Jan-Karl Burkhardt

Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival

BACKGROUND This prospective, single-center study assesses progression-free survival (PFS) and overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) treated with a single dose of superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) after blood-brain barrier disruption (BBBD). Patients were initially enrolled in our phase I study, for which the primary end point was to determine the safety and maximum tolerated dose of SIACI BV. METHODS Fourteen patients with recurrent GBM were recruited between August 2009 and November 2010 after failing the standard treatment with radiation therapy and temozolomide. None of these patients were previously treated with BV. After receiving a single dose of IA BV (2 to 15 mg/kg), standard IV BV chemotherapy was continued in 12 of 14 patients (86%). The recently updated Response Assessment in Neuro-Oncology Working Group (RANO) criteria were used to evaluate PFS, and the Kaplan-Meier estimator was used to evaluate PFS and OS. RESULTS Using RANO criteria, the median PFS in these patients was 10 months. The median OS estimation for this cohort was 8.8 months. The OS was less than the PFS because 4 patients died without progressing. Toxicity attributed to the IA BV treatment was present in 2 patients (wound dehiscence and rash). Another patient suffered from seizures 1 week after the SIACI procedure; however, this patient had epilepsy before and seizure type/frequency were similar before and after therapy. CONCLUSIONS Our study shows that for patients naïve to BV, a single dose of SIACI BV after BBBD followed by IV BV offers an encouraging outcome in terms of PFS when compared with previous trials using IV BV with and without concomitant irinotecan (CPT-11). Larger phase II trials are warranted to determine whether repeated IA BV alone is superior to IV BV for recurrent GBM.

A comparative effectiveness study of patient-rated and radiographic outcome after 2 types of decompression with fusion for spondylotic myelopathy: anterior cervical discectomy versus corpectomy

OBJECT Both anterior cervical discectomy with fusion (ACDF) and anterior cervical corpectomy with fusion (ACCF) are used to treat cervical spondylotic myelopathy; however, there is currently no evidence for the superiority of one over the other in terms of patient-rated outcomes. This comparative effectiveness study compared the patient-rated and radiographic outcomes of 2-level ACDF versus 1-level ACCF. METHODS This single-center study was nested within the EuroSpine Spine Tango data acquisition system. Inclusion criteria were the following: consecutive patients presenting with signs of cervical spondylotic myelopathy who underwent 2-level ACDF or 1-level ACCF between 2004 and 2011. Before and 12 months after surgery, patients completed the multidimensional Core Outcome Measures Index (COMI) and also rated global treatment outcome and satisfaction with care on 5-point Likert scales. Cervical lordosis, segmental height, and fusion rate were assessed radiographically before and immediately after surgery and at the last follow-up (20.4 ± 13.7 months, mean ± SD). RESULTS In total, 118 consecutive patients (80 in the ACDF group and 38 in the ACCF group) were included. Age, sex, comorbidity, baseline symptoms, baseline radiographic data, operation duration, and complication rates did not differ significantly between the 2 groups. Blood loss was significantly (p < 0.04) lower in the ACDF group. Postoperative mean segmental height was significantly (p = 0.0006) greater for ACDF (42.0 ± 4.2 mm, mean ± SD) than for ACCF (39.0 ± 4.0 mm), and global average lordosis improved to a significantly (p = 0.003) greater extent in ACDF (by 1.6° ± 4.1°) than in ACCF (by -1.0° ± 4.0°). Fusion rates for ACDF were 97.5% and for ACCF were 94.7% (p = 0.59). The 12-month patient-rated outcomes did not differ significantly between ACDF and ACCF: 82.4% and 68.6% had a good global outcome (operation helped/helped a lot) (p = 0.10), 86.5% and 82.9% were satisfied/very satisfied with care (p = 0.62), and the reduction in the multidimensional COMI was 2.8 ± 2.7 and 2.2 ± 3 points (p = 0.30), respectively. The postoperative increase in lordosis angle showed low but significant correlations with the improvement in arm pain (r = 0.25, p = 0.014), highest pain (r = 0.25, p = 0.013), and function (r = 0.24, p = 0.016). CONCLUSIONS Both ACDF and ACCF are safe and effective in the treatment of cervical spondylotic myelopathy, indicated by similarly good patient-rated outcomes 1 year after surgery. This precludes any conclusions regarding the superiority of one technique over the other, although it should be noted that ACDF resulted in less blood loss and greater improvements in cervical lordosis and segmental height than ACCF. Patients with improved lordosis angle had a better clinical outcome.

