Long-Term Time Series Forecasting and Updates on Survival Analysis of Glioblastoma Multiforme: A 1975-2018 Population-Based Study.

OBJECTIVE: Glioblastomas multiforme (GBMs) are the most common primary CNS tumors. Epidemiologic studies have investigated the effect of demographics on patient survival, but the literature remains inconclusive. METHODS: This study included all adult patients with intracranial GBMs reported in the surveillance epidemiology and end results (SEER)-9 population database (1975-2018). The sample consisted of 32,746 unique entries. We forecast the annual GBM incidence in the US population through the year 2060 using time series analysis with autoregressive moving averages. A survival analysis of the GBM-specific time to death was also performed. Multivariate Cox proportional hazards (PH) regression revealed frank violations of the PH assumption for multiple covariates. Parametric models best described the GBM population's survival pattern; the results were compared to the semi-parametric analysis and the published literature. RESULTS: We predicted an increasing GBM incidence, which demonstrated that by the year 2060, over 1,800 cases will be reported annually in the SEER. All eight demographic variables were significant in the univariable analysis. The calendar year 2005 was the cutoff associated with an increased survival probability. A male survival benefit was eliminated in the year-adjusted Cox. Infratentorial tumors, nonmetropolitan areas, and White patient race were the factors erroneously associated with survival in the multivariate Cox analysis. Accelerated Failure Time (AFT) lognormal regression was the best model to describe the survival pattern in our patient population, identifying age >30 years old as a poor prognostic and patients >70 years old as having the worst survival. Annual income >USD 75,000 and supratentorial tumors had good prognostics, while surgical intervention provided the strongest survival benefit. CONCLUSIONS: Annual GBM incidence rates will continue to increase by almost 50% in the upcoming 30 years. Cox regression analysis should not be utilized for time-to-event predictions in GBM survival statistics. AFT lognormal distribution best describes the GBM-specific survival pattern, and as an inherent population characteristic, it should be implemented by researchers for future studies. Surgical intervention provides the strongest survival benefit, while patient age >70 years old is the worst prognostic. Based on our study, the demographics such as gender, race, and county type should not be considered as meaningful prognostics when designing future trials.

Vertebral body fracture after anterior cervical discectomy and fusion with zero-profile anchored cages in adjacent levels: a cautionary tale.

BACKGROUND CONTEXT: Zero-profile (also called self-locking, anchored or stand-alone cages) have been recently proposed as an interesting alternative for anterior cervical discectomy and fusion (ACDF), as they are supposed to reduce the rates of post-operative cage extrusion without necessarily incurring in the additional surgical time and increased rates of dysphagia associated with plating. Nevertheless, the exact indications of zero-profile anchored cages have not yet been established in the literature. PURPOSE: To report the first case of a vertebral body fracture between the blades of zero-profile anchored cages after ACDFs in adjacent levels and to review the available literature on hardware-related complications after multi-level ACDFs with zero-profile anchored cages. STUDY DESIGN: Case report and systematic literature review. METHODS: The authors report the first case of a vertebral body fracture between the blades of zero-profile anchored cages after ACDFs in adjacent levels. The patient presented with refractory mechanical neck pain at the 1-month post-operative follow-up, ultimately requiring a posterior instrumented fusion. A comprehensive systematic literature review on the available data regarding the safety, complications as well as radiological and clinical outcomes of zero-profile anchored cages is also performed. RESULTS: In the reported case, the use of zero-profile anchored cages in adjacent levels on the cervical spine led to a fracture of the vertebral body between the cages at the 1-month follow-up, with anterior avulsion of the part of the vertebral body where the blades from the two cages converged. According to the systematic literature review which included 409 patients from 10 different clinical series (with a total cumulative follow-up of approximately 535 patients-year), there were only two reported hardware-related complications after ACDF with zero-profile anchored cages, none of them involving fracture at the level of convergence of blades or screws. CONCLUSIONS: Although hardware-related complications after the use of zero-profile anchored cages seem to be rare events, future biomechanical and clinical studies are warranted in order to evaluate the safety of employing such devices for the treatment of multilevel degenerative disc disease in the cervical spine.

Sources, Identification, and Clinical Implications of Heterogeneity in Human Umbilical Cord Stem Cells.

