BACKGROUND CONTEXT:Endoscopic spine surgery (ESS) is rapidly emerging as a viable minimally invasive technique to successfully treat symptomatic degenerative spinal conditions. Widespread adoption has been limited in part due to the learning curve. PURPOSE:To systematically review the learning curve for uniportal and biportal ESS and compare the 2 techniques. STUDY DESIGN/SETTING:A systematic review based on PRISMA guidelines. PATIENT SAMPLE:About 29 studies were included with 18 studies investigating uniportal learning curves and 11 biportal studies. There were 1,493 patients across all uniportal studies. There was a total of 1,005 patients across all biportal studies. OUTCOME MEASURES:Number of patients, technique type, patient reported outcomes, complications, operative time before the learning curve threshold, operative time after learning curve threshold, number of cases required to meet threshold, number of surgeons in the study, and cases per surgeon were collected and analyzed. METHODS:A comprehensive literature search was conducted using PubMed, Medline, and Embase from 2000 to present date. Data was extracted by 3 independent reviewers. RESULTS:The learning curve studies were reviewed and summarized. The overall median number of cases to reach the learning curve threshold was significantly less in uniportal vs biportal studies (20 vs 37.5, p=.0463). When stratifying by various procedures, there was no significant difference between the techniques with number of cases required or improvement of operative time. Operative time for biportal discectomies decreased by a significantly greater amount vs uniportal (44.5% vs 21.4%, p=.0332). CONCLUSIONS:The learning curve literature for ESS was systematically reviewed and ways to overcome the learning curve were discussed. The overall median number of cases for the learning curve was significantly fewer in uniportal vs biportal but the improvement in operative time was significantly greater with biportal discectomies, typically the entry level procedure by novice surgeons. Overcoming the learning curve for ESS is a critical factor to widespread adoption and understanding it may aid surgeons in progressing to proficiency while mitigating the risk of complications.

Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million individuals worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancer (NSCLC) patients harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, whose tumors are characterized by a predominance of neutrophils and an immune suppressive tumor microenvironment (TME) that are resistant to ICI. Our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized a murine model of NSCLC (Kras G12D P53−/−Lkb1−/−; KPL) to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. We further observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models with or without LKB1 loss. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis indicated a reduction of neutrophils as well as an enrichment in T cell and natural killer (NK) cell populations in the TME. Furthermore, scRNA-seq analysis revealed elevated expression of interferon (IFN) downstream genes in multiple immune subpopulations in the TME. Preliminary ex vivo studies indicated that ATRA increases NOX2 levels, intracellular reactive oxygen species (ROS), and IFN signaling in the myeloid-derived suppressor cells (MDSC) of KPL tumors. Our findings suggest that ATRA may reshape the TME by activating IFN signaling in multiple cell subtypes to sensitize resistant tumors to ICI immunotherapy. Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu. ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5157.

Abstract Background: Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those who are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with chemokine gene-engineered functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment to promote both local and systemic antitumor responses. The chemokine CCL21 promotes co-localization of naive T cells and antigen-experienced dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust CCL21-DC mediated antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC. Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by pembrolizumab once every three weeks for up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment, and this updated abstract will highlight the feasibility of repeated IT injections in treated patients. Citation Format: Bin Liu, Aaron Lisberg, Ramin Salehi-Rad, Michael Oh, Jay M. Lee, Linh M. Tran, Kostyantyn Krysan, Raymond J. Lim, Camelia Dumitras, Zhe Jing, Fereidoun Abtin, Robert D. Suh, Scott J. Genshaft, Scott S. Oh, Gregory A. Fishbein, Anita Kaul, Kanwarpal S. Kahlon, Shahryar A. Ashouri, Jonathan W. Goldman, David A. Elashoff, Edward Garon, Steven M. Dubinett. Phase I trial of intratumoral administration of autologous CCL21 gene-modified dendritic cells in combination with pembrolizumab for advanced NSCLC: Feasibility of repeated IT injections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT153.

