Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway.
Ahmed J. Awad, Terry C. Burns, Ying Zhang and Roger Abounader
Terry C. Burns, Ahmed J. Awad, Matthew D. Li and Gerald A. Grant
Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.
I. Jonathan Pomeraniec, Alexander Ksendzovsky, Ahmed J. Awad, Francis Fezeu and John A. Jane Jr.
The natural and surgical history of Chiari malformation Type I (CM-I) in pediatric patients is currently not well described. In this study the authors discuss the clinical and radiological presentation and outcomes in a large cohort of pediatric CM-I patients treated with either conservative or surgical management.
The authors retrospectively reviewed 95 cases involving pediatric patients with CM-I who presented between 2004 and 2013. The patients ranged in age from 9 months to 18 years (mean 8 years) at presentation. The cohort was evenly split between the sexes. Twenty-five patients underwent posterior fossa decompression (PFD) with either dural splitting or duraplasty. Seventy patients were managed without surgery. Patients were followed radiologically (mean 44.8 months, range 1.2–196.6 months) and clinically (mean 66.3 months, range 1.2–106.5 months).
Seventy patients were treated conservatively and followed with serial outpatient neurological and radiological examinations, whereas 25 patients were treated with PFD. Of these 25 surgical patients, 11 were treated with duraplasty (complete dural opening) and 14 were treated with a dura-splitting technique (incomplete dural opening). Surgical intervention was associated with better clinical resolution of symptoms and radiological resolution of tonsillar ectopia and syringomyelia (p = 0.0392). Over the course of follow-up, 20 (41.7%) of 48 nonsurgical patients who were symptomatic at presentation experienced improvement in symptoms and 18 (75%) of 24 symptomatic surgical patients showed clinical improvement (p = 0.0117). There was no statistically significant difference in resolution of symptoms between duraplasty and dura-splitting techniques (p = 0.3572) or between patients who underwent tonsillectomy and tonsillopexy (p = 0.1667). Neither of the 2 patients in the conservative group with syrinx at presentation showed radiological evidence of resolution of the syrinx, whereas 14 (87.5%) of 16 patients treated with surgery showed improvement or complete resolution of syringomyelia (p = 0.0392). In the nonsurgical cohort, 3 patients (4.3%) developed new or increased syrinx.
The overwhelming majority of CM-I patients (92.9%) managed conservatively do not experience clinical or radiological progression, and a sizeable minority (41.7%) of those who present with symptoms improve. However, appropriately selected symptomatic patients (sleep apnea and dysphagia) and those presenting with syringomyelia should be considered surgical candidates because of the high rates of clinical (75%) and radiological improvement (87.5%).
Jonathan A. Forbes, Ahmed J. Awad, Scott Zuckerman, Kevin Carr and Joseph S. Cheng
The authors' goal was to better define the relationship between biomechanical parameters of a helmeted collision and the likelihood of concussion.
The English-language literature was reviewed in search of scholarly articles describing the rotational and translational accelerations observed during all monitored impact conditions that resulted in concussion at all levels of American football.
High school players who suffer concussion experience an average of 93.9g of translational acceleration (TA) and 6505.2 rad/s2 of rotational acceleration (RA). College athletes experience an average of 118.4g of TA and 5311.6 rad/s2 of RA. While approximately 3% of collisions are associated with TAs greater than the mean TA associated with concussion, only about 0.02% of collisions actually result in a concussion. Associated variables that determine whether a player who experiences a severe collision also experiences a concussion remain hypothetical at present.
The ability to reliably predict the incidence of concussion based purely on biomechanical data remains elusive. This study provides novel, important information that helps to quantify the relative insignificance of biomechanical parameters in prediction of concussion risk. Further research will be necessary to better define other factors that predispose to concussion.
Alexander G. Chartrain, Ahmed J. Awad, Jonathan J. Rasouli, Robert J. Rothrock and Brian H. Kopell
A 59-year-old woman with a 30-year history of essential tremor refractory to medical therapy underwent staged deep brain stimulation of the ventralis intermedius nucleus of the thalamus (VIM). Left-sided lead placement was performed first. Once in the operating room, microelectrode recording (MER) was performed to confirm the appropriate trajectory and identify the VIM border with the ventralis caudalis nucleus. MER was repeated after repositioning 2 mm anteriorly to reduce the likelihood of stimulation-induced paresthesias. Physical examination prior to permanent lead placement demonstrated micro-lesion effect, suggesting optimal trajectory. After implantation of the permanent lead, physical examination showed excellent results.
The video can be found here: https://youtu.be/nn3KRdmRCZ4.
Ahmed J. Awad, Brian P. Walcott, Christopher J. Stapleton, Vijay Yanamadala, Brian V. Nahed and Jean-Valery Coumans
Dabigatran etexilate (Pradaxa) is a novel oral anticoagulant that has gained FDA approval for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In randomized trials, the incidence of hemorrhagic events has been demonstrated to be lower in patients treated with dabigatran compared with the traditional anticoagulant warfarin. However, dabigatran does not have reliable laboratory tests to measure levels of anticoagulation and there is no pharmacological antidote. These drawbacks are challenging in the setting of intracerebral hemorrhage. In this article, the authors provide background information on dabigatran, review the existing anecdotal experiences with treating intracerebral hemorrhage related to dabigatran therapy, present a case study of intracranial hemorrhage in a patient being treated with dabigatran, and suggest clinical management strategies. The development of reversal agents is urgently needed given the growing number of patients treated with this medication.
Ahmed J. Awad, Justin R. Mascitelli, Reham R. Haroun, Reade A. De Leacy, Johanna T. Fifi and J Mocco
Fusiform aneurysms are uncommon compared with their saccular counterparts, yet they remain very challenging to treat and are associated with high rates of rebleeding and morbidity. Lack of a true aneurysm neck renders simple clip reconstruction or coil embolization usually impossible, and more advanced techniques are required, including bypass, stent-assisted coiling, and, more recently, flow diversion. In this article, the authors review posterior circulation fusiform aneurysms, including pathogenesis, natural history, and endovascular treatment, including the role of flow diversion. In addition, the authors propose an algorithm for treatment based on their practice.
Paul E. Kaloostian, Patricia L. Zadnik, Ahmed J. Awad, Edward McCarthy, Jean-Paul Wolinsky and Daniel M. Sciubba
Resection of metastatic pheochromocytomas may be complicated by transient postoperative neurological deficits due to hypotension. The authors report the first case of en bloc excision of a spinal pheochromocytoma with associated long-term hypertensive management off all medication. Interestingly, this is the first case of transient hypotension following en bloc resection of pheochromocytoma associated with temporary hypotension-associated neurological decline that resolved completely after correction of hypotension postoperatively. A 23-year-old man with a prior adrenalectomy for pheochromocytoma presented with focal thoracic pain. He had a known T-10 vertebral body lesion for which he received chemotherapy and radiation therapy. Imaging demonstrated increased destruction of the T-10 vertebral body, which was concerning for tumor growth. The patient underwent angiographic embolization followed by single-stage posterior en bloc vertebrectomy with placement of a cage and posterior instrumentation and fusion without event. However, approximately 24 hours after surgery, the patient's systolic blood pressure was consistently no higher than 70 mm Hg. During this time, he began suffering from severe bilateral lower-extremity weakness. His systolic blood pressure increased with dopamine, and his strength immediately improved. The patient's oral regimen of adrenergic blockade was stopped, and he recovered without event. Since that time, the patient has been symptom free and requires no antihypertensive medication. The role of en bloc resection for metastatic lesions of the spine is controversial but may be warranted in cases of metastatic pheochromocytoma. En bloc resection avoids intralesional tumor resection and thus may help prevent complications of hypertensive crisis associated with hormonal secretion and extensive blood loss, which are not uncommon with pheochromocytoma resection surgeries. Additionally, the role of en bloc spondylectomy in this setting may allow for metabolic treatment as patients with actively secreting tumors may no longer require antiadrenergic medications.
Robert M. Starke, Colin J. Przybylowski, Mukherjee Sugoto, Francis Fezeu, Ahmed J. Awad, Dale Ding, James H. Nguyen and Jason P. Sheehan
Stereotactic radiosurgery (SRS) has become a common treatment modality for intracranial meningiomas. Skull base meningiomas greater than 8 cm3 in volume have been found to have worse outcomes following SRS. When symptomatic, patients with these tumors are often initially treated with resection. For tumors located in close proximity to eloquent structures or in patients unwilling or unable to undergo a resection, SRS may be an acceptable therapeutic approach. In this study, the authors review the SRS outcomes of skull base meningiomas greater than 8 cm3 in volume, which corresponds to a lesion with an approximate diameter of 2.5 cm.
