, Henry Brem
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ABSTRACT: Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.
Neuro-Oncology 07/2011; 13(7):700-9. · 5.72 Impact Factor
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ABSTRACT: Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(®)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36 μg/h for single-orifice devices and an 88 μg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.
Biomaterials 04/2011; 32(10):2532-9. · 7.40 Impact Factor
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Steven S Brem,
Philip J Bierman, Henry Brem,
Nicholas Butowski,
Marc C Chamberlain,
Ennio A Chiocca,
Lisa M DeAngelis,
Robert A Fenstermaker,
Allan Friedman,
Mark R Gilbert, [......],
Maciej Mrugala,
Louis Burt Nabors,
Herbert B Newton,
Jana Portnow,
Jeffrey J Raizer,
Lawrence Recht,
Dennis C Shrieve,
Allen K Sills,
Frank D Vrionis,
Patrick Y Wen
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ABSTRACT: Overview In 2010, an estimated 22,020 new cases of primary brain and other nervous system neoplasms were diagnosed in the United States,(1) and approximately 13,140 deaths occurred from these tumors. The incidence of primary malignant brain tumors has been increasing over the past 30 years, especially in elderly persons.(2) Metastatic disease to the central nervous system (CNS) occurs much more frequently, with an estimated incidence approximately 10 times that of primary brain tumors. Between 20% and 40% of patients with systemic cancer will develop brain metastases.(3) NOTE: This manuscript highlights only a portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System Cancers. Please refer to www.NCCN.org for the complete NCCN Guidelines. Principles of Management Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. Primary brain tumors range from pilocytic astrocytomas, which are very uncommon, noninvasive, and surgically curable, to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable. Likewise, patients with metastatic brain disease may have rapidly progressive systemic disease or no systemic cancer at all. These patients may have one or dozens of brain metastases, and may have a malignancy that is either highly responsive or highly resistant to radiation or chemotherapy. Because of this marked heterogeneity, the prognostic features and treatment options for brain tumors must be carefully reviewed on an individual basis and sensitively communicated to each patient. In addition, CNS tumors are associated with...
Journal of the National Comprehensive Cancer Network: JNCCN 04/2011; 9(4):352-400. · 4.41 Impact Factor
