Markus J. Bookland

Local delivery of OncoGel delays paresis in rat metastatic spinal tumor model

OBJECT Spinal column metastatic disease clinically affects thousands of cancer patients every year. Local chemotherapy represents a new option in the treatment of metastatic disease of the spine. Despite the clinical impact of metastatic spine disease, the literature currently lacks an accurate animal model for the effective dosing of local chemotherapeutic agents within the vertebral column. METHODS Female Fischer 344 rats, weighing 150 to 200 g each, were used in this study. After induction of anesthesia, a transabdominal approach to the ventral vertebral body of L-6 was performed. A small hole was drilled and 5 microL of ReGel (blank polymer), OncoGel (paclitaxel and ReGel) 1.5%, OncoGel 3.0%, or OncoGel 6.0% were immediately injected to determine drug toxicity. Based on these results, efficacy studies were performed by intratumoral injection of 5 microL of ReGel, OncoGel 3.0%, and OncoGel 6.0% on Day 6 in a CRL- 1666 breast adenocarcinoma metastatic spine tumor model. Hind limb function was tested pre- and postoperatively using the Basso-Beattie-Bresnahan rating scale. Histological analysis of the spinal cord and vertebral column was performed when the animal died or was killed. RESULTS There were no signs of toxicity observed in association with any of the agents under study. No increased benefit was seen in the blank polymer group compared with the control group (tumor only). OncoGel 3.0% and OncoGel 6.0% were effective in delaying the onset of paralysis in the respective study groups. CONCLUSIONS These findings demonstrate the potential benefit of OncoGel in cases of subtotal resections of metastatic spinal column tumors. OncoGel 6.0% is the most efficacious drug concentration and offers the best therapeutic option in this experimental model. These results provide promise for the development of local chemotherapeutic means to treat spinal metastases.

Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma

Glioblastomas continue to carry poor prognoses for patients despite advances in surgical, chemotherapeutic, and radiation regimens. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and expression levels of hypoxia-inducible factor-1 α (HIF-1α). HIF-1α expression allows metabolic adaptation to low oxygen availability, partly through upregulation of VEGF and increased tumor angiogenesis. Here, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) by hypoxia in glioblastoma cells. AEG-1 has the capacity to promote anchorage-independent growth and cooperates with Ha-ras in malignant transformation. In addition, AEG-1 was recently demonstrated to serve as an oncogene and can induce angiogenesis in glioblastoma. Results from in vitro studies show that hypoxic induction of AEG-1 is dependent on HIF-1α stabilization during hypoxia and that PI3K inhibition abrogates AEG-1 induction during hypoxia through loss of HIF-1α stability. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) production prevents this induction. Additionally, AEG-1 knockdown results in increased ROS production and increased glucose deprivation-induced cytotoxicity. On the other hand, AEG-1 overexpression prevents ROS production and decreases glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of cell stress. These observations link AEG-1 overexpression in glioblastoma with hypoxia and glucose deprivation, and targeting these physiological pathways may lead to therapeutic advances in the treatment of glioblastoma in the future. See commentary: Astrocyte-elevated gene-1 (AEG-1): Glioblastomas helping hand during times of hypoxia and glucose deprivation?

Return to system within 30 days of discharge following pediatric shunt surgery

OBJECT The rate of readmission after CSF shunt surgery is significant and has caught the attention of purchasers of health care. However, a detailed description of clinical scenarios that lead to readmissions and reoperations after index shunt surgery is lacking in the medical literature. METHODS This study included 1755 shunt revision and insertion surgeries that were performed at a single institution between May 1, 2009, and April 30, 2013. Demographic, socioeconomic, and clinical characteristics were prospectively collected in the administrative, business, and operating room databases. Clinical events within the 30 days following discharge were reviewed and analyzed. Two events of interest, Emergency Department (ED) utilization and reoperation, were further analyzed for risk factor associations by using multivariate logistic regression. RESULTS There were 290 readmissions within 30 days of discharge (16.5%). Admission sources included ED (n = 216), hospital transfers (n = 23), and others. Of the 290 readmissions, 184 were associated with an operation, but only 165 of these were performed by the neurosurgical service. These included surgeries for shunt occlusion and externalization (n = 150), wound revision (n = 7), and other neurosurgical procedures that were not shunt related (n = 8). The remaining readmissions (n = 106) were not associated with an operation, and only 59 patients were admitted for issues related to the index shunt surgery. When return to the ED was the dependent variable in a multivariate regression model, patients who returned to the ED were more likely to be from the Atlanta metropolitan area and to be either uninsured or insured with public assistance. When reoperation was the dependent variable, patients whose surgery started after 3 p.m. were more likely to undergo subsequent CSF shunt revision surgery on readmission. CONCLUSIONS Of the readmissions within 30 days of shunt surgery, 74.5% were related to the index shunt surgery. Whether and to what extent these readmissions are preventable continues to be controversial. Further study is needed to identify modifiable risk factors that may eventually improve patient care.