Introduction Both Orthopedic Surgery (OS) and Neurosurgery (NS) perform spine surgery in the setting of trauma. However, it is unknown whether outcomes differ between these specialties. This study compares management and outcomes for vertebral fractures between NS and OS, hypothesizing similar operation rate, length of stay (LOS), and readmission. Research question Do outcomes differ between NS and OS in the management of vertebral fractures following trauma? Methods A retrospective single-center study was conducted on adult patients with cervical, thoracic, lumbar, and sacral fractures treated at a single trauma center, where no standardized pathway exists across NS and OS. Patients were compared for injury profile, diagnostic imaging, and operative techniques as well as LOS, mortality, and complications. Results A total of 630 vertebral fracture patients (OS:350 (55.6%); NS:280 (44.4%)) were included. NS utilized magnetic resonance imaging (MRI) more commonly (36.4% vs. 22.6%, p < 0.001). NS patients more often underwent operation (13.2% vs. 7.4%, p = 0.016) despite similar fracture number and severity (p > 0.05). Post-operative complications, LOS, and readmission rates were similar between cohorts (p > 0.05). Discussion and conclusion Despite similar injury profiles, NS had higher rates of MRI usage and operative interventions in the context of traumatic spine fractures. Despite differences in management, major clinical outcomes were similar between NS and OS. However, we do call for further standardization of evaluation and treatment of patients based on established algorithms from such as the AOSpine Thoracolumbar Spine Injury Classification System (ATLICS).

Background Anterior cervical discectomy and fusion (ACDF) interbody implants are shaped anatomically, with a convex superior aspect, or lordotically, with an angle and flat surfaces. However, the effect of implant shape on cervical sagittal balance (CSB) is not well described. Methods Of the 192 cases reviewed from 2018 to 2019, 118 were included with matching pre- and postoperative imaging. Cases were categorized by interbody implant type (anatomic or lordotic) and number of levels fused (1-level, 2-level, etc.). SurgiMap was used to measure cervical lordosis (CL), C2-C7 sagittal vertical axis (cSVA), T1 slope (T1S), and T1S minus CL (T1S-CL) on pre- and postoperative imaging. Pre- and postoperative parameters were compared within and between each cohort. Change in CL (Delta CL), cSVA (Delta cSVA), and T1S-CL (Delta T1S-CL) were calculated as the difference between pre- and postoperative values and were compared accordingly (1) anatomic versus lordotic and (2) 1-level versus 2-level versus 3-level fusion. Results Thirty-nine (33.1%), 57 (48.3%), and 22 (18.6%) cases comprised the anatomic, lordotic, and mixed (anatomic and lordotic) groups, respectively. ACDFs improved CL and T1S-CL by 5.71 degrees (p<.001) and 3.32 degrees (p<.01), respectively. CL was improved in the lordotic (5.27 degrees; p<.01) and anatomic (4.57 degrees; p<.01) groups, while only the lordotic group demonstrated improvement in T1S-CL (3.4 degrees; p=.02). There were no differences in Delta CL (p=.70), Delta cSVA (p=.89), or Delta T1S-CL (p=.1) between the groups. Two- and 3-level fusions improved CL by 7.48 degrees (p<.01) and 9.62 degrees (p<.01), and T1S-CL by 4.43 degrees (p<.01) and 5.96 degrees (p<.01), respectively. Conclusions Overall, ACDFs significantly improved CL and T1S-CL however, there were no differences in CSB correction between the anatomic and lordotic groups. Two- and 3-level fusions more effectively improved CL (vs. single-level) and T1S-CL (vs. 3-level). These results suggest that implants should continue to be personalized to the patient's anatomy, however, future research is needed to validate these findings and incorporate the effects of preoperative deformities.

BACKGROUND:Chronic low back pain secondary to degenerative changes in the spine is a common cause of disability, and disc degeneration is one of the most frequent imaging findings. Intervertebral vacuum phenomenon (IVP) is usually observed in advanced degeneration. Recently, this phenomenon has gained interest due to a relatively new surgical technique called percutaneous discoplasty, aimed at treating low back pain secondary to degenerative disc disease in elderly patients.PURPOSE:To analyze the prevalence and related factors of the vacuum phenomenon in adult patients.MATERIAL AND METHODS:A retrospective cohort study was performed of patients who underwent abdominal computed tomography (CT) for non-spine-related reasons. Age, body mass index, smoking, and CT-based characteristics as presence of IVP, subchondral sclerosis, and facet joint degeneration at the lumbar spine from L1 to the sacrum were included in order to determine the prevalence of the vacuum phenomenon in this population and establish a relationship between this condition and patient demographics and other signs of spine degeneration, such as sclerosis and facet joint disease.RESULTS:A total of 238 patients were included in the study (114 men, 124 women; mean age = 75.6 ± 12.3 years. In total, 91 (38%) patients had at least one level of IVP; 59 (25%) patients exhibited subchondral sclerosis, and 235 (98%) facet joint degeneration. Among risk factors, age, smoking, and subchondral sclerosis were significantly associated with the presence of vacuum.CONCLUSION:IVP was present in 38% of participants. Risk factors associated with vacuum were age, smoking, and subchondral sclerosis.

