The Cytoskeleton Effectors Rho-Kinase (ROCK) and Mammalian Diaphanous-Related (mDia) Formin Have Dynamic Roles in Tumor Microtube Formation in Invasive Glioblastoma Cells.

Glioblastoma (GBM) is a progressive and lethal brain cancer. Malignant control of actin and microtubule cytoskeletal mechanics facilitates two major GBM therapeutic resistance strategies-diffuse invasion and tumor microtube network formation. Actin and microtubule reorganization is controlled by Rho-GTPases, which exert their effects through downstream effector protein activation, including Rho-associated kinases (ROCK) 1 and 2 and mammalian diaphanous-related (mDia) formins (mDia1, 2, and 3). Precise spatial and temporal balancing of the activity between these effectors dictates cell shape, adhesion turnover, and motility. Using small molecules targeting mDia, we demonstrated that global agonism (IMM02) was superior to antagonism (SMIFH2) as anti-invasion strategies in GBM spheroids. Here, we use IDH-wild-type GBM patient-derived cell models and a novel semi-adherent in vitro system to investigate the relationship between ROCK and mDia in invasion and tumor microtube networks. IMM02-mediated mDia agonism disrupts invasion in GBM patient-derived spheroid models, in part by inducing mDia expression loss and tumor microtube network collapse. Pharmacological disruption of ROCK prevented invasive cell-body movement away from GBM spheres, yet induced ultralong, phenotypically abnormal tumor microtube formation. Simultaneously targeting mDia and ROCK did not enhance the anti-invasive/-tumor microtube effects of IMM02. Our data reveal that targeting mDia is a viable GBM anti-invasion/-tumor microtube networking strategy, while ROCK inhibition is contraindicated.

Targeting the mDia Formin-Assembled Cytoskeleton Is an Effective Anti-Invasion Strategy in Adult High-Grade Glioma Patient-Derived Neurospheres.

High-grade glioma (HGG, WHO Grade III⁻IV) accounts for the majority of adult primary malignant brain tumors. Failure of current therapies to target invasive glioma cells partly explains the minimal survival advantages: invasive tumors lack easily-defined surgical margins, and are inherently more chemo- and radioresistant. Much work centers upon Rho GTPase-mediated glioma invasion, yet downstream Rho effector roles are poorly understood and represent potential therapeutic targets. The roles for the mammalian Diaphanous (mDia)-related formin family of Rho effectors have emerged in invasive/metastatic disease. mDias assemble linear F-actin to promote protrusive cytoskeletal structures underlying tumor cell invasion. Small molecule mDia intramimic (IMM) agonists induced mDia functional activities including F-actin polymerization. mDia agonism inhibited polarized migration in Glioblastoma (WHO Grade IV) cells in three-dimensional (3D) in vitro and rat brain slice models. Here, we evaluate whether clinically-relevant high-grade glioma patient-derived neuro-sphere invasion is sensitive to formin agonism. Surgical HGG samples were dissociated, briefly grown as monolayers, and spontaneously formed non-adherent neuro-spheres. IMM treatment dramatically inhibited HGG patient neuro-sphere invasion, both at neuro-sphere embedding and mid-invasion assay, inducing an amoeboid morphology in neuro-sphere edge cells, while inhibiting actin- and tubulin-enriched tumor microtube formation. Thus, mDia agonism effectively disrupts multiple aspects of patient-derived HGG neuro-sphere invasion.

Microsurgical Clipping of an Anterior Communicating Artery Aneurysm Using a Novel Robotic Visualization Tool in Lieu of the Binocular Operating Microscope: Operative Video.

