The influence of osteoporosis on mechanical complications in lumbar fusion surgery: a systematic review.

Background: Adults undergoing spine surgery often have underlying osteoporosis, which may be a risk factor for postoperative complications. Although these associations have been described, osteoporosis remains profoundly underdiagnosed and undertreated in the spine surgery population. A thorough, comprehensive systematic review summarizing the relationships between bone mineral density (BMD) and specific complications of lumbar fusion surgery could be a valuable resource for raising awareness and supporting clinical practice changes. Methods: PubMed, Embase, and Web of Science databases were searched for original clinical research articles reporting on BMD, or surrogate measure, as a predictor of complications in adults undergoing elective lumbar fusion for degenerative disease or deformity. Endpoints included cage subsidence, screw loosening, pseudarthrosis, vertebral fracture, junctional complications, and reoperation. Results: A total of 71 studies comprising 12,278 patients were included. Overall, considerable heterogeneity in study populations, methods of bone health assessment, and definition and evaluation of clinical endpoints precluded meta-analysis. Nevertheless, low BMD was associated with higher rates of implant failures like cage subsidence and screw loosening, which were often diagnosed with concomitant pseudarthrosis. Osteoporosis was also a significant risk factor for proximal junctional kyphosis, particularly due to fracture. Many studies found surgical site-specific BMD to best predict focal complications. Functional outcomes were inconsistently addressed. Conclusions: Our findings suggest osteoporosis is a significant risk factor for mechanical complications of lumbar fusion. These results emphasize the importance of preoperative osteoporosis screening, which allows for medical and surgical optimization of high-risk patients. This review also highlights current practical challenges facing bone health evaluation in patients undergoing elective surgery. Future prospective studies using standardized methods are necessary to strengthen existing evidence, identify optimal predictive thresholds, and establish specialty-specific practice guidelines. In the meantime, an awareness of the surgical implications of osteoporosis and utility of preoperative screening can provide for more informed, effective patient care.

Association between opioid utilization and patient-reported outcome measures following lumbar spine surgery.

BACKGROUND CONTEXT: The patient-reported outcomes measurement information system (PROMIS), created by the National institute of Health, is a reliable and valid survey for patients with lumbar spine pathology. Preoperative opioid use has been shown to be an important predictor variable of self-reported health status in legacy patient-reported outcome measures. PURPOSE: To investigate the impact of chronic preoperative opiate use on PROMIS survey scores. STUDY DESIGN: Retrospective database analysis. PATIENT SAMPLE: Between March 2019 and November 2021, 227 patients underwent lumbar decompression ± ≤ 2 level fusion. Fifty-seven patients (25.11%) had chronic preoperative opioid use. OUTCOME MEASURES: Oswestry disability index (ODI) and PROMIS survey scores. METHODS: A retrospective analysis of a prospectively maintained single center patient-reported outcome database was performed with a minimum of 2 year follow-up. PROMIS Anxiety, Depression, Fatigue, Pain Interference (PI), Physical Function (PF), Sleep disturbance (SD), and Social Roles (SR) surveys were recorded at preoperative intake with subsequent follow-up at 6, 12, and 24 months postoperatively. Patients were grouped into chronic opioid users as defined by >6-month duration of use. Differences in mean survey scores were evaluated using Welch t-tests. RESULTS: Two hundred and twenty-seven patients met our inclusion criteria of completed PROMIS surveys at the designated timepoints. A total of 57 (25.11%) were chronic opioid users (COU) prior to surgery. Analysis of patient-reported health outcomes shows that long term opioid use correlated with worse ODI and PROMIS scores at baseline compared to nonchronic users (NOU). At 1 and 2 year follow-up, the COU cohort continued to have significantly worse ODI, PROMIS Fatigue, PF, PI, SD, and SR scores. There is a statistical difference in the magnitude of change in health status between the 2 cohorts at 1 year follow-up in PROMIS Depression (-5.04±7.88 vs -2.49±8.73, p=.042), PF (6.25±7.11 vs 9.03±9.04, p=.019), and PI (-7.40±7.37 vs -10.58±9.87, p=.011) and 2 year follow-up in PROMIS PF (5.58±6.84 vs 7.99±9.64, p=.041) and PI (-6.71±8.32 vs -9.62±10.06, p=.032). Mean improvement in PROMIS scores for the COU cohort at 2 year follow-up exceeded minimal clinically important difference (MCID) in all domains except PROMIS Depression, SR and SD. CONCLUSION: Patients with chronic opioid use status have worse baseline PROMIS scores compared with patients who had nonchronic use. However, patients in the COU cohort displayed clinically significant postoperative improvement in multiple PROMIS domains. These results show that patients with chronic opioid use can benefit greatly from surgical intervention and will allow physicians to better set expectations with their patients.

Degenerative lumbar spondylolisthesis: review of current classifications and proposal of a novel classification system.

