Six-Year Follow-up of a Randomized Controlled Trial of i-FACTOR Peptide-Enhanced Bone Graft Versus Local Autograft in Single-Level Anterior Cervical Discectomy and Fusion.

BACKGROUND: Previous analyses of the US Food and Drug Administration (FDA) Investigational Device Exemption study demonstrated the superiority of i-FACTOR compared with local autograft bone in single-level anterior cervical discectomy and fusion (ACDF) at 12 and 24 months postoperatively in a composite end point of overall success. OBJECTIVE: To report the final, 6-year clinical and radiological outcomes of the FDA postapproval study. METHODS: Of the original 319 subjects enrolled in the Investigational Device Exemption study, 220 participated in the postapproval study (106 i-FACTOR and 114 control). RESULTS: The study met statistical noninferiority success for all 4 coprimary end points. Radiographic fusion was achieved in 99% (103/104) and 98.2% (109/111) in i-FACTOR and local autograft subjects, mean Neck Disability Index improvement from baseline was 28.6 (24.8, 32.3) in the i-FACTOR and 29.2 (25.6, 32.9) in the control group, respectively (noninferiority P < .0001). The neurological success rate at 6 years was 95.9% (70/73) in i-FACTOR subjects and 93.7% (70/75) in local autograft subjects (noninferiority P < .0001). Safety outcomes were similar between the 2 groups. Secondary surgery on the same or different cervical levels occurred in 20/106 (18.9%) i-FACTOR subjects and 23/114 (20.2%) local autograft subjects ( P = .866). Secondary outcomes (pain, SF-36 physical component score and mental component score) in i-FACTOR subjects were similar to those in local autograft subjects. CONCLUSION: i-FACTOR met all 4 FDA-mandated noninferiority success criteria and demonstrated safety and efficacy in single-level anterior cervical discectomy and fusion for cervical radiculopathy through 6 years postoperatively. Safety outcomes are acceptable, and the clinical and functional outcomes observed at 12 and 24 months remained at 72 months.

Two-Year Clinical and Radiological Outcomes in Patients With Diabetes Undergoing Single-Level Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Secondary analysis of data from the multicenter, randomized, parallel-controlled Food and Drug Administration (FDA) investigational device exemption study. OBJECTIVE: Studies on outcomes following anterior cervical discectomy and fusion (ACDF) in individuals with diabetes are scarce. We compared 24-month radiological and clinical outcomes in individuals with and without diabetes undergoing single-level ACDF with either i-FACTOR or local autologous bone. METHODS: Between 2006 and 2013, 319 individuals with single-level degenerative disc disease (DDD) and no previous fusion at the index level underwent ACDF. The presence of diabetes determined the 2 cohorts. Data collected included radiological fusion evaluation, neurological outcomes, Neck Disability Index (NDI), Visual Analog Scale (VAS) scores, and the 36-Item Short Form Survey Version 2 (SF-36v2) Physical and Mental component summary scores. RESULTS: There were 35 individuals with diabetes (11.1%; average body mass index [BMI] = 32.99 kg/m2; SD = 5.72) and 284 without (average BMI = 28.32 kg/m2; SD = 5.67). The number of nondiabetic smokers was significantly higher than diabetic smokers: 73 (25.70%) and 3 (8.57%), respectively. Preoperative scores of NDI, VAS arm pain, and SF-36v2 were similar between the diabetic and nondiabetic participants at baseline; however, VAS neck pain differed significantly between the cohorts at baseline (P = .0089). Maximum improvement for NDI, VAS neck and arm pain, and SF-36v2 PCS and MCS scores was seen at 6 months in both cohorts and remained stable until 24 months. CONCLUSIONS: ACDF is effective for cervical radiculopathy in patients with diabetes. Diabetes is not a contraindication for patients requiring single-level surgery for cervical DDD.

Efficacy of i-Factor Bone Graft versus Autograft in Anterior Cervical Discectomy and Fusion: Results of the Prospective, Randomized, Single-blinded Food and Drug Administration Investigational Device Exemption Study.