Heterogeneity among different subpopulations of human umbilical cord mesenchymal stem cell (hUCMSCs) lines is an ubiquitous phenomenon, with such variability being related to several factors including the identity of the individual donor, tissue source (Wharton's jelly vs. umbilical cord blood), culture conditions, as well as random variations in the cloning expansion process. In this chapter, we provide a general overview on the sources as well as available experimental techniques for proper identification of heterogeneity in hUCMSCs. Finally, we provide a brief discussion on the current scientific evidence regarding the potential superiority of subpopulations of hUCMSCs for specific clinical applications. Taking into account the exponential growth on the available experimental data on hUCMSCs in the past few years, this chapter is not intended to be comprehensive in nature, but rather is intended to provide a general overview about the central role which the topic of heterogeneity has in both basic science and clinical research in umbilical cord stem cells.

Talking to others' selves: Why a valuational paradigm of agency fails to provide an adequate theoretical framework for moral responsibility, social accountability, and legal liability.

In this commentary, I highlight the importance of a proper discussion of the pragmatic implications of John Doris's paradigm for allocation of personal responsibility proposed in his new book Talking to Our Selves. By employing some classic concepts of the American common law tradition, I discuss why Doris's valuational understanding of agency fails to provide an adequate framework for moral responsibility, social accountability, and legal liability.

The 'Lumbar Fusion Outcome Score' (LUFOS): a new practical and surgically oriented grading system for preoperative prediction of surgical outcomes after lumbar spinal fusion in patients with degenerative disc disease and refractory chronic axial low back pain.

In order to evaluate the predictive effect of non-invasive preoperative imaging methods on surgical outcomes of lumbar fusion for patients with degenerative disc disease (DDD) and refractory chronic axial low back pain (LBP), the authors conducted a retrospective review of 45 patients with DDD and refractory LBP submitted to anterior lumbar interbody fusion (ALIF) at a single center from 2007 to 2010. Surgical outcomes - as measured by Visual Analog Scale (VAS/back pain) and Oswestry Disability Index (ODI) - were evaluated pre-operatively and at 6 weeks, 3 months, 6 months, and 1 year post-operatively. Linear mixed-effects models were generated in order to identify possible preoperative imaging characteristics (including bone scan/99mTc scintigraphy increased endplate uptake, Modic endplate changes, and disc degeneration graded according to Pfirrmann classification) which may be predictive of long-term surgical outcomes . After controlling for confounders, a combined score, the Lumbar Fusion Outcome Score (LUFOS), was developed. The LUFOS grading system was able to stratify patients in two general groups (Non-surgical: LUFOS 0 and 1; Surgical: LUFOS 2 and 3) that presented significantly different surgical outcomes in terms of estimated marginal means of VAS/back pain (p = 0.001) and ODI (p = 0.006) beginning at 3 months and continuing up to 1 year of follow-up. In conclusion,  LUFOS has been devised as a new practical and surgically oriented grading system based on simple key parameters from non-invasive preoperative imaging exams (magnetic resonance imaging/MRI and bone scan/99mTc scintigraphy) which has been shown to be highly predictive of surgical outcomes of patients undergoing lumbar fusion for treatment for refractory chronic axial LBP.

Cavitational kyphoplasty: a new technique for reducing the rates of cement extravasation through targeted low-pressure cement injection.

BACKGROUND: Previous studies have demonstrated lower rates of cement extravasation when comparing balloon kyphoplasty with vertebroplasty, an effect attributed to the low-pressure injection. However, in patients with isolated endplate fractures, balloon kyphoplasty may lead to further endplate damage and increased risks of intradiscal extravasation. METHODS: The author provides a stepwise description of a new technique called cavitational kyphoplasty that allows targeted low-pressure cement injection without the necessity of balloon inflation. CONCLUSIONS: The new technique of cavitational kyphoplasty has been shown to be specially useful in patients with isolated endplate fractures without significant loss of the vertebral body height.

A game theory appraisal of the insurance hypothesis: Specific polymorphisms in the energy homeostasis network as imprints of a successful minimax strategy.

The existence of specific polymorphisms in genes of key hormones of the energy homeostasis network that have been shown to predispose to obesity and the so-called metabolic syndrome provides further biological support for the proposed insurance hypothesis. In a broader sense, such polymorphisms can be understood as biological imprints of an evolutionarily successful minimax strategy employed by ancient Homo sapiens subpopulations in a one-player game against nature.