Hydrocephalus in 389 patients with aneurysm-associated subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) often leads to hydrocephalus, which is commonly treated by placement of a ventriculoperitoneal (VP) shunt. There is controversy over which factors affect the need for such treatment. In this study, data were prospectively collected from 389 consecutive patients who presented with an aneurysm-associated SAH at a single center. External ventricular drainage placement was performed as part of the treatment for acute hydrocephalus, and VP shunts were placed in patients with chronic hydrocephalus. The data were retrospectively analyzed using two-sample t-tests, Fishers exact test and logistic regression analysis. Overall, shunt dependency occurred in 91 of the 389 patients (23.4%). Using logistic regression analysis, two factors were found to be significantly associated with VP shunt placement: an initial Glasgow Coma Scale (GCS) score of 8-14 (8-14 versus 3-7, p = 0.016; 15 versus 3-7, p = 0.55); and aneurysm coiling (p = 0.017). Patients with an initial GCS score of 8-14 after aneurysm-associated SAH had a 2.5-fold higher risk of receiving a VP shunt than those with a GCS score of 3-7. Those with a GCS of 15 had a 50% lower risk of becoming shunt dependent than did the subgroup with a GCS score of 8-14. To clarify and strengthen these observations, prospective, randomized trials are needed.

Superselective Intra-Arterial Cerebral Infusion of Novel Agents After Blood–Brain Disruption for the Treatment of Recurrent Glioblastoma Multiforme: A Technical Case Series

Glioblastoma multiforme constitutes the most common primary brain tumor and carries a grim prognosis for patients treated with conventional therapy including surgery, radiation therapy, and chemotherapy. There has been a recent revival of selective intra-arterial delivery of targeted agents for the treatment of glioblastoma multiforme. Because these agents are less toxic and their delivery leads to a higher tumor-drug concentration, this combination may provide a better outcome in patients with high-grade glioma. This article discusses early experiences in patients who received superselective intra-arterial cerebral infusion of bevacizumab, cetuximab, and temozolamide after blood-brain barrier disruption with mannitol.

Neurosurgical venous considerations for tumors of the pineal region resected using the infratentorial supracerebellar approach

The authors present a microsurgical technique for the resection of a heterogeneous group of pineal-region tumors and discuss the key points for successfully performing this surgery. Twenty-six consecutive patients with pineal-region tumors were resected by the senior author (H.B.) and analyzed retrospectively. For all 26 patients, the operation was conducted using the infratentorial supracerebellar (ITSC) approach in the sitting (23 patients) or Concorde (three patients) positions. Twenty-five patients had symptomatic obstructive hydrocephalus and were treated with ventricular drainage, a previously inserted ventriculoperitoneal shunt, or an endoscopic third ventriculostomy before undergoing resection of the pineal-region tumor. The gross total removal of the tumor was achieved in 23 patients and subtotal removal was achieved in three patients. The tumors were pathologically diagnosed mainly as pineocytomas (10), pilocytic astrocytomas (6), or pineal cysts (4). Twenty-five of the patients clinically improved after surgery, and there was no mortality. Two patients experienced transient postoperative neurological deterioration: one patient developed Parinaud syndrome, and one patient developed intermittent diplopia. Successful surgery and patient outcome when treating tumors of the pineal region using the ITSC approach requires: (i) preservation of the venous flow of the Galenic draining system; (ii) preservation of the thick bridging veins of the tentorial surface of the cerebellum, especially the hemispheric bridging veins; and (iii) minimizing retraction of the cerebellum during surgery to avoid adverse effects caused by both direct cerebellar compression and disturbance of the venous circulation.

Endovascular management of intracranial dural arteriovenous fistulas: A review

Dural arteriovenous fistulas (DAVFs) are rare pathological entities presenting with a diverse clinical course, ranging from benign to life-threatening. Digital subtraction angiography remains the gold standard in the diagnosis of clinically suspected DAVFs. This article reviews the ethiopathogenesis, natural history, classification systems, clinical and angiographic features, and the current treatment strategies for these complex lesions. The management of DAVFs may include conservative treatment, endovascular intervention, microsurgery, and stereotactic radiosurgery. A multidisciplinary approach involving a neurosurgeon, interventional neuroradiologist, and neurologist is required before considering any type of treatment modality. The indication for the best therapeutic alternative must be individualized for each patient.

