C. Rory Goodwin

Cyr61 Mediates Hepatocyte Growth Factor–Dependent Tumor Cell Growth, Migration, and Akt Activation

Certain tumor cell responses to the growth factor-inducible early response gene product CCN1/Cyr61 overlap with those induced by the hepatocyte growth factor (HGF)/c-Met signaling pathway. In this study, we investigate if Cyr61 is a downstream effector of HGF/c-Met pathway activation in human glioma cells. A semiquantitative immunohistochemical analysis of 112 human glioma and normal brain specimens showed that levels of tumor-associated Cyr61 protein correlate with tumor grade (P < 0.001) and with c-Met protein expression (r(2) = 0.4791, P < 0.0001). Purified HGF rapidly upregulated Cyr61 mRNA (peak at 30 minutes) and protein expression (peak at 2 hours) in HGF(-)/c-Met(+) human glioma cell lines via a transcription- and translation-dependent mechanism. Conversely, HGF/c-Met pathway inhibitors reduced Cyr61 expression in HGF(+)/c-Met(+) human glioma cell lines in vitro and in HGF(+)/c-Met(+) glioma xenografts. Targeting Cyr61 expression with small interfering RNA (siRNA) inhibited HGF-induced cell migration (P < 0.01) and cell growth (P < 0.001) in vitro. The effect of Cyr61 on HGF-induced Akt pathway activation was also examined. Cyr61 siRNA had no effect on the early phase of HGF-induced Akt phosphorylation (Ser(473)) 30 minutes after stimulation with HGF. Cyr61 siRNA inhibited a second phase of Akt phosphorylation measured 12 hours after cell stimulation with HGF and also inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase 3alpha. We treated preestablished subcutaneous glioma xenografts with Cyr61 siRNA or control siRNA by direct intratumoral delivery. Cyr61 siRNA inhibited Cyr61 expression and glioma xenograft growth by up to 40% in a dose-dependent manner (P < 0.05). These results identify a Cyr61-dependent pathway by which c-Met activation mediates cell growth, cell migration, and long-lasting signaling events in glioma cell lines and possibly astroglial malignancies.

A Comprehensive Review of Complication Rates After Surgery for Adult Deformity: A Reference for Informed Consent

OBJECTIVE An up-to-date review of recent literatures and a comprehensive reference for informed consent specific to ASD complications is lacking. The goal of the present study was to determine current complication rates after ASD surgery, in order to provide a reference for informed consent as well as to determine differences between three-column and non-three-column osteotomy procedures to aid in shared decision making. METHODS A review of the literature was conducted using the PubMed database. Randomized controlled trials, nonrandomized trials, cohort studies, case-control studies, and case series providing postoperative complications published in 2000 or later were included. Complication rates were recorded and calculated for perioperative (both major and minor) and long-term complication rates. Postoperative outcomes were all stratified by surgical procedure (ie, three-column osteotomy and non-three-column osteotomy). RESULTS Ninety-three articles were ultimately eligible for analysis. The data of 11,692 patients were extracted; there were 3,646 complications, mean age at surgery was 53.3 years (range: 25-77 years), mean follow-up was 3.49 years (range: 6 weeks-9.7 years), estimated blood loss was 2,161 mL (range: 717-7,034 mL), and the overall mean complication rate was 55%. Specifically, major perioperative complications occurred at a mean rate of 18.5%, minor perioperative complications occurred at a mean rate of 15.7%, and long-term complications occurred at a mean rate of 20.5%. Furthermore, three-column osteotomy resulted in a higher overall complication rate and estimated blood loss than non-three-column osteotomy. CONCLUSIONS A review of recent literatures providing complication rates for ASD surgery was performed, providing the most up-to-date incidence of early and late complications. Providers may use such data in helping to counsel patients of the literature-supported complication rates of such procedures despite the planned benefits, thus obtaining a more thorough informed consent.

A review on the management of epilepsy associated with hypothalamic hamartomas.

IntroductionHypothalamic hamartomas are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Patients may be asymptomatic, but the usual presentation is gelastic seizures, precocious puberty, and/or developmental delay.Clinical presentationWithout surgical intervention, the gelastic seizures, which are typically present in childhood, may progress to other seizure types, including generalized epilepsy, and are generally refractory to antiepileptic drugs.SummaryThis review will discuss the clinical and electrophysiologic aspects of these lesions, as well as treatment options, including surgery, endoscopy, and radiosurgery.

Outcomes following surgical intervention for impending and gross instability caused by multiple myeloma in the spinal column

OBJECT Multiple myeloma is the most common primary tumor of the spine and is the most common primary malignant tumor of bone. Although spinal myeloma is classically a radiosensitive lesion, clinical or radiographic signs of instability merit surgical intervention. The authors present the epidemiology, surgical indications, and outcome data of a series of consecutive cases involving 31 surgically treated patients with diagnoses of multiple myeloma and plasmacytoma of the spine (the largest such series reported to date). METHODS Surgical instability was the criterion for operative intervention in this patient cohort. The Spinal Instability Neoplastic Score (SINS) was used to make this assessment of instability. The cases were analyzed using location of the lesion, spinal levels involved, Frankel score, adjuvant therapy, functional outcome, and patient survival. RESULTS All patients undergoing surgical intervention were determined to have indeterminate or gross spinal column instability according to SINS criteria. The median survival was 78.9 months. No significant difference in survival was seen for patients with higher SINS scores or for older patients (> 55 years). There was a statistically significant difference in survival benefit observed for patients receiving chemotherapy and radiation versus radiation alone as an adjuvant to surgery (p = 0.02). CONCLUSIONS In this 10-year analysis, the authors report outcomes of surgical intervention for patients with indeterminate or gross spinal instability due to multiple myeloma and plasmacytoma of the spine with improved neurological function following surgery and low rates of instrumentation failure.

Mobile spine chordoma: results of 166 patients from the AOSpine Knowledge Forum Tumor database

OBJECT A chordoma is an indolent primary spinal tumor that has devastating effects on the patients life. These lesions are chemoresistant, resistant to conventional radiotherapy, and moderately sensitive to proton therapy; however, en bloc resection remains the preferred treatment for optimizing patient outcomes. While multiple small and largely retrospective studies have investigated the outcomes following en bloc resection of chordomas in the sacrum, there have been few large-scale studies on patients with chordomas of the mobile spine. The goal of this study was to review the outcomes of surgically treated patients with mobile spine chordomas at multiple international centers with respect to local recurrence and survival. This multiinstitutional retrospective study collected data between 1988 and 2012 about prognosis-predicting factors, including various clinical characteristics and surgical techniques for mobile spine chordoma. Tumors were classified according to the Enneking principles and analyzed in 2 treatment cohorts: Enneking-appropriate (EA) and Enneking-inappropriate (EI) cohorts. Patients were categorized as EA when the final pathological assessment of the margin matched the Enneking recommendation; otherwise, they were categorized as EI. METHODS Descriptive statistics were used to summarize the data (Student t-test, chi-square, and Fisher exact tests). Recurrence and survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox proportional hazard modeling. RESULTS A total of 166 patients (55 female and 111 male patients) with mobile spine chordoma were included. The median patient follow-up was 2.6 years (range 1 day to 22.5 years). Fifty-eight (41%) patients were EA and 84 (59%) patients were EI. The type of biopsy (p < 0.001), spinal location (p = 0.018), and if the patient received adjuvant therapy (p < 0.001) were significantly different between the 2 cohorts. Overall, 58 (35%) patients developed local recurrence and 57 (34%) patients died. Median survival was 7.0 years postoperative: 8.4 years postoperative for EA patients and 6.4 years postoperative for EI patients (p = 0.023). The multivariate analysis showed that the EI cohort was significantly associated with an increased risk of local recurrence in comparison with the EA cohort (HR 7.02; 95% CI 2.96-16.6; p < 0.001), although no significant difference in survival was observed. CONCLUSIONS EA resection plays a major role in decreasing the risk for local recurrence in patients with chordoma of the mobile spine.