Fractionated, single-port radiotherapy delays paresis in a metastatic spinal tumor model in rats

OBJECT Spinal column metastatic disease affects thousands of cancer patients every year. Radiation therapy frequently represents the primary treatment for this condition. Despite the enormous clinical impact of spinal column metastatic disease, the literature currently lacks an accurate animal model for testing the efficacy of irradiation on spinal column metastases. METHODS After anesthesia was induced, female Fischer 344 rats underwent a transabdominal approach to the ventral vertebral body (VB) of L-6. A 2- to 3-mm-diameter bur hole was drilled for the implantation of a section of CRL-1666 breast adenocarcinoma. After the animals had recovered from the surgery, they underwent fractionated, single-port radiotherapy beginning on postoperative Day 7. Each group of animals underwent five daily fractions of radiation treatment. Group I animals received a total dose of 10 Gy in 200-cGy daily fractions, Group II animals received a total dose of 20 Gy in 400-cGy daily fractions, and Group III animals received a total dose of 30 Gy in 600-cGy daily fractions. A control group of rats with implanted VB lesions did not receive radiation. To test the effects of radiation toxicity alone, additional rats without implanted tumors received radiation treatments in the same fractions as the rats with tumors. Hindlimb function in all rats was rated before and after radiation treatment using the Basso-Beattie-Bresnahan locomotor rating scale. Histological analysis of spinal cord and vertebral column sections was performed after each animals death. RESULTS Functional assessments demonstrated a statistically significant delay in the onset of paresis between the three treatment groups and the control group (tumor implanted but no radiotherapy). The rats in the three treatment groups, however, did not exhibit any significant differences related to hindlimb function. A dose-dependent relationship was found for the percentage of animals who had become paralyzed at the time of death, with all members of the control group and no members of the 30-Gy group exhibiting paralysis. The results of this study do not indicate any overall survival benefit for any level of radiation dose. CONCLUSIONS These findings demonstrate the efficacy of focal spinal irradiation in delaying the onset of paralysis in a rat metastatic spine tumor model, but without a clear survival benefit. Because of the dose-related toxicity observed in the rats treated with 30 Gy, this effect was most profound for the 20-Gy group. This finding parallels the observed clinical course of spinal column metastatic disease in humans and provides a basis for the future comparison of novel local and systemic treatments to augment the observed effects of focal irradiation.

Use of a cyanoacrylate skin adhesive to reduce external ventricular drain infection rates.

UNLABELLED OBJECT.: Ventriculitis related to external ventricular drain (EVD) placement is a significant source of morbidity in neurological intensive care patients. Current rates of EVD-related infections range from 2% to 45% in the literature. The authors sought to determine if a 2-octyl cyanoacrylate adhesive would result in lower infection rate than standard semiocclusive dressings. METHODS The authors tracked ventriculitis rates via CSF cultures among 259 patients whose EVD sites were dressed with sterile semiocclusive dressings and underwent routine sterile dressing exchanges every 48 hours. They analyzed data obtained in an additional 113 patients whose EVD sites were dressed one time with a surgical adhesive, 2-octyl cyanoacrylate. RESULTS Ventriculitis rate in patients with standard bioocclusive dressings and wound care was 15.1%, whereas that in patients with a 2-octyl cyanoacrylate dressing was 3.54% (p = 0.002). Staphylococcus genus accounted for 79.5% of instances of ventriculitis among patients with bioocclusive dressings and routine wound care, whereas it accounted for 25.0% of the instances of ventriculitis among patients with a liquid polymer sealant dressing. A 90% reduction in Staphylococcus infection completely accounts for the observed effect (p = 0.04). CONCLUSIONS The one-time application of 2-octyl cyanoacrylate to EVD wounds and exit sites provided superior protection against EVD-related ventriculitis compared to conventional EVD-site wound care. Likely this protection results from a barrier to the entry of gram-positive skin flora along the EVD exit tract. The results should be validated in a randomized trial.