Subdural Drainage versus Subperiosteal Drainage in Burr-Hole Trepanation for Symptomatic Chronic Subdural Hematomas

BACKGROUND Symptomatic chronic subdural hematoma (scSDH) is one of the most frequent diseases in neurosurgical practice, and its incidence is increasing. However, treatment modalities are still controversial. OBJECT The aim of this retrospective single-center study is to compare for the first time two surgical methods in the treatment of subdural hematoma that have been proven to be efficient in previous studies in a direct comparison. METHODS We analyzed the data of 143 scSDHs in 113 patients undergoing surgery for subdural hematoma with placement of subperiosteal or subdural drainage after double burr-hole trepanation for hematoma evacuation. RESULTS Overall, there were no statistically significant differences regarding general patient characteristics, preoperative and postoperative symptoms, postoperative hematoma remnant, rates of recurrences, mortality, complications, and outcome at discharge and at 3-month follow up between the groups. There was a close to significant tendency of lower mortality after placement of subperiosteal drainage system and a tendency towards lower rate of recurrent hematoma after placement of subdural drainage system. CONCLUSIONS Our study shows for the first time a direct comparison of two mainly used surgical techniques in the treatment of scSDH. Both methods proved to be highly effective, and general patient data, complications, outcome and mortality of both groups are equal or superior compared with previously published series. Because there is a clear tendency to less mortality and fewer serious complications, treatment with double burr-hole trepanation, irrigation, and placement of subperiosteal drainage is our treatment of choice in patients with predictable high risk of complications.

Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: From bedside to bench

Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival.

Intra-arterial chemotherapy for malignant gliomas: a critical analysis.

Intra-arterial (IA) chemotherapy for malignant gliomas including glioblastoma multiforme was initiated decades ago, with many preclinical and clinical studies having been performed since then. Although novel endovascular devices and techniques such as microcatheter or balloon assistance have been introduced into clinical practice, the question remains whether IA therapy is safe and superior to other drug delivery modalities such as intravenous (IV) or oral treatment regimens. This review focuses on IA delivery and surveys the available literature to assess the advantages and disadvantages of IA chemotherapy for treatment of malignant gliomas. In addition, we introduce our hypothesis of using IA delivery to selectively target cancer stem cells residing in the perivascular stem cell niche.

Metabolic response of glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab: a proton MR spectroscopic imaging study.

BACKGROUND AND PURPOSE: SIACI of bevacizumab has emerged as a promising novel therapy in the treatment of recurrent GB. This study assessed the potential of 1H-MRS as an adjunctive technique in detecting metabolic changes reflective of antiproliferative effects of targeted infusion of bevacizumab in the treatment of GB. MATERIALS AND METHODS: Eighteen patients enrolled in a phase I/II study of SIACI of bevacizumab for treatment of recurrent GB were included. Concurrent MR imaging and 1H-MRS scans were performed before and after treatment. Five distinct morphologic ROIs were evaluated for structural and metabolic changes on MR imaging and 1H-MRS, which included enhancing, nonenhancing T2 hyperintense signal abnormality, and multiple control regions. Pre- and post-SIACI of bevacizumab peak areas for NAA, tCho, tCr, as well as tCho/tCr and tCho/NAA ratios, were derived for all 5 ROIs and compared using the Wilcoxon signed-rank test. RESULTS: A significant median decrease of 25.99% (range −55.76 to 123.94; P = .006) in tCho/NAA was found post-SIACI of bevacizumab relative to pretreatment values in regions of enhancing disease. A trend-level significant median decrease of 6.45% (range −23.71 to 37.67; P = .06) was noted in tCho/NAA posttreatment in regions of nonenhancing T2-hyperintense signal abnormality. CONCLUSIONS: The results of this 1H-MRS analysis suggest that GB treatment with SIACI of bevacizumab may be associated with a direct antiproliferative effect, as demonstrated by significant reductions of tCho/NAA after the intervention.