Sanford Larson, MD, PhD: a pioneering neurosurgeon, scientist, and educator.

Dr. Sanford Larson, MD, PhD (1929-2012), was an influential figure in spinal neurosurgery. Dr. Larson played a pivotal role in establishing neurosurgery's foothold in spinal surgery by serving as the inaugural chair of the Joint Section on Disorders of the Spine and Peripheral Nerves and as a president of the Cervical Spine Research Society. He made many advances in spine care, most notably the modification and popularization of the lateral extracavitary approach to the thoracolumbar spine. Dr. Larson established the neurosurgery residency program at the Medical College of Wisconsin; he also instituted the program's spine fellowship, the first in the United States for neurological surgeons. His mentorship produced numerous leaders in organized neurosurgery and neurosurgical education, including Edward Benzel, MD, Dennis Maiman, MD, PhD, Joseph Cheng, MD, Shekar Kurpad, MD, PhD, and Christopher Wolfla, MD. Dr. Larson was a prominent leader in spinal neurosurgery and his legacy carries on today through his contributions to research, education, and surgical technique.

Patterns and outcomes of intracranial pressure monitoring in traumatic brain injury: An analysis of the National Inpatient Sample.

INTRODUCTION: Elevated intracranial pressure (ICP) can cause progressive neurological deterioration following traumatic brain injury (TBI). ICP can be monitored to guide subsequent treatment decisions. However, there is conflicting data in the literature regarding the utility of ICP monitoring. We aim to describe patterns and outcomes of ICP monitoring in the United States with the use of a nationwide healthcare database. METHODS: We performed a 5-year analysis of the Nationwide Inpatient Sample database. We identified all adult TBI patients with a Glasgow Coma Scale (GCS) measuring 3-8 using International Classification of Diseases diagnostic codes. Propensity score matching (1:2 ratio) was performed to control for demographics, injury parameters and comorbidities. Outcome measures included inpatient mortality, length of stay (LOS), cost of care, and discharge disposition. RESULTS: After propensity score matching, a cohort of 1664 patients was obtained (monitored, 555; non-monitored, 1109). Index outcomes with respect to monitor and no-monitor are as follows: inpatient mortality (35.1%, 42.4%, P <0.01), median LOS (15 days, 6 days, P<0.001), median total charge (289,797 USD, 154,223 USD, P <0.001), discharge home (7.9%, 19.3%, P <0.001) and discharge to another facility (53.9%, 35.4%, P <0.001). DISCUSSION: ICP monitoring in TBI patients is associated with decreased inpatient mortality and discharge to home, and it is associated with an increased hospital LOS, total charge, and chance of discharge to another facility. CONCLUSION: The risks and benefits of ICP monitoring should be seriously considered when managing adults with severe TBI.

Ventriculoureteral shunt: Narrative review of contemporary cases and its historical role in the development of renal transplantation.

Ventriculo-ureteral (VU) shunting is a little-known method of managing hydrocephalus. This paper reviews contemporary uses of this shunting technique and describes its historical significance to the field of organ transplantation. The ureter may serve as a possible backup, or alternative, distal drainage site compared to the more common peritoneum, atrium, and pleural space. Sporadic contemporary uses of the VU shunt have been reported in unique situations, demonstrating a possible utility in modern neurosurgery. Interestingly, the VU shunt played an important role in the development of kidney transplantation. In the late 1940s and early 1950s, David Hume, a general surgery resident, and colleagues at the PBBH undertook a series of human kidney transplantations. Concurrently, Donald Matson, a pediatric neurosurgeon at Peter Bent Brigham, was utilizing the VU shunt in hydrocephalic patients. Dr. Matson's VU shunt technique involved total nephrectomy, and some of the kidneys harvested from Dr. Matson's were used by his general surgery colleagues in their transplantation trials. Although none of the transplanted kidneys from this series were successful, the transplant team in Boston, minus David Hume, went on to perform the world's first kidney transplant a few years later. This relatively unfamiliar procedure may be applicable to specific situations, and it is of historical importance to the field of transplantation.

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.

A Population-Based Study of Patients with Sleep-Wake Disorders Undergoing Elective Instrumented Spinal Surgery.