INTRODUCTION: The binocular operating microscope has been the visualization instrument of choice for microsurgical clipping of intracranial aneurysms for many decades. OBJECTIVE: To discuss recent technological advances that have provided novel visualization tools, which may prove to be superior to the binocular operating microscope in many regards. METHODS: We present an operative video and our operative experience with the BrightMatterTM Servo System (Synaptive Medical, Toronto, Ontario, Canada) during the microsurgical clipping of an anterior communicating artery aneurysm. To the best of our knowledge, the use of this device for the microsurgical clipping of an intracranial aneurysm has never been described in the literature. RESULTS: The BrightMatterTM Servo System (Synaptive Medical) is a surgical exoscope which avoids many of the ergonomic constraints of the binocular operating microscope, but is associated with a steep learning curve. The BrightMatterTM Servo System (Synaptive Medical) is a maneuverable surgical exoscope that is positioned with a directional aiming device and a surgeon-controlled foot pedal. While utilizing this device comes with a steep learning curve typical of any new technology, the BrightMatterTM Servo System (Synaptive Medical) has several advantages over the conventional surgical microscope, which include a relatively unobstructed surgical field, provision of high-definition images, and visualization of difficult angles/trajectories. CONCLUSION: This device can easily be utilized as a visualization tool for a variety of cranial and spinal procedures in lieu of the binocular operating microscope. We anticipate that this technology will soon become an integral part of the neurosurgeon's armamentarium.

A cohort study of the morbidity of combined anterior-posterior cervical spinal fusions: incidence and predictors of postoperative dysphagia.

PURPOSE: To identify risk factors that may lead to the development of dysphagia after combined anterior and posterior (360°) cervical fusion surgery. METHODS: A single center, retrospective analysis of patients who had same-day, 360° fusion at Henry Ford Hospital between 2008 and 2012 was performed. Variables analyzed included demographics, medical co-morbidities, levels fused, and degree of dysphagia. RESULTS: The overall dysphagia rate was 37.7 %. Patients with dysphagia had a longer mean length of stay (p < 0.001), longer mean operative time (p < 0.001), greater intraoperative blood loss (p = 0.002), and fusion above the fourth cervical vertebra, C4, (p = 0.007). There were no differences in the rates of dysphagia when comparing patients undergoing primary or revision surgery (p = 0.554). CONCLUSION: Prolonged surgery and fusion above C4 lead to higher rates of dysphagia after 360° fusions. Prior anterior cervical fusion does not increase the risk of dysphagia development.

Preoperative external tissue expansion for complex cranial reconstructions.

OBJECTIVE Reconstruction of large solitary cranial defects after multiple craniotomies is challenging because scalp contraction generally requires more than simple subcutaneous undermining to ensure effective and cosmetically appealing closure. In plastic and reconstructive surgery, soft tissue expansion is considered the gold standard for reconstructing scalp defects; however, these techniques are not well known nor are they routinely practiced among neurosurgeons. The authors here describe a simple external tissue expansion technique that is associated with low morbidity and results in high cosmetic satisfaction among patients. METHODS The authors reviewed the medical records of patients with large cranial defects (> 5 cm) following multiple complicated craniotomies who had undergone reconstructive cranioplasty with preoperative tissue expansion using the DermaClose RC device. In addition to gathering data on patient age, sex, primary pathology, number of craniotomies and/or craniectomies, history of radiation therapy, and duration of external scalp tissue expansion, the authors screened patient charts for cerebrospinal fluid (CSF) leak, meningitis, intracranial abscess formation, dermatitis, and patient satisfaction rates. RESULTS The 6 identified patients (5 female, 1 male) had an age range from 36 to 70 years. All patients had complicating factors such as recalcitrant scalp infections after multiple craniotomies or cranial radiation, which led to secondary scalp tissue scarring and retraction. All patients were deemed to be potential candidates for rotational flaps with or without skin grafts. All patients underwent the same preoperative tissue expansion followed by standard cranial bone reconstruction. None of the patients developed CSF leak, meningitis, intracranial abscess, dermatitis, or permanent cosmetic defects. None of the patients required a reoperation. Mean follow-up was 117 days. CONCLUSIONS Preoperative scalp tissue expansion with the DermaClose RC device allows for simple and reliable completion of complicated cranial reconstruction with low morbidity rates and high cosmetic satisfaction among patients.

