Bone grafting and biologics for spinal fusion in the pediatric population: current understanding and future perspective.

Pediatric spinal fusions have been associated with nonunion rates of approximately 25%, putting patients at risk for neurological complications while simultaneously incurring significant costs for revision surgery. In an effort to decrease nonunion rates, various bone grafts and biologics have been developed to increase osseous formation and arthrosis. The current gold-standard bone graft is autologous bone taken from the iliac crest or ribs, but this procedure is associated with significant morbidity and postoperative pain due to an additional graft harvesting procedure. Other bone graft substitutes and biologics include allografts, demineralized bone matrix, bone morphogenetic protein, and bioactive glass. Ultimately, these substitutes have been studied more extensively in the adult population, and there is a paucity of strong evidence for the use of these agents within the pediatric population. In this review, the authors will discuss in detail the characteristics of the various bone graft substitutes, their fusion efficacy, and their safety profile in this subpopulation.

The effect of anterior lumbar interbody fusion staging order on perioperative complications in circumferential lumbar fusions performed within the same hospital admission.

OBJECTIVE: Anterior lumbar interbody fusion (ALIF) is a powerful technique that provides wide access to the disc space and allows for large lordotic grafts. When used with posterior spinal fusion (PSF), the procedures are often staged within the same hospital admission. There are limited data on the perioperative risk profile of ALIF-first versus PSF-first circumferential fusions performed within the same hospital admission. In an effort to understand whether these procedures are associated with different perioperative complication profiles, the authors performed a retrospective review of their institutional experience in adult patients who had undergone circumferential lumbar fusions. METHODS: The electronic medicals records of patients who had undergone ALIF and PSF on separate days within the same hospital admission at a single academic center were retrospectively analyzed. Patients carrying a diagnosis of tumor, infection, or traumatic fracture were excluded. Demographics, surgical characteristics, and perioperative complications were collected and assessed. RESULTS: A total of 373 patients, 217 of them women (58.2%), met the inclusion criteria. The mean age of the study cohort was 60 years. Surgical indications were as follows: degenerative disease or spondylolisthesis, 171 (45.8%); adult deformity, 168 (45.0%); and pseudarthrosis, 34 (9.1%). The majority of patients underwent ALIF first (321 [86.1%]) with a mean time of 2.5 days between stages. The mean number of levels fused was 2.1 for ALIF and 6.8 for PSF. In a comparison of ALIF-first to PSF-first cases, there were no major differences in demographics or surgical characteristics. Rates of intraoperative complications including venous injury were not significantly different between the two groups. The rates of postoperative ileus (11.8% vs 5.8%, p = 0.194) and ALIF-related wound complications (9.0% vs 3.8%, p = 0.283) were slightly higher in the ALIF-first group, although the differences did not reach statistical significance. Rates of other perioperative complications were no different. CONCLUSIONS: In patients undergoing staged circumferential fusion with ALIF and PSF, there was no statistically significant difference in the rate of perioperative complications when comparing ALIF-first to PSF-first surgeries.

A novel technique for awake, minimally invasive transforaminal lumbar interbody fusion: technical note.

Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is associated with improved patient-reported outcomes in well-selected patients. Recently, some neurosurgeons have aimed to further improve outcomes by utilizing multimodal methods to avoid the use of general anesthesia. Here, the authors report on the use of a novel awake technique for MI-TLIF in two patients. They describe the successful use of liposomal bupivacaine in combination with a spinal anesthetic to allow for operative analgesia.

Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions.

Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging.

Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history.

Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the CDKN2A tumor suppressor gene on chromosome 9p21. While some families with germline CDKN2A mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous-system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline CDKN2A inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the CDKN2A and CDKN2B tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of CDKN2A/B due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included BRAF p.V600E mutation in the pleomorphic xanthoastrocytoma and PTPN11, ATRX, and NF1 mutations in the diffuse astrocytoma. The presence of germline CDKN2A/B inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the CDKN2A/B deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate.
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Predictors of recurrence in the management of chordoid meningioma.