STUDY DESIGN: A prospective, randomized, controlled, parallel, single-blinded noninferiority multicenter pivotal FDA IDE trial. OBJECTIVE: The objective of this study was to investigate efficacy and safety of i-Factor Bone Graft (i-Factor) compared with local autograft in single-level anterior cervical discectomy and fusion (ACDF) for cervical radiculopathy. SUMMARY OF BACKGROUND DATA: i-Factor is a composite bone substitute material consisting of the P-15 synthetic collagen fragment adsorbed onto anorganic bone mineral and suspended in an inert biocompatible hydrogel carrier. P-15 has demonstrated bone healing efficacy in dental, orthopedic, and nonhuman applications. METHODS: Patients randomly received either autograft (N = 154) or i-Factor (N = 165) in a cortical ring allograft. Study success was defined as noninferiority in fusion, Neck Disability Index (NDI), and Neurological Success endpoints, and similar adverse events profile at 12 months. RESULTS: At 12 months (follow-up rate 87%), both i-Factor and autograft subjects demonstrated a high fusion rate (88.97% and 85.82%, respectively, noninferiority P = 0.0004), significant improvements in NDI (28.75 and 27.40, respectively, noninferiority P < 0.0001), and high Neurological Success rate (93.71% and 93.01%, respectively, noninferiority P < 0.0001). There was no difference in the rate of adverse events (83.64% and 82.47% in the i-Factor and autograft groups, respectively, P = 0.8814). Overall success rate consisting of fusion, NDI, Neurological Success and Safety Success was higher in i-Factor subjects than in autograft subjects (68.75% and 56.94%, respectively, P = 0.0382). Improvements in VAS pain and SF-36v2 scores were clinically relevant and similar between the groups. A high proportion of patients reported good or excellent Odom outcomes (81.4% in both groups). CONCLUSION: i-Factor has met all four FDA mandated noninferiority success criteria and has demonstrated safety and efficacy in single-level ACDF for cervical radiculopathy. i-Factor and autograft groups demonstrated significant postsurgical improvement and high fusion rates. LEVEL OF EVIDENCE: 1.

Multi-site study of surgical practice in neurosurgery based on surgical process models.

Surgical Process Modelling (SPM) was introduced to improve understanding the different parameters that influence the performance of a Surgical Process (SP). Data acquired from SPM methodology is enormous and complex. Several analysis methods based on comparison or classification of Surgical Process Models (SPMs) have previously been proposed. Such methods compare a set of SPMs to highlight specific parameters explaining differences between populations of patients, surgeons or systems. In this study, procedures performed at three different international University hospitals were compared using SPM methodology based on a similarity metric focusing on the sequence of activities occurring during surgery. The proposed approach is based on Dynamic Time Warping (DTW) algorithm combined with a clustering algorithm. SPMs of 41 Anterior Cervical Discectomy (ACD) surgeries were acquired at three Neurosurgical departments; in France, Germany, and Canada. The proposed approach distinguished the different surgical behaviors according to the location where surgery was performed as well as between the categorized surgical experience of individual surgeons. We also propose the use of Multidimensional Scaling to induce a new space of representation of the sequences of activities. The approach was compared to a time-based approach (e.g. duration of surgeries) and has been shown to be more precise. We also discuss the integration of other criteria in order to better understand what influences the way the surgeries are performed. This first multi-site study represents an important step towards the creation of robust analysis tools for processing SPMs. It opens new perspectives for the assessment of surgical approaches, tools or systems as well as objective assessment and comparison of surgeon's expertise.

Supraphysiological expression of survival motor neuron protein from an adenovirus vector does not adversely affect cell function.

Spinal muscular atrophy (SMA) is the most common inherited neurodegenerative disease that leads to infant mortality. It is caused by mutations in the survival motor neuron (SMN) protein resulting in death of alpha motor neurons. Increasing evidence suggests that several other tissues are also affected in SMA, including skeletal and cardiac muscle, liver, and pancreas, indicating that systemic delivery of therapeutics may be necessary for true disease correction. Due to the natural biodistribution of therapeutics, a level of SMN several-fold above physiological levels can be achieved in some tissues. In this study, we address whether supraphysiological levels of SMN adversely affects cell function. Infection of a variety of cell types with an adenovirus (Ad) vector encoding SMN leads to very high expression, but the resulting protein correctly localizes within the cell, and associates with normal cellular partners. Although SMN affects transcription of certain target genes and can alter the splicing pattern of others, we did not observe any difference in select target gene splicing or expression in cells overexpressing SMN. However, normal human fibroblasts treated with Ad-SMN showed a slight reduction in growth rate, suggesting that certain cell types may be differently impacted by high levels of SMN.

Pedicle violation and Navigational errors in pedicle screw insertion using the intraoperative O-arm: A preliminary report.