Abstract Neurofibromatosis type 1 (NF-1) is the most common cancer predisposition syndrome in which 15-20% of affected individuals develop glioma. Large scale DNA and RNA bulk profiling showed the molecular complexity of NF-1 glioma with the tumor cellular ecosystem constituted by multiple malignant phenotypes and heterogenous immune microenvironment. However, the composition and function of infiltrating cells was hidden in the bulk tumor, and the extended granularity of NF-1 glioma tumor microenvironment (TME) remained still unexplored. Here, we collected glioma samples from 46 NF-1 patients including 22 high-grade (HGG) and 24 low-grade (LGG) tumors, and we analyzed their gene expression by single nuclei RNA sequencing. A total of 239,044 single cells were classified into tumor and non-tumor components by integrating multiple computational approaches (including genomic copy number inference, gene signature enrichment, and clustering). We defined the pattern of intra-tumor heterogeneity of NF-1 glioma cells using non-negative matrix factorization and derived 7 malignant meta-programs (MPs) that we respectively defined as Neuronal-like, EMT, Astrocyte-like, Dividing Radial Glia-like, Ependymal-like, Immune, and Glycolytic/Hypoxic-like. These MPs recapitulated normal brain cell subtypes, thereby reflecting broad cell plasticity. The non-tumor cell compartment (121,364 cells, 51%) was dissected for the characterization of the cell types that populate the TME of NF-1 glioma. We identified different subpopulations exhibiting specific immune functions within myeloid and lymphoid components. Different glioma ecomodules were highlighted by comparing the relative composition of the TME across the tumors. Recruitment and activation of cytotoxic CD8+ T cells and natural killers by an active crosstalk with dendritic and pro-inflammatory myeloid cells defined an immune-supportive phenotype that could mediate a potential anti-tumor response in low-grade NF-1 glioma (LGG immune high). Conversely, regulatory T cell infiltration and effector T cell exhaustion induced immune suppression in a low-grade glioma immune dysfunctional ecomodule. The absence of lymphocytes characterized a large set of cold tumors, mostly including high-grade glioma. Together, the complex interplay of tumor cell states with different TME compartments elucidated the existence of separate ecomodules in NF-1 glioma, with the LGG immune high TME associated with Neuronal-like and the LGG immune dysfunctional with Ependymal-like tumor cells. The Ependymal-like state also exhibits maximal association with brain-specific normal cells, including oligodendrocytes, neurons and astrocytes, whereas the HGG are enriched with Dividing Radial Glia- and Glycolytic/Hypoxic-like tumor cell states. The elucidation of different ecomodules provides novel insights for the application of targeted therapies in NF-1 glioma patients. Citation Format: Luciano Garofano, Fulvio D'Angelo, Michael Oh, Michele Ceccarelli, Franck Bielle, Marc Sanson, Anna Lasorella, Antonio Iavarone. Identification of distinct tumor-TME ecomodules in glioma from neurofibromatosis type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6938.

Background Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.Methods Murine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy.Results ISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses.Conclusions CCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC.