BACKGROUND: Sleep-wake disorders (SWDs) are associated with multiple systemic pathologies; however, the clinical risk that such disorders carry for spinal surgery patients is not well understood. In the present population-based study, we comprehensively evaluated the significance of sleep-related risk factors on instrumented spinal surgery outcomes. METHODS: National Inpatient Sample data for the hospitalization of patients who had undergone elective instrumented spine surgery from 2008 to 2014 were analyzed using national estimates. The cohorts were defined as those admissions with or without a coexisting SWD diagnosis identified by International Classification of Diseases, ninth revision, codes. Postoperative complications, mortality rate, length of stay, discharge status, and the total cost of admission were compared between the groups using bivariate and multivariate analyses. RESULTS: A coexisting SWD was present in 234,640 of 2,171,167 instrumented spinal surgery hospitalizations (10.8%). Multivariate binary logistic regression accounting for these variables confirmed that a SWD is a significant risk factor for postoperative complications (odds ratio [OR], 1.160; 95% confidence interval [CI], 1.140-1.179; P < 0.0001), length of stay greater than the 75th percentile (OR, 1.303; 95% CI, 1.288-1.320; P < 0.0001), nonroutine discharge (OR, 1.147; 95% CI, 1.131-1.163; P < 0.0001), and death (OR, 1.533; 95% CI, 1.131-2.078; P < 0.01), but not for total charges greater than the 75th percentile (OR, 0.975; 95% CI, 0.962-0.989; P < 0.001). CONCLUSIONS: SWDs confer an increased risk of morbidity and mortality for elective instrumented spine surgery. Understanding the specific contributions of SWDs to postoperative morbidity and mortality will help physicians implement prophylactic measures to reduce complications and improve postoperative patient recovery.

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.

Outcomes and prognostic stratification of patients with recurrent glioblastoma treated with salvage stereotactic radiosurgery.

OBJECTIVE: Glioblastoma (GBM) is the most malignant form of astrocytoma. The average survival is 6-10 months in patients with recurrent GBM (rGBM). In this study, the authors evaluated the role of stereotactic radiosurgery (SRS) in patients with rGBMs. METHODS: The authors performed a retrospective review of their brain tumor database (1997-2016). Overall survival (OS) and progression-free survival (PFS) after salvage SRS were the primary endpoints evaluated. Response to SRS was assessed using volumetric MR images. RESULTS: Fifty-three patients with rGBM underwent salvage SRS targeting 75 lesions. The median tumor diameter and volume were 2.55 cm and 3.80 cm3, respectively. The median prescription dose was 18 Gy (range 12-24 Gy) and the homogeneity index was 1.90 (range 1.11-2.02). The median OS after salvage SRS was estimated to be 11.0 months (95% CI 7.1-12.2) and the median PFS after salvage SRS was 4.4 months (95% CI 3.7-5.0). A Karnofsky Performance Scale score ≥ 80 was independently associated with longer OS, while small tumor volume (< 15 cm3) and less homogeneous treatment plans (homogeneity index > 1.75) were both independently associated with longer OS (p = 0.007 and 0.03) and PFS (p = 0.01 and 0.002, respectively). Based on these factors, 2 prognostic groups were identified for PFS (5.4 vs 3.2 months), while 3 were identified for OS (median OS of 15.2 vs 10.5 vs 5.2 months). CONCLUSIONS: SRS is associated with longer OS and/or PFS in patients with good performance status, small-volume tumor recurrences, and heterogeneous treatment plans. The authors propose a prognostic model to identify a cohort of rGBM patients who may benefit from SRS.

Streptococcus Mutans: A Potential Risk Factor in Recurrent Hemorrhagic Stroke.

Stroke is the fifth leading cause of death and is responsible for approximately nine percent of all deaths worldwide. Cases of Streptococcus mutans (S. mutans)-induced intracerebral hemorrhage as a result of bloodstream infections have seldom been reported. New reports show that bacteria with specific collagen binding proteins (CBPs), such as the Cnm type produced by S. mutans, may inhibit platelet aggregation and cause bleeding. In this article, we report on a 62-year-old man with a recent history of left frontal intracerebral hemorrhage (ICH) who presented to the emergency department after a fall due to suspected seizure while in rehabilitation. Computed tomography (CT) scan of the brain showed a right cerebellar hemorrhage with surrounding edema and mass effect on the fourth ventricle. A suboccipital craniotomy to evacuate the cerebellar ICH was completed without complication. Radiologic and angiographic assessments regarding the etiology of this patient's stroke did not reveal any evidence of vascular pathology or mycotic aneurysms to explain his recurrent intracranial hemorrhages. Through persistent patient and family interviews, it came to light that a few weeks prior to the patient's first ICH, he was diagnosed with a bloodstream infection by S. mutans. Bacteremia is known to be associated with embolic stroke, but only recently has it been shown that bacteremia can also be implicated in hemorrhagic stroke. S. mutans of the k serotype have specific CBPs that are attracted to exposed collagen in previously damaged small vessel walls. These bacterial proteins can interrupt the blood clotting cascade through the prevention of platelet aggregation, increasing the risk of intracerebral hemorrhage.

Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases.

OBJECTIVE The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated. METHODS An institutional review board-approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months. RESULTS The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non-small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)-but not uncommon pathologies-were independent prognostic factors for the subgroup with symptomatic radiation necrosis. CONCLUSIONS A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma.

OBJECT: The impact of extent of resection (EOR) on survival for patients with glioblastoma (GBM) continues to be a point of debate despite multiple studies demonstrating that increasing EOR likely extends survival for these patients. In addition, contrast-enhancing residual tumor volume (CE-RTV) alone has rarely been analyzed quantitatively to determine if it is a predictor of outcome. The purpose of this study was to evaluate the effect of CE-RTV and T2/FLAIR residual volume (T2/F-RV) on overall survival. METHODS: A retrospective review of 128 patients who underwent primary resection of supratentorial GBM followed by standard radiation/chemotherapy was undertaken utilizing quantitative, volumetric analysis of pre- and postoperative MR images. The results were compared with clinical data obtained from the patients' medical records. RESULTS: At analysis, 8% of patients were alive, and no patients were lost to follow-up. The overall median survival was 13.8 months, with a median Karnofsky Performance Scale (KPS) score of 90 at presentation. The median contrast-enhancing preoperative tumor volume (CE-PTV) was 29.0 cm(3), and CE-RTV was 1.2 cm(3), equating to a 95.8% median EOR. The median T2/F-RV was 36.8 cm(3). CE-PTV, CE-RTV, T2/F-RV, and EOR were all statistically significant predictors of survival when controlling for age and KPS score. A statistically significant benefit in survival was seen with a CE-RTV less than 2 cm(3) or an EOR greater than 98%. Evaluation of the volumetric analysis methodology was performed by observers of varying degrees of experience-an attending neurosurgeon, a fellow, and a medical student. Both the medical student and fellow recorded correlation coefficients of 0.98 when compared with the attending surgeon's measured volumes of CE-PTV, while for CE-RTV, correlation coefficients of 0.67 and 0.71 (medical student and fellow, respectively) were obtained. CONCLUSIONS: CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM.

The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study.

Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011-December 2012) using the NeuroBlate(®) System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43 °C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow-up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 ± 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria-(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line-had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery.

Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery.

PURPOSE: Approximately 12,000 glioblastomas are diagnosed annually in the United States. The median survival rate for this disease is 12 months, but individual survival rates can vary with patient-specific factors, including extent of surgical resection (EOR). The goal of our investigation is to develop a reliable strategy for personalized survival prediction and for quantifying the relationship between survival, EOR, and adjuvant chemoradiotherapy. PATIENTS AND METHODS: We used accelerated failure time (AFT) modeling using data from 721 newly diagnosed patients with glioblastoma (from 1993 to 2010) to model the factors affecting individualized survival after surgical resection, and we used the model to construct probabilistic, patient-specific tools for survival prediction. We validated this model with independent data from 109 patients from a second institution. RESULTS: AFT modeling using age, Karnofsky performance score, EOR, and adjuvant chemoradiotherapy produced a continuous, nonlinear, multivariable survival model for glioblastoma. The median personalized predictive error was 4.37 months, representing a more than 20% improvement over current methods. Subsequent model-based calculations yield patient-specific predictions of the incremental effects of EOR and adjuvant therapy on survival. CONCLUSION: Nonlinear, multivariable AFT modeling outperforms current methods for estimating individual survival after glioblastoma resection. The model produces personalized survival curves and quantifies the relationship between variables modulating patient-specific survival. This approach provides comprehensive, personalized, probabilistic, and clinically relevant information regarding the anticipated course of disease, the overall prognosis, and the patient-specific influence of EOR and adjuvant chemoradiotherapy. The continuous, nonlinear relationship identified between expected median survival and EOR argues against a surgical management strategy based on rigid EOR thresholds and instead provides the first explicit evidence supporting a maximum safe resection approach to glioblastoma surgery.