Venous sinus stenting is a valuable treatment for fulminant idiopathic intracranial hypertension

Over the past 10 years, transverse sinus stenting has grown in popularity as a treatment for idiopathic intracranial hypertension. Although promising results have been demonstrated in several reported series, the vast majority of patients in these series have been treated on an elective basis rather than in the setting of fulminant disease with acute visual deterioration. We identified four patients who presented with severe acute vision loss between 2008 and 2012 who were treated with urgent transverse sinus stenting with temporary cerebrospinal fluid (CSF) diversion with lumbar puncture or lumbar drain as a bridge to therapy. All patients presented with headache, and this was stable or had improved at last follow-up. Three patients had improvement in some or all visual parameters following stenting, whereas one patient who presented with severe acute vision loss and optic disc pallor progressed to blindness despite successful stenting. We hypothesize that she presented too late in the course of the disease for improvement to occur. Although the management of fulminant idiopathic intracranial hypertension remains challenging, we believe that transverse sinus stenting, in conjunction with temporary CSF diversion, represents a viable treatment option in the acute and appropriate setting.

Profiling the dynamics of a human phosphorylome reveals new components in HGF/c-Met signaling.

Protein phosphorylation is a dynamic and reversible event that greatly influences cellular function. Identifying the key regulatory elements that determine cellular phenotypes during development and oncogenesis requires the ability to dynamically monitor proteome-wide events. Here, we report the development of a new strategy to monitor dynamic changes of protein phosphorylation in cells and tissues using functional protein microarrays as the readout. To demonstrate this technologys ability to identify condition-dependent phosphorylation events, human protein microarrays were incubated with lysates from cells or tissues under activation or inhibition of c-Met, a receptor tyrosine kinase involved in tissue morphogenesis and malignancy. By comparing the differences between the protein phosphorylation profiles obtained using the protein microarrays, we were able to recover many of the proteins that are known to be specifically activated (i.e., phosphorylated) upon c-Met activation by the hepatocyte growth factor (HGF). Most importantly, we discovered many proteins that were differentially phosphorylated by lysates from cells or tissues when the c-Met pathway was active. Using phosphorylation-specific antibodies, we were able to validate several candidate proteins as new downstream components of the c-Met signaling pathway in cells. We envision that this new approach, like its DNA microarray counterpart, can be further extended toward profiling dynamics of global protein phosphorylation under many different physiological conditions both in cellulo and in vivo in a high-throughput and cost-effective fashion.

Automatic Localization of Target Vertebrae in Spine Surgery: Clinical Evaluation of the LevelCheck Registration Algorithm

Study Design. A 3-dimensional-2-dimensional (3D-2D) image registration algorithm, “LevelCheck,” was used to automatically label vertebrae in intraoperative mobile radiographs obtained during spine surgery. Accuracy, computation time, and potential failure modes were evaluated in a retrospective study of 20 patients. Objective. To measure the performance of the LevelCheck algorithm using clinical images acquired during spine surgery. Summary of Background Data. In spine surgery, the potential for wrong level surgery is significant due to the difficulty of localizing target vertebrae based solely on visual impression, palpation, and fluoroscopy. To remedy this difficulty and reduce the risk of wrong-level surgery, our team introduced a program (dubbed LevelCheck) to automatically localize target vertebrae in mobile radiographs using robust 3D-2D image registration to preoperative computed tomographic (CT) scan. Methods. Twenty consecutive patients undergoing thoracolumbar spine surgery, for whom both a preoperative CT scan and an intraoperative mobile radiograph were available, were retrospectively analyzed. A board-certified neuroradiologist determined the “true” vertebra levels in each radiograph. Registration of the preoperative CT scan to the intraoperative radiograph was calculated via LevelCheck, and projection distance errors were analyzed. Five hundred random initializations were performed for each patient, and algorithm settings (viz, the number of robust multistarts, ranging 50–200) were varied to evaluate the trade-off between registration error and computation time. Failure mode analysis was performed by individually analyzing unsuccessful registrations (>5 mm distance error) observed with 50 multistarts. Results. At 200 robust multistarts (computation time of ∼26 s), the registration accuracy was 100% across all 10,000 trials. As the number of multistarts (and computation time) decreased, the registration remained fairly robust, down to 99.3% registration accuracy at 50 multistarts (computation time ∼7 s). Conclusion. The LevelCheck algorithm correctly identified target vertebrae in intraoperative mobile radiographs of the thoracolumbar spine, demonstrating acceptable computation time, compatibility with routinely obtained preoperative CT scans, and warranting investigation in prospective studies. Level of Evidence: N/A