e18747 Background: Despite the deleterious effects of systemic cancer treatment on fertility, many young adult cancer patients do not receive fertility preservation. Historically, oncofertility was discussed by the medical oncologist (MO), but an increasing advanced practice provider (APP) oncology workforce provides opportunities for quality improvement (QI) in oncofertility care. To identify levers for QI interventions, we explored how fertility beliefs, knowledge, and practice of MOs differ from APPs. Methods: MOs and APPs working in inpatient, outpatient, academic and community clinical settings were identified from providers at The Jonsson Comprehensive Cancer Center (JCCC). Participants completed an online survey prior to a fertility preservation seminar. Survey questions queried beliefs about fertility preservation, knowledge about guideline recommendations, and individual fertility practices in the 3 months prior to survey completion. Responses were collected anonymously through a HIPAA-compliant web platform. Pearson chi-squared and two-sample T tests were used for statistical comparisons between MOs and APPs using STATA v15.1. This study received exempt status from the University of California Los Angeles (UCLA) Institutional Review Board. Results: 32 (52.5%) APPs and 29 (47.5%) MOs completed the survey. APPs were younger than MOs (28% vs. 14% were 30-39 years, p = 0.072) and more frequently female (91% vs. 38%, p < 0.001). Practice specialties varied equally between both groups and they had similar distribution of post-training oncology experience. Participants saw an average of 6.0 (APP) and 5.7 (MO) new cancer patients of reproductive age per month. While APPs and MOs reported concern about the effects of cancer treatment on fertility, APPs were more likely to agree with the statement “Offering fertility preservation to patients before cancer therapy compromises their oncological treatment” than MOs (44% vs. 31%, p = 0.047). APPs reported less familiarity with fertility preservation guidelines (scale 0-10, mean 4.3 vs. 5.8, p = 0.013) and MOs were more comfortable discussing specific fertility preservation techniques. There were no significant differences in referral practices. In the 3 months prior to survey, MOs reported having fertility discussions more frequently than APPs (52% vs 28%, p = 0.047) and more regularly had discussions before treatment initiation (97% vs. 78%, p = 0.033). Conclusions: Improving oncofertility care for young cancer patients is an important quality metric. This exploratory study demonstrated significant differences in beliefs, knowledge, and practice between MOs and APPs regarding fertility preservation for cancer patients. These results will shape our future QI initiatives, which will target system, practice, and education with a specific focus on non-MO providers.

PDF file - 251K, Fig. 1S: Depiction of drug model for nanoparticle release and delayed transmembrane transport of self-assembling cis-platinum nanoparticles (SACNs) and free cisplatin in an acidic environment. Fig. 2S: Flowchart showing the computational algorithm used to fit parameters in the mathematical model. Fig. 3S: (Data points) The release profile of cisplatin nanoparticles was evaluated at 37 degrees C in neutral and acidic (tumor like) pH in triplicates.

Abstract Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million individuals worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancer (NSCLC) patients harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, whose tumors are characterized by a predominance of neutrophils and an immune suppressive tumor microenvironment (TME) that are resistant to ICI. Our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized a murine model of NSCLC (Kras G12D P53−/−Lkb1−/−; KPL) to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. We further observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models with or without LKB1 loss. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis indicated a reduction of neutrophils as well as an enrichment in T cell and natural killer (NK) cell populations in the TME. Furthermore, scRNA-seq analysis revealed elevated expression of interferon (IFN) downstream genes in multiple immune subpopulations in the TME. Preliminary ex vivo studies indicated that ATRA increases NOX2 levels, intracellular reactive oxygen species (ROS), and IFN signaling in the myeloid-derived suppressor cells (MDSC) of KPL tumors. Our findings suggest that ATRA may reshape the TME by activating IFN signaling in multiple cell subtypes to sensitize resistant tumors to ICI immunotherapy. Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu. ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5157.

The anterior lumbar interbody fusion (ALIF) procedure involves several surgical specialties, including general, vascular, and spinal surgery due to its unique approach and anatomy involved. It also carries its own set of complications that differentiate it from posterior lumbar fusion surgeries. The demonstrated benefits of treatment guidelines, such as Enhanced Recovery after Surgery in other surgical procedures, and the lack of current recommendations regarding the anterior approach, underscores the need to develop protocols that specifically address the complexities of ALIF. We aimed to create an evidence-based protocol for pre-, intra-, and postoperative care of ALIF patients and implementation strategies for our health system. A 12-member multidisciplinary workgroup convened to develop an evidence-based treatment protocol for ALIF using a Delphi consensus methodology and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for rating the quality of evidence and strength of protocol recommendations. The quality of evidence, strength of the recommendation and specific implementation strategies for Methodist Health System for each recommendation were described. The literature search resulted in 295 articles that were included in the development of protocol recommendations. No disagreements remained once the authors reviewed the final GRADE assessment of the quality of evidence and strength of the recommendations. Ultimately, there were 39 protocol recommendations, with 16 appropriate preoperative protocol recommendations (out of 17 proposed), 9 appropriate intraoperative recommendations, and 14 appropriate postoperative recommendations. This novel set of evidence-based recommendations is designed to optimize the patient's ALIF experience from the preoperative to the postoperative period.