Modern surgical techniques for management of soft tissue sarcomas involving the spine: outcomes and complications.

Several types of soft tissue sarcomas may locally extend to the spine. The best therapeutic strategy for such lesions strongly depends on the histological diagnosis. In this article the authors provide an up-to-date review of current guidelines regarding the management of soft tissue sarcomas involving the spine. Special attention is given to outcomes and complications of modern surgical series in order to highlight current challenges in the management of such lesions.

"Extremely minimally invasive": recent advances in nanotechnology research and future applications in neurosurgery.

The term "nanotechnology" refers to the development of materials and devices that have been designed with specific properties at the nanometer scale (10(-9) m), usually being less than 100 nm in size. Recent advances in nanotechnology have promised to enable visualization and intervention at the subcellular level, and its incorporation to future medical therapeutics is expected to bring new avenues for molecular imaging, targeted drug delivery, and personalized interventions. Although the central nervous system presents unique challenges to the implementation of new therapeutic strategies involving nanotechnology (such as the heterogeneous molecular environment of different CNS regions, the existence of multiple processing centers with different cytoarchitecture, and the presence of the blood-brain barrier), numerous studies have demonstrated that the incorporation of nanotechnology resources into the armamentarium of neurosurgery may lead to breakthrough advances in the near future. In this article, the authors present a critical review on the current 'state-of-the-art' of basic research in nanotechnology with special attention to those issues which present the greatest potential to generate major therapeutic progresses in the neurosurgical field, including nanoelectromechanical systems, nano-scaffolds for neural regeneration, sutureless anastomosis, molecular imaging, targeted drug delivery, and theranostic strategies.

Surgical challenges in the management of cervical kyphotic deformity in patients with severe osteoporosis: an illustrative case of a patient with Hajdu-Cheney syndrome.

PURPOSE: No standard strategy exists for the management of cervical kyphotic deformity in patients with severe osteoporosis. In fact, in such subpopulation, standard algorithms commonly used in patients with normal bone mineral density may not be applicable. In this Grand Rounds, the authors present a challenging case of a patient with Hajdu-Cheney syndrome, a rare disorder of bone metabolism induced by a Notch-2 mutation, who presented with cervical kyphotic deformity and severe osteoporosis. METHODS: A 65-year-old female patient with a previous diagnosis of Hajdu-Cheney syndrome presented with cervical myelopathy and cervical kyphotic deformity. The initial MRi demonstrated multilevel cervical canal stenosis. The CT-scan also revealed marked spondylolisthesis of C6 over C7 as well as numerous laminar and pedicle fractures, resulting in a cervical kyphosis of approximately 50 degrees. RESULTS: The patient was submitted to 360-degree decompression and fusion of the cervical spine consisting of a staged C6 anterior corpectomy and multilevel microdiscectomies with wide opening of the posterior longitudinal ligament in order to provide a satisfactory release of anterior spinal structures, followed by 24 h of cervical halo-traction, a second anterior approach for bone graft implantation in the site of the corpectomy as well as insertion of allografts and completion of the ACDF C2-T1 and plating, and, finally, a posterior C2-T3 pedicle screw instrumentation using intra-operative CT-scan (O-arm) navigation guidance. CONCLUSIONS: This case illustrates some intra-operative nuances as well as specific surgical recommendations for cervical deformity surgery in patients with severe osteoporosis, such as avoidance of Caspar pins for interbody distraction, use of intra-operative fluoroscopy for achievement of bicortical purchase of anterior cervical screws and placement of pedicle screws during posterior instrumentation. Moreover, such illustrative case demonstrates that, in the subpopulation of patients with severe osteoporosis, it may be possible to successfully apply cervical distraction after an isolated anterior approach with a satisfactory improvement in the cervical alignment, possibly avoiding more laborious 540-degree approaches such as the previously described back-front-back or front-back-front surgical algorithms.

The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes.

Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.

Clinical outcomes of temporary shunting for infants with cerebral pseudomeningocele.

OBJECTIVE: Although in the case of subdural collections temporary shunting has been suggested as a viable alternative for definitive drainage of the accumulated fluid until restoration of the normal CSF dynamics, there is no agreement on the best management strategy for pseudomeningocele. METHODS: The authors performed a retrospective chart review in order to evaluate the clinical outcomes of infants temporarily shunted for pseudomeningocele without encephalocele at our institution (The University of Illinois at Peoria/Illinois Neurological Institute) in the period from 2004 to 2012. The epidemiological characteristics, clinical management, and final outcomes of such subpopulation were compared with a control group which received temporary shunting for subdural hematomas (SDH) during the same period. RESULTS: Four patients (100% male) ranging in age from 8.9 to 27.1 months (mean = 13.88) with pseudomeningocele and 17 patients (64.7% male) ranging in age from 1.9 to 11.8 months (mean = 4.15) with SDH were identified. Although the initial management included sequential percutaneous subdural tapping in 82% of the patients, all children ultimately failed such strategy, requiring either subdural-peritoneal (81% of the cases) or subgaleal-peritoneal (19% of the cases) shunting. The mean implant duration was 201 days for the pseudomeningocele group and 384 days for the SDH one. Mean post-shunt hospitalization was 2 days for patients with pseudomeningocele and 4 days for patients with SDH. There was no statistical difference in terms of complications, length of hospitalization post-shunting, or clinical outcomes between the patients with pseudomeningocele and those with SDH. CONCLUSIONS: Temporary shunting of infants with pseudo-meningocele constitutes a viable therapeutic alternative with favorable clinical outcomes and a low risk of shunt dependency similar to those of children with SDH.

Schmorl's nodes: current pathophysiological, diagnostic, and therapeutic paradigms.

Schmorl's nodes were first described by the pathologist Christian Schmorl in 1927 as a herniation of the nucleus pulposus through the cartilaginous and bony endplate into the vertebral body. Although such lesions present most commonly as incidental findings in asymptomatic patients (or in patients with back or radicular pain due to other etiology), there have been several reports emphasizing the deleterious effects of the inflammatory response and endplate changes elicited by the herniation of for such reasons, Schmorl's nodes have been occasionally implicated in the etiology of chronic axial pain as well as in pathological osteoporotic fractures. In this article, a thorough literature review about the most relevant historical studies on Schmorl's nodes previously published is performed. Furthermore, the authors provide an overview about the recent advances in basic science research on the pathophysiology of such lesions, as well as on current diagnostic and therapeutic paradigms.

Current state-of-the-art and future perspectives of robotic technology in neurosurgery.

Neurosurgery is one of the most demanding surgical specialties in terms of precision requirements and surgical field limitations. Recent advancements in robotic technology have generated the possibility of incorporating advanced technological tools to the neurosurgical operating room. Although previous studies have addressed the specific details of new robotic systems, there is very little literature on the strengths and drawbacks of past attempts, currently available platforms and prototypes in development. In this review, the authors present a critical historical analysis of the development of robotic technology in neurosurgery as well as a comprehensive summary of the currently available systems that can be expected to be incorporated to the neurosurgical armamentarium in the near future. Finally, the authors present a critical analysis of the main technical challenges in robotic technology development at the present time (such as the design of improved systems for haptic feedback and the necessity of incorporating intraoperative imaging data) as well as the benefits which robotic technology is expected to bring to specific neurosurgical subspecialties in the near future.

Progressive kyphotic deformity in comminuted burst fractures treated non-operatively: the Achilles tendon of the Thoracolumbar Injury Classification and Severity Score (TLICS).