Management of chordoid meningiomas (CMs) is complicated by high rates of recurrence, particularly following subtotal resection. Optimal management is not established given the paucity of published experience. To identify prognostic factors for recurrence following resection, the authors conducted the largest systematic review of CMs to date. A comprehensive search on MEDLINE (OVID and Pubmed), Scopus, Embase, and Web of Science utilizing the search terms "chordoid" AND "meningioma" was performed to identify all reports of pathologically confirmed intracranial CMs. A total of 221 patients were included, comprising 120 females and 101 males. Mean age, MIB-1/Ki67, and tumor size was 45.5 years, 4.3% (range 0.1-26.6%), and 4.1 cm (range 0.8-10 cm), respectively. 5-, and 10- year progression free survival was 67.5 and 54.4%, respectively. Gross total resection (GTR) and subtotal resection was achieved in 172 and 48 patients, respectively. Adjuvant radiotherapy (RT) was given to 30 patients. Multivariate analysis found GTR was strongly correlated with decreased recurrence rates (HR 0.04, p = <0.0001), while higher MIB-1 labeling index (≥5 vs <5%) was associated with increased recurrence (HR 7.08; p = 0.016). Adjuvant RT, age, gender, and tumor location were not associated with recurrence. GTR resection is the strongest predictor of tumor control, and should be the goal to minimize local progression. Additionally, higher MIB-1 labeling was associated with increased rates of tumor recurrence. Tumors that are subtotally resected or demonstrate higher MIB-1 are at greater recurrence and warrant consideration for RT and close long term follow up.

Immunomonitoring in glioma immunotherapy: current status and future perspectives.

Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response.

Heat shock protein vaccines against glioblastoma: from bench to bedside.

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

Extensive carcinoma cuniculatum of the mandible.

Carcinoma cuniculatum (CC) is a rare variant of squamous cell carcinoma first described in 1954. Cases of CC in the head and neck are exceedingly rare, with 66 cases reported since 1977. These tumors are generally low-grade, well-differentiated and locally aggressive malignancies. Patients are often subjected to a long period of misdiagnoses given the clinical similarity of these entities to odontogenic cysts and abscesses. We report a case of a carcinoma cuniculatum of the mandible with very advanced local involvement of disease, highlighting the unusual characteristics of this rare tumor that are important for clinicians to recognize. Clinical presentation, histology, risk factors, treatment options, and prognosis are also reviewed.

Superior Laryngeal Nerve Palsy After Anterior Cervical Diskectomy and Fusion: A Case Report and Cadaveric Description.

BACKGROUND AND IMPORTANCE: Superior laryngeal nerve (SLN) injury after high cervical dissection can result in changes in vocal pitch due to cricothyroid denervation and dysphagia with aspiration risk because of decreased sensation of the supraglottic larynx. CLINICAL PRESENTATION: We describe a 69-year-old singer with cervical spondylotic myelopathy who underwent elective C3/4 and C4/5 anterior cervical diskectomy and fusion. Postoperatively, the patient reported changes in his voice, most noticeable with higher registers. A number of studies confirmed severe right superior laryngeal neuropathy. A cadaveric description included to highlight anatomic relationships critical in minimizing risk of SLN injury during an anterior cervical diskectomy and fusion approach. CONCLUSION: The SLN is a critical structure vulnerable to iatrogenic injury during high cervical dissections for anterior approaches to the spine. Therefore, it is critical for spine surgeons to have a firm understanding of SLN anatomy for these approaches.

The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments.