Background: We analyzed the role of hypoalbuminemia, dialysis, and other risk factors that increase morbidity/ mortality following surgery for primary pyogenic spinal infections (PSIs). The American College of Surgeons’ National Surgical Quality Improvement Program (ACS-NSQIP) that included 627 patients was utilized as our database. Methods: Primary spinal surgery for spondylodiscitis was evaluated in a ACS-NSQIP database involving 627 patients between 2010 and 2019. Outcome assessment included evaluation of 30-day postoperative morbidity, and mortality rates. Results: Within 30 postoperative days, complications occurred in 14.6% (92/627) of patients; 59 (9.4%) required readmission, and 39 (6.2%) required additional surgery. The most common complications were: wound infections, pneumonia, septic shock, and death (1.8%). Hypoalbuminemia (i.e., significantly associated with unplanned readmission and reoperation), and dialysis were the two major risk factors contributing to increased perioperative morbidity and mortality. Conclusion: Among 627 ACS-NSQIP patients undergoing primary surgery for PSIs, hypoalbuminemia and dialysis were associated with higher risks of major perioperative morbidity (i.e., within 30 postoperative days – mostly readmissions and reoperations) and mortality.

Current transcriptomic classification of Glioblastoma Multiforme (GBM) has been ineffective to predict survival and therapeutic vulnerabilities. Recently, we proposed a four-group functional classification of GBM that included proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic subtypes with prognostic and therapeutic implications as the mitochondrial subtype carries the best survival and exhibits distinct sensitivity to mitochondrial OXPHOS inhibitors. To uncover novel therapeutic targets for each functional GBM subtype, we focused on protein kinases for their attractive features as both drivers and drug targets, with current availability of 62 FDA-approved inhibitors available for cancer precision therapeutics. We designed an unbiased integrative, machine learning-based proteomics/phosphoproteomics network for the identification of Master Kinases (MKs) responsible for effecting key phenotypic hallmarks of each of the four GBM subtypes. Here we report the identification and validation of protein kinase C delta (PRKCd) and DNA-PKcs as MKs that sustain the glycolytic/plurimetabolic and proliferative/progenitor GBM subtypes, respectively. Genetic and pharmacologic inactivation of PKCd in GBM patient-derived organoids of the glycolytic/plurimetabolic subtype blocked glucose uptake and lipid accumulation, resulting in marked anti-tumor effects. We also validated the role of PKCd in oncometabolic processes at the intersection between insulin, IGF, and lipid metabolism. DNA-PKcs was qualified as MK for the proliferative/progenitor GBM subtype, which is characterized by high basal level of replication stress. Biochemical experiments showed activation of DNA-PK in GBM patient-derived organoids of the proliferative/progenitor subgroup. Targeting DNA-PK in proliferative/progenitor GBM organoids with the clinically tested DNA-PKcs inhibitor nedisertib in association with gamma irradiation, the essential component of the standard of care for patients with GBM, led to an unsustainable level of DNA damage and massive GBM cell death selectively in this GBM subtype. As DNA-PKcs inhibitors have been introduced into clinical trials, our findings suggest that pre-selection of patient with PPR tumors is likely to enhance therapeutic success.

Study Design: Retrospective radiologic analysis. Objective: The aim was to investigate if lateral flexion-extension radiographs identify additional cases of degenerative cervical spondylolisthesis (DCS) that would be missed by obtaining solely neutral upright radiographs, and determine the reliability of magnetic resonance imaging (MRI) in diagnosis. Summary of Background Data: DCS and instability can be a cause of neck pain, radiculopathy, and even myelopathy. Standard anteroposterior and lateral radiographs and MRI of the cervical spine will identify most cervical spine pathology, but spondylolisthesis and instability are dynamic issues. Standard imaging may also miss DCS in some cases. Methods: We compared the number of patients who demonstrated cervical spondylolisthesis on lateral neutral and flexion-extension radiographs in addition to MRI. We used established criteria to define instability as ≥2 mm of listhesis on neutral imaging, and ≥1 mm of motion between flexion-extension radiographs. Results: A total of 111 patients (555 cervical levels) were analyzed. In all, 41 patients (36.9%) demonstrated cervical spondylolisthesis on neutral and/or flexion-extension radiographs. Of the 77 levels of spondylolisthesis, 17 (22.1%) were missed on neutral radiographs (P,0.05). Twenty levels (26.0%) were missed when flexion-extension radiographs were used alone (P=0.02). Twenty-nine levels (37.7%) of DCS identified on radiograph were missed by MRI (P=0.004). Conclusions: Lateral flexion-extension views can be useful in the diagnosis of DCS. These views provide value by identifying a significant cohort of patients that would be undiagnosed based on neutral radiographs alone. Moreover, MRI missed 38% of DCS cases identified by radiographs. Therefore, lateral radiographs can be a useful adjunct to neutral radiographs and MRI when instability is suspected or if these imaging modalities are unable to identify the source of a patient’s neck or arm pain.

