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.
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
utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.
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.
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.
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.
Highlights • Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor. • CD44 is a transmembrane molecule overexpressed in GBM. • Processes involving CD44 promote GBM invasion, ...proliferation and therapy resistance. • Targeting CD44 is a promising GBM therapy.
Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. ...Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1
+
myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1 co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells.
Highlights • Embolization has been used to decrease surgical bleeding of hemangioblastomas. • Embolization does not increase rates of gross total resection. • Embolization does not substantially ...decrease surgical blood loss. • Embolization is associated with significant risk for procedural complications. • Embolization is not recommended for treatment of intracranial hemangioblastomas.
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.
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.
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.
Highlights • Chordoid glioma is a rare subtype of low grade glioma typically located within the 3rd ventricle. • Gross total resection is associated with improved tumor control and should be the ...primary therapeutic goal. • Surgical morbidity following resection of chordiod glioma is high due deep tumor location. • Adjuvant radiotherapy has mainly been utilized following subtotal resection.
Abstract Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved ...rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6 years, and the mean tumor diameter was 3.36 cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5 year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively ( p = 0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio HR 0.20; p = 0.009). Additionally, age >45 years (HR 5.88; p = 0.01) and the presence of visual deficits (HR 7.59; p = 0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life.
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