The authors reviewed the data in a prospectively compiled database documenting the outcomes of 469 patients with skull base meningiomas treated with single-session Gamma Knife radiosurgery (GKRS). Seventy-five patients had tumors greater than 8 cm3 in volume, which was defined as a large tumor. All patients had a minimum follow-up of 6 months, but patients were included if they had a complication at any time point. Thirty patients were treated with upfront GKRS, and 45 were treated following microsurgery. Patient and tumor characteristics were assessed to determine predictors of new or worsening neurological function and tumor progression following GKRS.
After a mean follow-up of 6.5 years (range 0.5–21 years), the tumor volume was unchanged in 37 patients (49%), decreased in 26 patients (35%), and increased in 12 patients (16%). Actuarial rates of progression-free survival at 3, 5, and 10 years were 90.3%, 88.6%, and 77.2%, respectively. Four patients had new or worsened edema following GKRS, but preexisting edema decreased in 3 patients. In Cox multivariable analysis, covariates associated with tumor progression were 1) presentation with any cranial nerve (CN) deficit from III to VI (hazard ratio [HR] 3.78, 95% CI 1.91–7.45; p < 0.001), history of radiotherapy (HR 12.06, 95% CI 2.04–71.27; p = 0.006), and tumor volume greater than 14 cm3 (HR 6.86, 95% CI 0.88–53.36; p = 0.066). In those patients with detailed clinical follow-up (n = 64), neurological function was unchanged in 37 patients (58%), improved in 16 patients (25%), and deteriorated in 11 patients (17%). In multivariate analysis, the factors predictive of new or worsening neurological function were history of surgery (OR 3.00, 95% CI 1.13–7.95; p = 0.027), presentation with any CN deficit from III to VI (OR 3.94, 95% CI 1.49–10.24; p = 0.007), and decreasing maximal dose (OR 0.76, 95% CI 0.63–0.93; p = 0.007). Tumor progression was present in 64% of patients with new or worsening neurological decline.
Stereotactic radiosurgery affords a reasonable rate of tumor control for large skull base meningiomas and does so with a low incidence of neurological deficits. Those with a tumor less than 14 cm3 in volume and without presenting CN deficit from III to VI were more likely to have effective tumor control.
Alexander G. Chartrain, Ahmed J. Awad, Christopher A. Sarkiss, Rui Feng, Yangbo Liu, J Mocco, Joshua B. Bederson, Stephan A. Mayer, Neha S. Dangayach and Errol Gordon
Patients who have experienced subarachnoid hemorrhage (SAH) often receive care in the setting of the ICU. However, SAH patients may not all require extended ICU admission. The authors established a protocol on January 1, 2015, to transfer select, low-risk patients to a step-down unit (SDU) to streamline care for SAH patients. This study describes the results of the implemented protocol.
In this retrospective chart review, patients presenting with SAH between January 2011 and September 2016 were reviewed for inclusion. The control group consisted of patients admitted prior to establishment of the SDU transfer protocol, while the intervention group consisted of patients admitted afterward.
Of the patients in the intervention group, 79.2% (57/72) were transferred to the SDU during their admission. Of these transferred patients, 29.8% (17/57) required return to the neurosurgical ICU (NSICU). There were no instances of morbidity or mortality directly related to care in the SDU. Patients in the intervention group had a mean reduced NSICU length of stay, by 1.95 days, which trended toward significance, and a longer average hospitalization, by 2.7 days, which also trended toward significance. In-hospital mortality and 90-day readmission rate were not statistically different between the groups. In addition, early transfer timing prior to 7 days was associated with neither a higher return rate to the NSICU nor higher 90-day readmission rate.
In this retrospective study, the authors demonstrated that the transfer protocol was safe, feasible, and effective in reducing the ICU length of stay and was independent of transfer timing. Confirmation of these results is needed in a large, multicenter study.