BACKGROUND:Primary spinal infections (PSIs) are a group of uncommon but serious infectious diseases that are characterized by inflammation of the endplate-disc unit. Pediatric spinal infection is rare and challenging to diagnose due to vague presenting symptoms. Most cases are conservatively managed with surgery rarely indicated. The authors performed a systematic review to study the baseline characteristics, clinical presentation, and outcomes of pediatric patients with PSIs who underwent surgical treatment.OBSERVATIONS:PSI in pediatric patients might behave differently in terms of epidemiology, clinical presentation, and outcomes when compared with nonpediatric patients. Overall, PSI ultimately managed surgically in pediatric patients is associated with a high rate of localized pain, neurological compromise, and treatment failure when compared with nonsurgically managed pediatric spinal infections.LESSONS:PSIs managed surgically in the pediatric population were found to be caused by Mycobacterium tuberculosis in 74.4% of cases and were associated with higher rates of localized pain, neurological compromise, and treatment failure than nonsurgically managed pediatric spinal infections. Thoracic involvement (71.8%) in the spinal infection was reported most commonly in our review. When omitting the cases involving M. tuberculosis infection, it was revealed that 50% of the pediatric cases involved infection in the cervical region, suggesting increased severity and disease course of cervical spinal infections in the pediatric population. Surgical treatment is indicated only in cases of severe neurological compromise and treatment failure.

BACKGROUND:Primary spinal infections (PSIs) are a group of uncommon but serious infectious diseases considered more prevalent and aggressive among patients with chronic immunocompromised states. Association of PSI and solid organ transplant has not been systematically analyzed. The authors performed a systematic review analyzing clinical presentation and mortality of patients with PSI in the setting of solid organ transplant.OBSERVATIONS:PSIs in patients with immunosuppressive therapy, such as those with solid organ transplant, may behave differently in terms of epidemiology, clinical presentation, and outcomes compared with nonimmunosuppressed patients. Overall PSI in solid organ transplant patients is associated with a high rate of neurological compromise, postoperative complications, and mortality.LESSONS:Accurate diagnosis and appropriate treatment of PSI require a multidisciplinary effort. Localized pain is the most frequently reported symptom associated with PSI. As opposed to PSI in patients without transplant, inflammatory and infectious markers such as white blood cells and C-reactive protein are often not elevated. Furthermore, the causative microorganism profile varies significantly when compared to pyogenic spinal infection in patients without transplant. Aspergillus species was responsible for spondylodiscitis in transplant patients in more than 50% of cases, and the incidence of Aspergillus infection is projected to rise in the coming years.

Background:Bone graft extenders are being used more in spine surgery as a substitute for iliac crest bone graft. However, potential conflict of interest could impact average fusion rates. The purpose of this study was to evaluate whether fusion rates reported in the literature were different in papers evaluating bone graft substitutes and extenders when there was potential conflict of interest versus no potential conflict of interest.Methods:Pubmed was searched for studies evaluating fusion rates when bone graft extenders including demineralized bone matrix, hydroxyapatite, and tricalcium sulfate were used. Studies were screened for one or two level fusions and for degenerative spinal conditions. The average fusion rates of subgroups were compared using unpaired Student's t-tests.Results:1928 studies were evaluated. 86 studies were included in the study. The fusion rates varied from 4 to 100%. There were 24 studies with a potential conflict of interest and 62 studies with no conflict of interest. The average fusion rate of all the studies was 84.63% with standard deviation of 18.33%. The average fusion rates of those studies with conflict of interest was 80.93% versus 86.06% without conflict of interest. This was not statistically significant (p>0.07). The average fusion rate of studies evaluated by CT scan was 79.8% versus 87.9% without CT. The average fusion rate of studies that employed an independent reviewer to evaluate the fusion was 82.61% versus 85.63% for studies with no independent reviewer.Conclusion:There is a great variability in the reported fusion rates of bone graft extenders. Counter to expectations, average fusion rates were lower in the studies where there was a potential conflict of interest. The use of CT scans and an independent reviewer seem to account for the lower reported fusion rates, and may be a means of negating the potential conflicts of interest in fusion studies.Level of Evidence:2.