INTRODUCTION: The Thoracolumbar Injury Classification and Severity (TLICS) scale has been considered one of the best available grading systems for evaluating thoracolumbar fractures, especially due to the fact that, differently from previous classifications, it can be used as a practical algorithm to orient the clinical decision-making between conservative and surgical management. CASE REPORT: The authors describe a case of a 54-year-old patient presenting with low-back pain after having struck her back on the handrail. The neurological exam was unremarkable. The CT-scan of the lumbar spine demonstrated a L1 comminuted burst fracture. The MRI demonstrated no evidence of posterior ligamentous complex injury. According to the TLICS classification (total score of 2) the patient was managed conservatively with a thoracolumbar brace. Although at the 1-month follow-up the X-rays demonstrated no major changes and the pain had clinically improved, the patient was lost to follow-up. After 12 months the patient presented back to the emergency department with complaints of increased back pain. The repeat CT-scan demonstrated a remarkable worsening of the vertebral body fracture, with a major kyphotic deformity. The patient was submitted to a staged anterior-posterior procedure consisting in posterior decompression of the T12-L2 levels, a T10-L4 pedicle screw fixation and, finally, a lateral transpsoas approach for L1 corpectomy and reconstruction with an expandable interbody cage and plate fixation. At the 6-months follow-up, the patient presented another episode of back pain and a new L4 endplate fracture was identified. After 2 months of failed conservative treatment, the patient was treated with percutaneous kyphoplasty. At the 12-months follow-up after the initial surgical procedure, the patient was pain free and with stable radiographs. CONCLUSIONS: In this Grand Rounds presentation, the authors perform a comprehensive discussion about the historical developments in the classification systems for thoracolumbar fractures with special emphasis in the new TLICS system. Although such score presents several advantages in relation to other grading systems, patients with comminuted burst fractures deserve special attention, even if initially classified as non-operative according to the TLICS algorithm. In such cases, if a decision of conservative management is taken, a close follow-up is recommended due to the high likelihood of long-term kyphotic deformity.

En bloc resection of primary malignant bone tumors of the cervical spine.

BACKGROUND: Due to the poor response of primary malignant bone tumors to adjuvant therapies, surgical resection performed in an en bloc fashion with free margins remains the best option for long-term recurrence-free survival of patients harboring such lesions. METHODS: In this article the authors provide a stepwise review of the technical details involved in the performance of en bloc resections of tumoral lesions in the cervical spine. CONCLUSIONS: Due to the anatomical peculiarities of the cervical spine related to the presence of functional nerve roots as well as the vertebral arteries, en bloc resections in this region remains a challenging surgical procedure.

Speech as a breakthrough signaling resource in the cognitive evolution of biological complex adaptive systems.

In self-adapting dynamical systems, a significant improvement in the signaling flow among agents constitutes one of the most powerful triggering events for the emergence of new complex behaviors. Ackermann and colleagues' comprehensive phylogenetic analysis of the brain structures involved in acoustic communication provides further evidence of the essential role which speech, as a breakthrough signaling resource, has played in the evolutionary development of human cognition viewed from the standpoint of complex adaptive system analysis.

The validity of Dawkins's selfish gene theory and the role of the unconscious in decision making.

Although the proposed Selfish Goal Theory constitutes a major theoretical tour de force for addressing the issue of inconsistencies in human actions and the role of motivational goals in behavior, as it is based on an unproven biological paradigm (Dawkins's selfish gene theory) and overemphasizes the role of unconscious processes in decision making, it provides a questionable model of the underlying psychological structure of human agency.

Interdisciplinary benefits of a theory of cultural evolution centered at the group-level: the emergence of macro-neuroeconomics and social evolutionary game theory.

The theoretical concepts developed in the target article, in which the author proposes a new paradigm of cultural evolution based not on the individuals' characteristics, but rather on more global collective properties described as "group-traits" (which emerge when a group of individuals exhibit both differentiation and organization), may have a broader scientific impact that transcend the boundaries of social and evolutionary psychology, paving the way for the emergence of macro-neuroeconomics and social evolutionary game theory.

Health Care Fraud and Abuse: Lessons From One of the Largest Scandals of the 21st Century in the Field of Spine Surgery.

Up to hundreds of billions of dollars are annually lost to fraud and abuse in the US health care, making it a significant burden on the system. This study investigates a specific instance of health care fraud in spine surgery, in which a medical device company ended up paying $75 million to settle violations of the False Claims Act. We review the surgical background regarding the kyphoplasty procedure, as well as its billing and reimbursement details. We also explore the official legal complaint brought by the US Department of Justice to tell the story of how one of the most significant medical innovations in spine surgery in the 21st century turned into a widespread fraudulent marketing scheme. In the sequence, we provide a detailed root cause analysis of this scandal and propose some proactive measures that can be taken to avoid such type of unfortunate events. Ultimately, this historical health care scandal constitutes a valuable lesson to surgeons, health care administrators, medical device companies, and policymakers on how misaligned incentives and subsequent unscrupulous practices can transform a medical innovation into an unfortunate tale of fraud and deceit.