BACKGROUND: Use of computer-assisted insertion of pedicle screws has some advantages owing to the reportedly decreased incidence of pedicle breach and clinical events. Registration-based methods based on preoperative computed tomography imaging, 2D fluoroscopy, and 3D fluoroscopy are the most popular, however each has its limitations. O-arm-based navigation, which uses intraoperative acquisition and registration of navigated images, may overcome many of these disadvantages. We set out to study the clinical accuracy and navigational accuracy for pedicle screw insertion using our recently acquired O-arm and present our preliminary findings. METHODS: The first 26 patients operated consecutively for L4-5 fusion were included in the study. O-arm-based navigation was used to insert the pedicle screws. Postoperative computed tomography images were acquired and assessed for pedicle breach and anterior cortical perforation. Planned trajectories of each screw were compared with the actual trajectories in the postoperative images to assess navigational accuracy in both axial and sagittal planes. RESULTS: A total of 104 screws were inserted. One screw (1%) breached the pedicle laterally. Nonsignificant anterolateral cortical perforations were noted in 7 screws (6.7%), all of which occurred at L5 level. The mean axial and sagittal navigational error was 2.3° (±1.7) and 3.1° (±2.3), respectively. There were no significant differences in the errors between L4 or L5 level. The occurrence of anterior perforation correlated with the degree of axial (P = .02) but not sagittal (P = .12) navigational error. There were no clinical events related to the screw insertion. CONCLUSION: Use of O-arm-guided pedicle screw insertion was associated with low incidence of pedicle breach (1%) and a low range of navigational error in both sagittal and axial planes. Anterolateral vertebral body perforation was higher at L5 without any negative clinical events. Despite the high need for technical support, we found that O-arm was a very efficient tool for accurate pedicle screw insertion.

Ultrasound-CT registration of vertebrae without reconstruction.

PURPOSE: While robust and accurate, our previously developed volume-to-volume ultrasound-CT registration of vertebrae required that the 2D ultrasound slices be reconstructed into a 3D volume, a time-consuming step that increased the total registration time per vertebra. We have modified our registration technique to a slices-to-volume strategy to eliminate the ultrasound reconstruction step in order to make the total registration time more practical intraoperatively. METHODS: The slices-to-volume registration is achieved by performing backward scan line tracing on individual ultrasound slices as they are acquired, and then registering them as a group to the posterior vertebral surface extracted from the pre-operative CT image. The technique is validated using a lumbosacral Sawbones phantom and the lumbosacral section of three porcine cadavers. RESULTS: The slices-to-volume registration reduced the total registration time per vertebra from 8 to 4 min. The registration accuracy and robustness of the slices-to-volume registration were found to be equal or superior to those of our previous volume-to-volume registration. In addition, a trade-off was found between registration accuracy and registration speed by changing the number of ultrasound slices used in the registration. CONCLUSIONS: The slices-to-volume ultrasound-CT registration significantly reduces the total registration time per vertebra, making this automated technique more practical intraoperatively.

Validation of automated ultrasound-CT registration of vertebrae.

PURPOSE: Image-guided spine surgery requires registration of the patient anatomy and preoperative computed tomography (CT) images. A technique for intraoperative ultrasound image registration to preoperative CT scans was developed and tested. Validation of the ultrasound-CT registration technique was performed using porcine cadavers. METHODS: An ultrasound-CT registration technique was evaluated using 18 thoracic and lumbar vertebrae of 3 porcine cadavers with 10 different sweep patterns for ultrasound acquisition. For each sweep pattern at each vertebra, 100 randomly simulated initial misalignments were introduced. Each misalignment was registered. The resulting registration transformations were compared to gold standard registrations based on implanted fiducials to assess accuracy and robustness of the technique. RESULTS: The orthogonal-sweep acquisition was found to perform best and yielded a registration accuracy of 1.65 mm across all vertebrae on all porcine cadavers, where 82.5% of the registrations resulted in target registration errors below the 2 mm threshold recommended by a joint report from the experts in the field. In addition, we found that registration accuracy varies by the sweep pattern and vertebral level, but neighboring vertebrae tend to result in statistically similar accuracy. Ultrasound-CT registration took an average of 2.5 min to run, and the total registration time per vertebra (also including time for ultrasound acquisition and reconstruction) is approximately 8 min. CONCLUSIONS: A previously described ultrasound-CT registration technique yields clinically acceptable accuracy and robustness on multiple vertebrae across multiple porcine cadavers. The total registration time is shorter than that of surface point-based manual registration.

The role of magnetic resonance imaging in the management of acute spinal cord injury.

Magnetic resonance imaging (MRI) has become the gold standard for imaging neurological tissues including the spinal cord. The use of MRI for imaging in the acute management of patients with spinal cord injury has increased significantly. This paper used a vigorous literature review with Downs and Black scoring, followed by a Delphi vote on the main conclusions. MRI is strongly recommended for the prognostication of acute spinal cord injury. The sagittal T2 sequence was particularly found to be of value. Four prognostication patterns were found to be predictive of neurological outcome (normal, single-level edema, multi-level edema, and mixed hemorrhage and edema). It is recommended that MRI be used to direct clinical decision making. MRI has a role in clearance, the ruling out of injury, of the cervical spine in the obtunded patient only if there is abnormality of the neurological exam. Patients with cervical spinal cord injuries have an increased risk of vertebral artery injuries but the literature does not allow for recommendation of magnetic resonance angiography as part of the routine protocol. Finally, time repetition (TR) and time echo (TE) values used to evaluate patients with acute spinal cord injury vary significantly. All publications with MRI should specify the TR and TE values used.