Deep brain stimulation of the globus pallidus suppresses post-traumatic dystonic tremor

Dystonic tremor is an unusual movement disorder that is highly disabling and difficult to treat medically. We describe an 18-year-old patient with dystonic tremor whose medical treatment failed, and was considered for surgery. The patient had a long-standing dystonic tremor and was recommended for globus pallidus (GP) deep brain stimulation. At 2 year follow-up, we observed substantial tremor suppression and best clinical effect with contact three, which, radiographically, is located in the internal globus pallidus/external globus pallidus transition area. The stimulation was more rostral than expected. We conclude that the GP is a potentially useful therapeutic target for dystonic tremor.

Primary Pineal Malignant Melanoma

Primary pineal malignant melanomas are a rare subset of primary central nervous system melanomas. This report presents the case of a 20-year-old female patient with a primary pineal region malignant melanoma who underwent endoscopic biopsy and adjuvant therapy. Her treatment consisted of stereotactic radiation to the pineal tumor, conventional whole-brain radiation and Temodar® for the disseminated disease. She required a ventriculo-peritoneal shunt for refractory ICP problems. This report details the clinical features of the case and summarizes the literature on a rare but aggressive neoplasm.

Growth inhibition of malignant glioblastoma by DING protein.

Malignant gliomas are a highly aggressive type of brain tumor with extremely poor prognosis. These tumors are highly invasive and are often surgically incurable and resistant to chemotherapeutics and radiotherapy. Thus, novel therapies that target pathways involved in growth and survival of the tumor cells are required for the treatment of this class of brain tumors. Previous studies revealed that epidermal growth factor receptor and extracellular-signal-regulated kinases (ERKs), which are involved in the induction of cell proliferation, are activated in the most aggressive type of glioma, i.e. glioblastoma multiforme (GBM). In fact, GBMs with increased levels of ERK activity exhibit a more aggressive phenotype than the others with moderate ERK activity, pointing to the importance of ERK and its kinase activity in the development and progression of these tumors. In this study, we have evaluated the effect of p38SJ, a novel member of the DING family of proteins, derived from Hypericum perforatum calluses, on the growth of malignant glioma cell lines, T98G and U-87MG by focusing on cell cycle and signaling pathways controlled by phosphorylation of various regulatory proteins including ERK. p38SJ, which exhibits profound phosphatase activity, shows the capacity to affect the phosphorylation status of several important kinases modulating signaling pathways, and cell growth and proliferation. Our results demonstrate that p38SJ reduces glioma cell viability and arrests cell cycle progression at G0/G1. The observed growth inhibitory effect of p38SJ is likely mediated by the downregulation of several cell cycle gatekeeper proteins, including cyclin E, Cdc2, and E2F-1. These results suggest that p38SJ may serve as a potential candidate for development of a therapeutic agent for the direct treatment of malignant gliomas and/or as a potential radiosensitizer.

Harms titanium mesh cage fracture

Interbody fusion has become a mainstay of surgical management for lumbar fractures, tumors, spondylosis, spondylolisthesis and deformities. Over the years, it has undergone a number of metamorphoses, as novel instrumentation and approaches have arisen to reduce complications and enhance outcomes. Interbody fusion procedures are common and successful, complications are rare and most often do not involve the interbody device itself. We present here a patient who underwent an anterior L4 corpectomy with Harms cage placement and who later developed a fracture of the lumbar titanium mesh cage (TMC). This report details the presentation and management of this rare complication, as well as discusses the biomechanics underlying this rare instrumentation failure.

Performance of minimally invasive sagittal synostectomy with supine patient positioning: technical note

The authors report their initial experience with supine patient positioning for minimally invasive treatment of sagittal craniosynostosis. Supine positioning offers potential advantages that include reduced anesthetic risk and may be considered as an option by craniofacial surgeons performing minimally invasive synostectomy for sagittal craniosynostosis.