Management of arteriovenous malformations in the elderly: a single-center case series and analysis of outcomes.

OBJECT Treatment of brain arteriovenous malformations (bAVMs) in the elderly remains a challenge for cerebrovascular surgeons. In this study the authors reviewed the patient characteristics, treatments, angiographic results, and clinical outcomes in 28 patients over 65 years of age who were treated at Henry Ford Hospital between 1990 and 2014. METHODS The bAVM database at the authors' institution was queried for records of elderly patients with bAVMs, and data regarding patient demographics, presenting symptoms, bAVM angioarchitecture, treatment modalities, angiographic results, clinical outcomes, and treatment complications were tabulated and analyzed. RESULTS There were 9 male (32%) and 19 female (68%) patients, with an average age ( ± SD) of 73.0 ± 6.95 years. The most common symptoms on presentation were hemorrhage (36%) and headaches (18%). The bAVMs were equally distributed between the supra- and infratentorial compartments. The most common Spetzler-Martin grade was II, observed in 57% of the patients. Eleven patients (39.3%) underwent resection, 4 patients (14.3%) received standalone radiation therapy, and 13 patients (46%) did not receive treatment or were managed expectantly. Four patients (14.3%) were lost to follow-up. Complete bAVM obliteration was achieved in 87% of the treated patients. None of the patients who received any form of treatment died; the overall mortality rate was 3.6%. CONCLUSIONS Surgical management of bAVMs in the elderly can result in complete obliteration and acceptable clinical outcomes.

Endovascular management of fusiform aneurysm of anterior temporal artery: Technical report.

BACKGROUND: The treatment of a rare, nontraumatic, fusiform aneurysm of the anterior temporal artery (ATA) via endovascular techniques is presented, and procedural nuances are highlighted. METHODS: We performed a retrospective chart review and collected demographic and clinical data on the patient presented here; procedural details were extracted from operative notes. RESULTS: Following successful balloon test occlusion (BTO) of the ATA, complete coil embolization of the ATA, and its associated fusiform aneurysm was performed. Postprocedurally, the patient did not suffer any adverse neurological sequelae. CONCLUSION: Selective BTO of intracranial branch vessels is safe, technically feasible, and could serve as a useful technical tool in the treatment of complex, fusiform intracranial aneurysms.

Surgical Management of Giant Intracranial Arteriovenous Malformations: A Single Center Experience over 32 years.

OBJECTIVE: Treatment of giant intracranial arteriovenous malformations (gAVMs) is a formidable challenge for neurosurgeons and carries significant morbidity and mortality rates for patients compared with smaller AVMs. In this study, we reviewed the treatments, angiographic results, and clinical outcomes in 64 patients with gAVMs who were treated at Henry Ford Hospital between 1980 and 2012. METHODS: The arteriovenous malformation (AVM) database at our institution was queried for patients with gAVMs (≥ 6 cm) and data regarding patient demographics, presentation, AVM angioarchitecture, and treatments were collected. Functional outcomes as well as complications were analyzed. RESULTS: Of the 64 patients, 33 (51.6%) were female and 31 (48.4%) were male, with an average age of 45.7 years (SD ± 15.5). The most common symptoms on presentation were headaches (50%), seizures (50%), and hemorrhage (41%). The mean AVM size was 6.65 cm (range, 6-9 cm). Only 6 AVMs (9.4%) were located in the posterior fossa. The most common Spetzler-Martin grade was V, seen in 64% of patients. Of the 64 patients, 42 (66%) underwent surgical excision, 10 (15.5%) declined any treatment, 8 (12.5%) were deemed inoperable and followed conservatively, 2 (3%) had stand-alone embolization, 1 (1.5%) had embolization before stereotactic radiosurgery, and 1 (1.5%) received stereotactic radiosurgery only. Complete obliteration was achieved in 90% of the surgical patients. Mortality rate was 19% in the surgical cohort compared with 22% in the observation cohort (P = 0.770). CONCLUSIONS: Treatment of gAVMs carries significant morbidity and mortality; however, good outcomes are attainable with a multimodal treatment approach in carefully selected patients.