Meningiomas are mostly benign, slow-growing tumors of the CNS that originate from arachnoidal cap cells. While monosomy 22 is the most frequent genetic abnormality found in meningiomas, a multitude of other aberrant chromosomal alterations, signaling pathways, and growth factors have been implicated in its pathogenesis. Losses on 22q12.2, a region encoding the tumor suppressor gene merlin, represent the most common genetic alterations in early meningioma formation. Malignant meningioma progression, however, is associated with more complex karyotypes and greater genetic instability. Cytogenetic studies of atypical and anaplastic meningiomas revealed gains and losses on chromosomes 9, 10, 14, and 18, with amplifications on chromosome 17. However, the specific gene targets in a majority of these chromosomal abnormalities remain elusive. Studies have also implicated a myriad of aberrant signaling pathways involved with meningioma tumorigenesis, including those involved with proliferation, angiogenesis, and autocrine loops. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. Despite advancements in our understanding of meningioma pathogenesis, the conventional treatments, including surgery, radiotherapy, and stereotactic radiosurgery, have remained largely stagnant. Surgery and radiation therapy are curative in the majority of lesions, yet treatment remains challenging for meningiomas that are recurrent, aggressive, or refractory to conventional treatments. Future therapies will include combinations of targeted molecular agents as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas.

Evaluating the Clinical Utility and Cost of Imaging Strategies in Adults with Newly Diagnosed Primary Intradural Spinal Tumors.

OBJECTIVE: In patients with new primary intradural spinal tumors, the best screening strategy for additional central nervous system (CNS) lesions is unclear. The goal of this study was to document the rate of additional CNS tumors in these patients. METHODS: Adults with primary intradural spinal tumors were retrospectively reviewed. Imaging strategy at diagnosis was classified as focused spine (cervical, thoracic, or lumbar), total spine, or complete neuraxis (brain and total spine). Tumor pathology, genetic syndromes, and presence of additional CNS lesions at diagnosis or follow-up were collected. RESULTS: The study comprised 319 patients with mean age of 51 years and mean follow-up of 41 months. In 151 patients with focused spine imaging, 3 (2.0%) were found to have new lesions with 2 (1.4%) requiring treatment. In 35 patients with total spine imaging, there were no additional lesions. In 133 patients with complete neuraxis imaging, 4 (3.0%) were found to have new lesions with 2 (1.5%) requiring treatment. There was no difference in the identification of new lesions (P = 0.542) or new lesions requiring treatment (P = 0.772) across imaging strategies. Among patients without genetic syndromes, rates of new lesions requiring treatment were 1.4% for focused spine, 0% for total spine, and 2.2% for complete neuraxis (P = 0.683). There were no cases of delayed identification causing risk to life or neurological function. Complete neuraxis imaging carried an increased charge of $4420 per patient. CONCLUSIONS: Among patients without an underlying genetic syndrome, the likelihood of identifying additional CNS lesions requiring treatment is low. In appropriate cases, focused spine imaging may be a more cost-effective strategy.

"July Effect" Revisited: July Surgeries at Residency Training Programs are Associated with Equivalent Long-term Clinical Outcomes Following Lumbar Spondylolisthesis Surgery.

STUDY DESIGN: Retrospective analysis of a prospective registry. OBJECTIVE: We utilized the Quality Outcomes Database (QOD) registry to investigate the "July Effect" at QOD spondylolisthesis module sites with residency trainees. SUMMARY OF BACKGROUND DATA: There is a paucity of investigation on the long-term outcomes following surgeries involving new trainees utilizing high-quality, prospectively collected data. METHODS: This was an analysis of 608 patients who underwent single-segment surgery for grade 1 degenerative lumbar spondylolisthesis at 12 high-enrolling sites. Surgeries were classified as occurring in July or not in July (non-July). Outcomes collected included estimated blood loss, length of stay, operative time, discharge disposition, complications, reoperation and readmission rates, and patient-reported outcomes (Oswestry Disability Index [ODI], Numeric Rating Scale [NRS] Back Pain, NRS Leg Pain, EuroQol-5D [EQ-5D] and the North American Spine Society [NASS] Satisfaction Questionnaire). Propensity score-matched analyses were utilized to compare postoperative outcomes and complication rates between the July and non-July groups. RESULTS: Three hundred seventy-one surgeries occurred at centers with a residency training program with 21 (5.7%) taking place in July. In propensity score-matched analyses, July surgeries were associated with longer operative times ( average treatment effect = 22.4 minutes longer, 95% confidence interval 0.9-449.0, P = 0.041). Otherwise, July surgeries were not associated with significantly different outcomes for the remaining perioperative parameters (estimated blood loss, length of stay, discharge disposition, postoperative complications), overall reoperation rates, 3-month readmission rates, and 24-month ODI, NRS back pain, NRS leg pain, EQ-5D, and NASS satisfaction score (P > 0.05, all comparisons). CONCLUSION: Although July surgeries were associated with longer operative times, there were no associations with other clinical outcomes compared to non-July surgeries following lumbar spondylolisthesis surgery. These findings may be due to the increased attending supervision and intraoperative education during the beginning of the academic year. There is no evidence that the influx of new trainees in July significantly affects long-term patient-centered outcomes.Level of Evidence: 3.