Towards accurate, robust and practical ultrasound-CT registration of vertebrae for image-guided spine surgery.

PURPOSE: Accurate registration of patient anatomy and preoperative computed tomography (CT) images is key to successful image-guided spine surgery. Current manual landmark and surface-based techniques are time-consuming and not always accurate. Intraoperative ultrasound imaging of the vertebrae, combined with automated registration, could improve surgery by improving accuracy, reducing operative time, and decreasing invasiveness. METHODS: We present a simple ultrasound-CT registration technique that is automated, accurate, and robust. Registration is achieved by aligning the posterior vertebral surface, extracted from both CT and ultrasound images, using a forward and a backward scan line tracing method, respectively. The registration technique is validated using a simple plastic phantom in a water bath and a more realistic porcine cadaver in a simulation of open back surgery. RESULTS: Clinically relevant accuracy was estimated by comparing automated registrations with gold standard imaging fiducial-based reference transformations, which yielded target registration errors of under 1 mm for the plastic phantom and under 1.6 mm for the porcine cadaver. CONCLUSIONS: Our registration technique demonstrates good accuracy and robustness under clinically realistic conditions and thus warrants further studies on its surgical application.

Dietary starch type affects body weight and glycemic control in freely fed but not energy-restricted obese rats.

This study comprised 2 experiments that tested the hypothesis that a high-amylose starch diet (AMO) would improve body weight and glycemic control relative to a high-amylopectin starch diet (AMN) in rats with diet-induced obesity. After inducing obesity with a high-fat and -energy diet (Expt. 1), male Sprague-Dawley rats (n = 46) were divided into 4 groups and given free or restricted access to either an AMN or an AMO diet for 4 wk (Expt. 2). After 3 wk, rats from each group underwent an oral glucose tolerance test. At the end of the experiment, food-deprived rats were killed by decapitation and blood and tissues were collected for analyses. AMO led to lower total energy intake, weight gain, fat pad mass, and glycemic response but higher insulin sensitivity index than AMN, only when consumed ad libitum (AL) (P < 0.05). AMO led to higher glucagon-like peptide-1 and peptide YY responses and mRNA levels, independent of feeding paradigm (P < 0.01). The mRNA levels of key neuropeptide systems involved in the regulation of food intake were affected only by energy restriction. On the other hand, AMO resulted in higher expression of uncoupling protein-1 in the brown adipose tissue than AMN in rats that consumed food AL (P < 0.05). The effects of AMO appear to be mediated by its high resistant starch content rather than its glycemic index. We conclude that starches high in AMO can be effective in weight and glycemic control in obesity.

Toxicity of cadmium, endosulfan, and atrazine in adrenal steroidogenic cells of two amphibian species, Xenopus laevis and Rana catesbeiana.

The effects of cadmium, endosulfan, and atrazine on corticosterone secretion and viability of adrenal cells of African clawed frog (Xenopus laevis) and bullfrog (Rana catesbeiana) were assessed in vitro using a new bioassay. The bioassay relies on stimulation with adrenocorticotropic hormone (ACTH), the endogenous secretagogue for corticosterone secretion, and with dibutyryl cyclic adenosine monophosphate (dbcAMP), an analogue of cAMP, to pinpoint the site of action of the xenobiotics within the steroidogenic cell. To compare the test toxicants according to their endocrine-disrupting potential, the lethal concentration needed to kill 50% of the cells:effective concentration of 50% (LC50:EC50) ratio was calculated, with LC50 as the concentration that kills 50% of the steroidogenic cells and the EC50 as the concentration that impairs corticosterone secretion by 50%. The higher the ratio, the higher the potential for endocrine disruption. Atrazine had no affect on cell viability and on corticosterone secretion in X. laevis, but its endocrine-disrupting potential was high in R. catesbeiana. The LC50:EC50 ratio for cadmium and endosulfan in X. laevis was 26.07 and 1.23, respectively, and for atrazine, cadmium, and endosulfan in R. catesbeiana it was 909, 41, and 3, respectively. The dbcAMP did not restore corticosterone secretion in the cells exposed to the test toxicants in both species. Our study suggests that the secretory capacity of adrenal cells of amphibians can be impaired by environmental chemicals, especially atrazine in the bullfrog, and that these adrenotoxicants disrupt the enzymatic pathways leading to corticosterone secretion downstream from the step-generating cAMP.