Novel technique for cranial reconstruction following retrosigmoid craniectomy using demineralized bone matrix.

OBJECTIVE: A versatile neurosurgical approach, the retrosigmoid craniectomy (RS) has traditionally been associated with high rates of post-operative cerebrospinal fluid (CSF) leak, headaches, and aesthetic defects. We introduce a simple surgical strategy for bony cranial reconstruction designed to minimize peri-operative complications and improve cosmetic outcomes. METHODS: In accordance with the Institutional Review Board, the senior author's (G.M.M.) records were queried between 2006 and 2014. We identified 50 consecutive patients who underwent demineralized bone matrix (DBM)-augmented cranioplasty after RS for MVD (DBM group) and 92 consecutive patients in whom standard cranial reconstruction was undertaken using autologous bone chips only after RS for MVD (non-DBM group). Demographic and clinical information regarding the laterality of each operation, intra-dural drilling for petrous hyperostosis, method of dural closure, length of hospitalization, presence of post-operative headaches, and procedure-related complications were collected and analyzed. RESULTS: The DBM and non-DBM cohorts were well matched for age, laterality of procedure, surgical indications, primary versus revision surgery, intra-dural drilling of petrous hyperostosis, and dural closure techniques. Trigeminal neuralgia was the most common surgical indication (98.6%) in each cohort. Post-operatively, 15% of patients in non-DBM group experienced chronic headaches at the last follow-up compared to only 8% of the patients in the DBM group (p=0.21). The non-DBM patients also suffered more incisional pain in comparison to the DBM patients (7.6% vs. 0%, p=0.045). CONCLUSION: DBM-augmented reconstruction of posterior fossa defects resulted in low rates of post-operative headaches, better cosmetic outcomes, and represents a simple and effective cranioplasty option for skull base surgeons.

Management of perisylvian arteriovenous malformations: a retrospective institutional case series and review of the literature.

OBJECT: Sylvian arteriovenous malformations (sAVMs) are challenging lesions of the central nervous system. The natural history of these unique lesions as well as clinical outcomes following treatment of sAVMs has been limited to case series owing to the rarity of these lesions. The authors present their experience with sAVMs and review the literature. METHODS: In accordance with the Henry Ford Institutional Review Board, medical records of patients with sAVMs treated from 2000 to 2012 were reviewed. Clinical data were retrospectively collected to calculate pre- and posttreatment modified Rankin Scale scores for all patients. RESULTS: The authors identified 15 patients with sAVMs who received treatment. Of these, 12 were female and 3 were male, and the average age at presentation was 39.6 ± 12.94 years (± SD). Two patients (13.3%) had Spetzler-Martin Grade I lesions, 6 patients (40%) had Grade II lesions, 5 patients (33.3%) had Grade III lesions, and another 2 (13.3%) harbored Grade IV arteriovenous malformations (AVMs). According to the Sugita classification, 6 patients (40%) had medial lesions, 6 (40%) had lateral lesions, 2 (13.3%) had deep lesions, and 1 patient (6.67%) had a pure sAVM. Eight patients (53.3%) underwent stereotactic radiosurgery while 7 patients (46.7%) had microsurgical resection; 1 patient underwent surgical extirpation after incomplete response following radiosurgery. After treatment, 9 patients were unchanged from pretreatment (60%), 3 patients worsened, and 2 patients had improved functional outcome (20% and 13.3%, respectively). The authors' literature search yielded 348 patients with sAVMs, most of them harboring Spetzler-Martin Grade II and III lesions. Approximately 98% of the patients underwent resection with excellent outcomes. CONCLUSIONS: While the ideal choice of therapeutic modality for cerebral AVMs remains controversial in light of the recent publication of the ARUBA (A Randomized trial of Unruptured Brain AVMs) trial, a multidisciplinary treatment approach for the management of sAVMs can lead to acceptable neurological outcome.