Oblique Lumbar Interbody Fusion With Stereotactic Navigation: Technical Note.

STUDY DESIGN: Surgical technical note. OBJECTIVES: Describe the preoperative evaluation, approach, and technical considerations for an oblique lumbar interbody fusion using neuronavigation. METHODS: A thorough review of previous technical and anatomic descriptions for pre- and transpsoas interbody techniques was performed and incorporated into the technical considerations warranting discussion for a navigated oblique lateral interbody fusion. RESULTS: The prepsoas technique, also known as an oblique lumbar interbody fusion (OLIF), is an alternative approach for lumbar interbody fusion that utilizes a retroperitoneal corridor between the aorta/inferior vena cava. This corridor is devoid of neurovascular structures and obviates the need for real time electromyography monitoring. This approach spares the psoas and provides direct visualization of key structures and minimizes risk of injury to the great vessels, ureter, and lumbar plexus. CONCLUSIONS: A navigated prepsoas retroperitoneal approach is an effective minimally invasive technique for lumbar interbody fusion that may help mitigate some of the vascular and neurologic complications present with anterior lumbar interbody fusion or lateral lumbar interbody fusion and minimize radiation exposure to the surgeon.

Ommaya Reservoir Insertion: A Technical Note.

Ommaya reservoir insertion is an elective neurosurgical procedure to deliver repeated intraventricular therapy, but placement can be complicated by malposition of the catheter, clogging, infection or poor postoperative cosmesis. Here, we describe the technique used by the senior author for accurate placement including preassembly of the reservoir and catheter, and recessing of the reservoir so that others may consider the technique for their practice. Results in a consecutive series of 27 Ommaya placements were reviewed. Catheter tip placement accuracy, complications and surgical times were reported. Indications were leptomeningeal cancer or infection. Postoperative imaging showed the catheter tip was located in the frontal horn (96%) or body (4%) of the ipsilateral lateral ventricle. The median surgical time was 36 minutes (range 17-63 minutes). There were no parenchymal or subarachnoid hemorrhages. Infections occurred in 7% (n=2) of cases, and both infections presented greater than 60 days postoperative. In conclusion, we have found that image guidance can optimize accuracy in placement, that preassembly of the reservoir and catheter may be used with a 25-gauge spinal needle stylet to minimize risk of clogging during placement, and that recessing of the reservoir produces the best aesthetic result.

Immediate Voice and Swallowing Complaints Following Revision Anterior Cervical Spine Surgery.