Risk factors for failed transverse sinus stenting in pseudotumor cerebri patients

BACKGROUND Idiopathic intracranial hypertension (IIH) when no underlying etiology is found, is a clinical syndrome characterized by elevated intracranial pressure (ICP) (>25 cm H2O), which may lead to headaches and visual symptoms. In patients with IIH who are found to have transverse sinus stenosis, placement of a venous stent across the stenosis has been shown to lower ICP and to resolve the symptoms in several case series, with generally favorable results. In this study, we examine common risk factors associated with failure of transvenous stenting for IIH. If venous sinus stenting fails, CSF diversion should be considered as the next line of treatment. METHODS We retrospectively reviewed the records of eighteen patients diagnosed with IIH who underwent venous sinus stenting for transverse sinus stenosis with a mean pressure gradient (MPG) of at least 4 mmHg. Fifteen of these patients did not need further treatment. We compared their pre- and post-treatment, neurological and neuro-ophthalmological evaluations to the three patients who went on to have a shunt placement as a second line treatment. RESULTS Shunting after stent placement patients (n=3) had a mean age of 30 years and a mean body mass index of 36.6 kg/m(2), whereas the group that underwent stent placement alone (n=15) had a mean age of 40.7 years and a mean body mass index of 33.3 kg/m(2). In the shunting after stent placement group, the mean opening pressure on the most recent lumbar puncture obtained prior to any intervention was 50 cm of H2O, whereas the group that underwent stent placement alone had an opening CSF pressure of 37 cm of H2O which was statistically significant (p<0.05). There were no other significant differences in pre- or post-intervention factors between the two groups. CONCLUSION In patients with IIH and documented evidence of venous sinus stenosis with a pressure gradient, venous sinus stenting should be the primary treatment of choice; however, some patients may be refractory to stenting and still require permanent CSF diversion, which can be complicated in these chronically anticoagulated patients. Patients with persistent papilledema post-stenting and highly elevated opening pressure pre-stenting should be followed closely as they are at greatest risk of requiring a shunt and failing stenting.

Evaluation and treatment of patients with suspected normal pressure hydrocephalus on long-term warfarin anticoagulation therapy.

OBJECTIVELong-term anticoagulation is often considered a contraindication to shunt surgery for elderly patients with normal pressure hydrocephalus (NPH). However, no studies have investigated this question. METHODSWe evaluated 25 patients who were taking warfarin for NPH between 2001 and 2004 with a protocol of cerebrospinal fluid (CSF) pressure monitoring and controlled CSF drainage via spinal catheter. Warfarin was stopped 5 to 7 days before lumbar puncture or shunt surgery and restarted 3 to 5 days after operation or at the time of discharge from the hospital. Programmable shunts with antisiphon devices set at the high-pressure range were preferentially used and adjusted in small increments. RESULTSAfter CSF drainage, 16 patients showed improvement and 15 underwent shunt surgery. Thirteen (87%) out of these 15 patients showed significant improvement in at least one symptom during a mean follow-up period of 8.2 months (range, 1–70 mo) after shunt surgery. There were two bleeding complications. One patient (6.7%) with cirrhosis who developed a subdural hematoma 13 days after operation had the shunt removed; another patient who developed an abdominal subcutaneous hematoma 5 days after operation required surgical evacuation and shunt revision surgery. Otherwise, 14 (93.3%) out of the 15 patients had no subdural hematoma during the follow-up period and there were no thromboembolic complications while the patients were not taking warfarin. CONCLUSIONElderly patients on long-term warfarin anticoagulation can be safely evaluated and treated for NPH using a protocol of continuous CSF drainage via spinal catheter for diagnosis, cautious periprocedural management of anticoagulation, and use of programmable shunts with antisiphon devices. The risk of subdural hematoma is not higher than reported series. Long-term anticoagulation with warfarin is not a contraindication per se for shunt surgery in NPH.