Laser interstitial thermal therapy in treatment of brain tumors--the NeuroBlate System.

Treatment of brain tumors remains challenging. Cytoreductive surgery is used as the first line treatment for most brain tumors. However complete, curative, resection is not achievable in many tumors leading to the need for adjuvant chemotherapy and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive cytoreductive treatment. A low voltage laser is used to induce hyperthermia and to kill tumor cells. The extent of thermal damage is controlled through use of real-time MR-thermography guidance. Initial results have shown the feasibility of LITT for a variety of brain pathologies. LITT can be considered as an alternative type of surgery for difficult to access brain tumors and also for tumors in patients who are deemed high risk for more traditional surgery. Randomized trials are currently planned to continue assessing the efficacy of LITT and long-term follow-up data are awaited.

Absence of immunostaining for growth hormone in a subset of patients with acromegaly.

The presence of growth hormone (GH) immunostaining in patients who lack the biochemical and clinical features of acromegaly has been described. In contrast, there is little information on the absence of GH immunostaining in patients with acromegaly. We describe five patients with acromegaly with no intratumoral immunostaining for GH. We reviewed all patients undergoing surgery for acromegaly. Out of 136 patients treated surgically in a 10 year period, five (3.7%) were found to have no GH immunostaining on repetitive testing at pathological examination. Their pathology slides were re-examined by an experienced neuropathologist, along with twenty nonfunctional pituitary tumors and ten GH-positive adenomas as negative and positive controls, respectively. All patients had clinical features consistent with acromegaly and elevated baseline insulin-like growth factor-1 (IGF-1) and GH. All patients had no immunostaining for GH on multiple inspections. Of twenty patients with nonfunctional tumors, two had ≤25% staining for GH in a scattered and non-coherent pattern and the rest were negative. In all ten positive control patients >25% of the tumor cells stained diffusely for GH. All five patients achieved biochemical remission at 1.4-8 years post-op using a combination of primary surgery alone (n = 1), repeat surgery (n = 1), radiotherapy (n = 3) and/or medical therapy (n = 2). GH immunostaining of an adenoma may not be sufficient to confirm the diagnosis of acromegaly. All patients in our small series achieved remission by multimodality therapies. Further studies are needed to evaluate the significance of our observation and whether this subset of patients follows a distinct long term clinical course.

Reduction of hypoxia by perfluorocarbon emulsion in a traumatic spinal cord injury model.

OBJECT: Few therapies have consistently demonstrated effectiveness in preserving O2 delivery after spinal cord injury (SCI). Perfluorocarbons (PFCs) offer great promise to carry and deliver O2 more efficiently than conventional measures. The authors investigated the use of Clark-type microelectrodes to monitor spinal cord oxygenation directly (intraparenchymal [IP] recording) and indirectly (cerebrospinal fluid [CSF] recording) in the context of SCI, O2 therapy, and PFC treatment. METHODS: After placement of a subdural/CSF Licox probe in rats, incremental increases in the fraction of inspired O2 (FiO2) up to 100% were administered to establish a dose-response curve. The probe was then placed in the parenchyma of the same animals for a second dose-response curve. In a second study, rats with CSF or IP probes underwent SCI with the NYU Impactor and treatment with O2, followed by administration of PFC, or saline in the control group. RESULTS: All animals in the first experiment responded to the FiO2 dose increase, with changes in PO2 evident in both CSF and IP levels. The SCI in the second experiment caused a marked drop in PO2 from a mean of 21.4 to 10.4 mm Hg, with most animals dropping to less than half their preinjury value. All animals responded to 100% O2 treatment. Every animal that received PFCs showed significant improvement, with a mean increase in PO2 of 23.3 mm Hg. Only 1 saline-treated animal showed any benefit. Oxygen values in the PFC treatment group reached up to 6 times the normal level. CONCLUSIONS: Oxygen levels in SCI show a profound drop almost immediately postinjury. Administration of PFCs combined with 100% O2 therapy can reverse tissue hypoxia and holds promise for reducing ischemic injury.