OBJECTIVE: To report on the incidence of dysphagia, dysphonia, and acute vocal fold motion impairment (VFMI) following revision anterior cervical spine surgery, as well as to identify risk factors associated with acute VFMI in the immediate postoperative period. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care center. SUBJECTS AND METHODS: All patients who underwent 2-team reoperative anterior cervical discectomy and fusion (ACDF) were retrospectively reviewed. Incidence of dysphonia, dysphagia, and acute VFMI was noted. Patient and operative factors were evaluated for association with risk of acute VFMI. RESULTS: The incidence of postoperative dysphonia and dysphagia was 25% (18/72) and 52% (37/72), respectively. The incidence of immediate VFMI was 21% (15/72). Subjective postoperative dysphonia (odds ratio, [OR] 8; 95% CI, 2.2-28; P = .001) and dysphagia (OR, 22; 95% CI, 2.5-168; P = .005) were significantly associated with increased risk of VFMI. Three patients with VFMI required temporary injection medialization for voice complaints and/or aspiration. Infection (OR, 14; 95% CI, 1.4-147, P = .025) and level C7/T1 (OR, 5.5; 95% CI, 1.3-23, P = .02) were significantly associated with an increased risk of acute VFMI on multivariate logistic regression analysis. Number of prior surgeries, laterality of approach, side of approach relative to prior operations, and number of levels exposed were not significant. CONCLUSION: Early involvement of an otolaryngologist in the care of a patient undergoing revision ACDF can be helpful to the patient in anticipation of voice and swallowing changes in the postoperative period. This may be particularly important in those being treated at C7/T1 or those with spinal infections.

The impact of obesity on perioperative complications in patients undergoing anterior lumbar interbody fusion.

OBJECTIVE: Anterior approaches to the lumbar spine provide wide exposure that facilitates placement of large grafts with high fusion rates. There are limited data on the effects of obesity on perioperative complications. METHODS: Data from consecutive patients undergoing anterior lumbar interbody fusion (ALIF) from 2007 to 2016 at a single academic center were analyzed. The primary outcome was any perioperative complication. Complications were divided into those occurring intraoperatively and those occurring postoperatively. Multivariate logistic regression was used to assess the association of obesity and other variables with these complications. An estimation table was used to identify a body mass index (BMI) threshold associated with increased risk of postoperative complication. RESULTS: A total of 938 patients were identified, and the mean age was 57 years; 511 were females (54.5%). The mean BMI was 28.7 kg/m2, with 354 (37.7%) patients classified as obese (BMI ≥ 30 kg/m2). Forty patients (4.3%) underwent a lateral transthoracic approach, while the remaining 898 (95.7%) underwent a transabdominal retroperitoneal approach. Among patients undergoing transabdominal retroperitoneal ALIF, complication rates were higher for obese patients than for nonobese patients (37.0% vs 28.7%, p = 0.010), a difference that was driven primarily by postoperative complications (36.1% vs 26.0%, p = 0.001) rather than intraoperative complications (3.2% vs 4.3%, p = 0.416). Obese patients had higher rates of ileus (11.7% vs 7.2%, p = 0.020), wound complications (11.4% vs 3.4%, p < 0.001), and urinary tract infections (UTI) (5.0% vs 2.5%, p = 0.049). In a multivariate model, age, obesity, and number of ALIF levels fused were associated with an increased risk of postoperative complication. An estimation table including 19 candidate cut-points, odds ratios, and adjusted p values found a BMI ≥ 31 kg/m2 to have the highest association with postoperative complication (p = 0.012). CONCLUSIONS: Obesity is associated with increased postoperative complications in ALIF, including ileus, wound complications, and UTI. ALIF is a safe and effective procedure. However, patients with a BMI ≥ 31 kg/m2 should be counseled on their increased risks and warrant careful preoperative medical optimization and close monitoring in the postoperative setting.

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth.

PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation. EXPERIMENTAL DESIGN: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.

Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study.

BACKGROUND: After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings. METHODS: TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13-15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7-18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal-Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini-Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov, number NCT02119182. FINDINGS: Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726-0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25-75th percentile 139·3-813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5-214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9-20·0), and healthy controls (8·0 pg/mL, 3·0-14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p<0·0001). INTERPRETATION: Analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 h of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up. FUNDING: National Institute of Neurological Disorders and Stroke and US Department of Defense.