PURPOSE: To review existing classification systems for degenerative spondylolisthesis (DS), propose a novel classification designed to better address clinically relevant radiographic and clinical features of disease, and determine the inter- and intraobserver reliability of this new system for classifying DS. METHODS: The proposed classification system includes four components: 1) segmental dynamic instability, 2) location of spinal stenosis, 3) sagittal alignment, and 4) primary clinical presentation. To establish the reliability of this system, 12 observers graded 10 premarked test cases twice each. Kappa values were calculated to assess the inter- and intraobserver reliability for each of the four components separately. RESULTS: Interobserver reliability for dynamic instability, location of stenosis, sagittal alignment, and clinical presentation was 0.94, 0.80, 0.87, and 1.00, respectively. Intraobserver reliability for dynamic instability, location of stenosis, sagittal alignment, and clinical presentation were 0.91, 0.88, 0.87, and 0.97, respectively. CONCLUSION: The UCSF DS classification system provides a novel framework for assessing DS based on radiographic and clinical parameters with established implications for surgical treatment. The almost perfect interobserver and intraobserver reliability observed for all components of this system demonstrates that it is simple and easy to use. In clinical practice, this classification may allow subclassification of similar patients into groups that may benefit from distinct treatment strategies, leading to the development of algorithms to help guide selection of an optimal surgical approach. Future work will focus on the clinical validation of this system, with the goal of providing for more evidence-based, standardized approaches to treatment and improved outcomes for patients with DS.

Benign Glioma.

Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may also be described as "low-grade" glioma (LGG) and are classified as WHO grade I or II lesions according to the Classification of Tumors of the Central Nervous System (CNS) (Louis et al. in Acta Neuropathol 114:97-109, 2007). Advances in molecular genetics have improved understanding of glioma tumorigenesis, leading to the identification of common mutation profiles with significant treatment and prognostic implications. The most recent WHO 2016 classification system has introduced several notable changes in the way that gliomas are diagnosed, with a new emphasis on molecular features as key factors in differentiation (Wesseling and Capper in Neuropathol Appl Neurobiol 44:139-150, 2018). Benign gliomas have a predilection for younger patients and are among the most frequently diagnosed tumors in children and young adults (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). These tumors can be separated into two clinically distinct subgroups. The first group is of focal, well-circumscribed lesions that notably are not associated with an increased risk of malignant transformation. Primarily diagnosed in pediatric patients, these WHO grade I tumors may be cured with surgical resection alone (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). Recurrence rates are low, and the prognosis for these patients is excellent (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). Diffuse gliomas are WHO grade II lesions with a more infiltrative pattern of growth and high propensity for recurrence. These tumors are primarily diagnosed in young adult patients, and classically present with seizures (Pallud et al. Brain 137:449-462, 2014). The term "benign" is a misnomer in many cases, as the natural history of these tumors is with malignant transformation and recurrence as grade III or grade IV tumors (Jooma et al. in J Neurosurg 14:356-363, 2019). For all LGG, surgery with maximal safe resection is the treatment of choice for both primary and recurrent tumors. The goal of surgery should be for gross total resection (GTR), as complete tumor removal is associated with higher rates of tumor control and seizure freedom. Chemotherapy and radiation therapy (RT), while not typically a component of first-line treatment in most cases, may be employed as adjunctive therapy in high-risk or recurrent tumors and in some select cases. The prognosis of benign gliomas varies widely; non-infiltrative tumor subtypes generally have an excellent prognosis, while diffusely infiltrative tumors, although slow-growing, are eventually fatal (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). This chapter reviews the shared and unique individual features of the benign glioma including diffuse glioma, pilocytic astrocytoma and pilomyxoid astrocytoma (PMA), subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), subependymoma (SE), angiocentric glioma (AG), and chordoid glioma (CG). Also discussed is ganglioglioma (GG), a mixed neuronal-glial tumor that represents a notable diagnosis in the differential for other LGG (Wesseling and Capper 2018). Ependymomas of the brain and spinal cord, including major histologic subtypes, are discussed in other chapters.

The Natural History of Coiled Cerebral Aneurysms Stratified by Modified Raymond-Roy Occlusion Classification.

OBJECTIVE: The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as stratified by the Modified Raymond-Roy Classification (MRRC). METHODS: First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD. RESULTS: A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001). CONCLUSIONS: MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.

CART Immunotherapy: Development, Success, and Translation to Malignant Gliomas and Other Solid Tumors.

T cell chimeric antigen receptor (CAR) technology has allowed for the introduction of a high degree of tumor selectivity into adoptive cell transfer therapies. Evolution of this technology has produced a robust antitumor immunotherapeutic strategy that has resulted in dramatic outcomes in liquid cancers. CAR-expressing T-cells (CARTs) targeting CD19 and CD20 have been successfully used in the treatment of hematologic malignancies, producing sustained tumor regressions in a majority of treated patients. These encouraging results have led to a historic and unprecedented FDA approval of CTL019, Novartis' CAR T-cell therapy for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the translation of this technology to solid tumors, like malignant gliomas (MG), has thus far been unsuccessful. This review provides a timely analysis of the factors leading to the success of CART immunotherapy in the setting of hematologic malignancies, barriers limiting its success in the treatment of solid tumors, and approaches to overcome these challenges and allow the application of CART immunotherapy as a treatment modality for refractory tumors, like malignant gliomas, that are in desperate need of effective therapies.

Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas.

Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies.

Recurrent glioma clinical trial, CheckMate-143: the game is not over yet.

Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.

Immune System, Friend or Foe of Oncolytic Virotherapy?

Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune-mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus-expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies.

Dendritic cell based vaccination strategy: an evolving paradigm.

Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines.