Posterior Interhemispheric-Transtentorial Approach for Resection of an Arteriovenous Malformation of the Superior Medullary Velum and Fourth Ventricle: 2-Dimensional Operative Video.

Brain arteriovenous malformations (AVMs) of the fourth ventricle represent a rare subtype associated with an aggressive natural course.1,2 In this case, a woman in her early 50s presented with dizziness. An AVM was diagnosed in the left superior cerebellar peduncle extending into the fourth ventricle. The AVM was supplied by superior cerebellar artery branches and classified as a Spetzler-Martin grade III and a Lawton-Young grade III, with a supplemented grade of 6.3,4 Being a single case report, institutional review board approval was not needed. Patient consent was obtained. The lesion was accessed through a torcular craniotomy and posterior interhemispheric-transtentorial approach, employing gravity to naturally retract the parietooccipital lobe.5-7 Dissection continued into the quadrigeminal and ambient cisterns, where the tentorium was incised parallelling the straight sinus to reach the superior vermis. Partial resection of the lingual and central lobules of the vermis facilitated access to the superior medullary velum. The superior cerebellar artery feeders were divided and followed to the superior cerebellar peduncle and through the superior medullary vellum. A vertical incision in the superior medullary velum facilitated entry into the fourth ventricle, where the AVM nidus was dissected circumferentially and resected en bloc. Intraoperative indocyanine green videoangiography and postoperative digital subtraction angiography confirmed complete obliteration of the AVM. After surgery, the patient experienced mild ataxia, but motor symptoms greatly improved during 3-month follow-up. This video illustrates resection of a complex fourth ventricular AVM through a posterior interhemispheric-transtentorial approach, highlighting pivotal considerations of patient positioning and approach selection to optimize treatment outcome for complex posterior fossa AVM resection.

Metastasis of Intracranial Meningioma to the Osseous Spine: Systematic Literature Review and Case Report.

BACKGROUND: Osseous spinal metastases from intracranial meningiomas are rare but represent a serious disease progression. A literature review was performed on this topic to understand the clinical course of patients with this disease entity. We also present a case of spinal metastasis in a patient with a World Health Organization grade III meningioma. METHODS: The PubMed/MEDLINE database was queried on August 15, 2021, using the keywords (meningioma) AND (metastasis) AND (vertebra∗ OR spin∗). All publications reporting outcomes of patients with meningioma metastatic to the spine were included. Disease characteristics, treatment modality, and outcomes were extracted from each study. Because data availability varied widely between studies, no meta-analysis was performed. RESULTS: A total of 30 articles with 33 cases were included. Outcome data varied greatly in terms of quality and length of follow-up. Of 28 cases with reported outcomes data, 20 resulted in patient mortality ranging from a few weeks to 5 years after spinal metastasis. Mean (standard deviation) survival time was 5.8 (6.4) years following initial diagnosis, but only 1.4 (3.2) years from spinal metastasis. The longest survivor was noted to have no recurrence of disease 4 years after spinal metastasis. CONCLUSIONS: Bony spinal metastasis from intracranial meningioma is an extremely rare occurrence. Within the limits of the available literature, outcomes of patients with this disease appear to be poor. However, data reporting is inconsistent, and several articles did not report any outcome data. Further study is needed to better clarify the course and prognosis of this disease.

Bilateral sacroiliac joint fusion in long constructs using self-harvesting porous S2-alar iliac screws with an integrated tulip: technical considerations and early clinical and radiographic experience.

OBJECTIVE: The incidence of sacroiliac joint (SIJ) dysfunction after lumbosacral fusion is high. Upfront bilateral SIJ fusion using novel fenestrated self-harvesting porous S2-alar iliac (S2AI) screws could reduce the incidence of SIJ dysfunction and need for subsequent SIJ fusion. In this study, the authors report their early clinical and radiographic results of SIJ fusion using this novel screw. METHODS: The authors began using self-harvesting porous screws in July 2022. This is a retrospective review of consecutive patients at a single institution who underwent long thoracolumbar surgery with extension to the pelvis using this porous screw. Radiographic parameters of regional and global alignment were collected preoperatively and at the time of last follow-up. The incidence of intraoperative complications and need for revision were collected. The incidences of mechanical complications, including screw breakage, implant loosening/pullout, and screw cap dislocation at the time of last follow-up were also collected. RESULTS: Ten patients with a mean age of 67 years were included, 6 of whom were male. Seven patients had a thoracolumbar construct with extension to the pelvis. Three patients had upper instrumented vertebrae at the proximal lumbar spine. Intraoperative breach was not encountered in any of the patients (0%). Postoperatively, 1 patient (10%) had screw breakage at the neck of the tulip of the modified iliac screw discovered at routine follow-up without clinical sequalae. CONCLUSIONS: Use of self-harvesting porous S2AI screws incorporated into long thoracolumbar constructs was safe and feasible, demanding unique technical considerations. Long-term clinical and radiographic follow-up with a large patient cohort is necessary to determine their durability and efficacy to achieve SIJ arthrodesis and prevent SIJ dysfunction.

Complications associated with single-position prone lateral lumbar interbody fusion: a systematic review and pooled analysis.

OBJECTIVE: Lateral lumbar interbody fusion (LLIF) is a workhorse surgical approach for lumbar arthrodesis. There is growing interest in techniques for performing single-position surgery in which LLIF and pedicle screw fixation are performed with the patient in the prone position. Most studies of prone LLIF are of poor quality and without long-term follow-up; therefore, the complication profile related to this novel approach is not well known. The objective of this study was to perform a systematic review and pooled analysis to understand the safety profile of prone LLIF. METHODS: A systematic review of the literature and a pooled analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies reporting prone LLIF were assessed for inclusion. Studies not reporting complication rates were excluded. RESULTS: Ten studies meeting the inclusion criteria were analyzed. Overall, 286 patients were treated with prone LLIF across these studies, and a mean (SD) of 1.3 (0.2) levels per patient were treated. The 18 intraoperative complications reported included cage subsidence (3.8% [3/78]), anterior longitudinal ligament rupture (2.3% [5/215]), cage repositioning (2.1% [2/95]), segmental artery injury (2.0% [5/244]), aborted prone interbody placement (0.8% [2/244]), and durotomy (0.6% [1/156]). No major vascular or peritoneal injuries were reported. Sixty-eight postoperative complications occurred, including hip flexor weakness (17.8% [21/118]), thigh and groin sensory symptoms (13.3% [31/233]), revision surgery (3.8% [3/78]), wound infection (1.9% [3/156]), psoas hematoma (1.3% [2/156]), and motor neural injury (1.2% [2/166]). CONCLUSIONS: Single-position LLIF in the prone position appears to be a safe surgical approach with a low complication profile. Longer-term follow-up and prospective studies are needed to better characterize the long-term complication rates related to this approach.

Ketogenic Metabolic Therapy for Glioma.

PURPOSE: This study describes a retrospective case series of patients with glioma who received ketogenic metabolic therapy through dietary adherence and intermittent fasting. METHODS: A retrospective chart review of a single surgeon's clinic records was performed to identify patients who maintained nutritional ketosis for at least four months between January 2015 and October 2020. RESULTS: Sixteen patients who met the inclusion criteria constituted a heterogeneous population of patients with diagnoses including eight World Health Organization (WHO) grade IV gliomas (seven glioblastoma, one gliosarcoma), seven WHO grade III gliomas (three oligodendroglioma, four astrocytoma), and one WHO grade II oligodendroglioma. IDH1 mutation status was present for 12 patients, and MGMT methylation status was present for eight patients. The mean (standard deviation [SD]) duration of ketogenic metabolic therapy was 20.6 (13.8) months. The Response Assessment in Neuro-oncology Criteria was applied during the ketogenic metabolic therapy interval, indicating a complete response in eight patients and partial response in eight patients. The mean (SD) progression-free survival while patients maintained ketogenic metabolic therapy was 20.0 (14.4) months. CONCLUSION: Ketogenic metabolic therapy appears to convey a survival advantage within this patient series, which highlights the possibility that this therapy, when strictly applied, can augment the standard of care. Further exploration of this modality in a prospective series is warranted to formally explore this therapy.

Residual Tumor Volume and Tumor Progression after Subtotal Resection and Observation of WHO Grade I Skull Base Meningiomas.

Objective This study investigated the impact of residual tumor volume (RTV) on tumor progression after subtotal resection and observation of WHO grade I skull base meningiomas. Study Design This study is a retrospective volumetric analysis. Setting This study was conducted at a single institution. Participants Patients who underwent subtotal resection of a WHO grade I skull base meningioma and postsurgical observation (July 1, 2007-July 1, 2017). Main Outcome Measure The main outcome was radiographic tumor progression. Results Sixty patients with residual skull base meningiomas were analyzed. The median (interquartile range) RTV was 1.3 (5.3) cm 3 . Tumor progression occurred in 23 patients (38.3%) at a mean duration of 28.6 months postsurgery. The 1-, 3-, and 5-year actuarial progression-free survival (PFS) rates were 98.3, 58.6, and 48.7%, respectively. The Cox multivariate analysis identified increasing RTV ( p = 0.01) and history of more than 1 previous surgery ( p = 0.03) as independent predictors of tumor progression. In a Kaplan-Meier analysis for PFS, the RTV threshold of 3 cm 3 maximized log-rank testing significance between groups of patients dichotomized at 0.5 cm 3 thresholds ( p < 0.01). The 3-year actuarial PFS rates for meningiomas with RTV ≤3 cm 3 and >3 cm 3 were 76.2 and 32.1%, respectively. When RTV >3 cm 3 was entered as a covariate in the Cox model, it was the only factor independently associated with tumor progression ( p < 0.01). Conclusion RTV was associated with tumor progression after subtotal resection of WHO grade I skull base meningioma in this cohort. An RTV threshold of 3 cm 3 was identified that minimized progression of the residual tumor when gross total resection was not safe or feasible.

ZAP-X Gyroscopic Radiosurgery System: A Preliminary Analysis of Clinical Applications within a Retrospective Case Series.

INTRODUCTION: The ZAP-X Gyroscopic Radiosurgery system (ZAP Surgical Systems, Inc., San Carlos, CA, USA) is a novel high-dose targeted stereotactic radiosurgery platform for outpatient use that includes self-shielding, X-ray image guidance, and the capacity to aim the radiation beam gyroscopically at an intracranial lesion using 5 independent degrees of freedom. The ZAP-X Gyroscopic Radiosurgery system accomplishes these actions while meeting widely accepted standards for dose gradient and accuracy. This retrospective study examined data of patients treated with gyroscopic radiosurgery (GRS) to document clinical outcomes. METHODS: Medical records of all outpatients treated with GRS over a 20-month period from January 2019 to August 2020 were searched to extract relevant details, including follow-up data until August 2021 (32-month study interval). Patients with <6 months of radiographical follow-up data were excluded unless death occurred. Data collection included pretreatment clinical history, pathological diagnosis, radiographical features, treatment parameters, and long-term clinical and radiographical follow-up. RESULTS: Sixty-eight patients received outpatient treatment with GRS during the 20-month treatment interval, with 59 patients remaining after exclusion for the minimum follow-up threshold, with a mean (standard deviation [SD]) fractionation of 1.85 (1.63). Eighty-two lesions were treated across a very heterogeneous patient population, including meningiomas (42.4%), metastases (39.0%), gliomas (6.8%), schwannomas (1.7%), and pituitary tumor (1.7%). Mean (SD) radiographical follow-up data (14.7 [6.60] months) were available for 56 patients. During that interval, 13 treated lesions in 13 patients (15.9%) demonstrated progression, 9 of which were stable during the initial posttreatment imaging surveillance period. Mean lesion volume was stable from pretreatment (2.54 cm3 [4.37 cm3]) to most recent follow-up (2.80 cm3 [8.20 cm3]) (t [79] = -0.310; p = 0.76). Minor adverse clinical events were noted in 3 (5.1%) of the 59 patients during the posttreatment phase that may have been related to the treatment. Ten (16.9%) patients died within the 32-month study interval. DISCUSSION/CONCLUSION: This preliminary assessment of the first series of patients treated with the Zap-X Gyroscopic Radiosurgery system documents its overall feasibility in clinical applications. Although the duration of follow-up was brief, GRS appeared to be both safe and effective. Additional analysis, with an ongoing prospective registry, is underway.

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.

Bevacizumab as a surgery-sparing agent for spinal ependymoma in patients with neurofibromatosis type II: Systematic review and case.

Neurofibromatosis type 2 (NF2) is a rare, hereditary tumor syndrome, often requiring repeated surgeries for multiple lesions with significant cumulative morbidity. As such, non-operative management should be considered when possible for this patient population. The aim of this study is to provide a systematic review of the literature regarding this treatment strategy. A descriptive case of a patient in whom bevacizumab treatments enabled over 15 years of surgical postponement for a symptomatic spinal cord ependymoma is also provided. Evidence suggests that bevacizumab is a reasonable surgery-deferring option for cystic lesions, and it may be especially useful in NF2 patients to reduce cumulative morbidity.

Digital subtraction cerebral angiography after negative computed tomography angiography findings in non-traumatic subarachnoid hemorrhage.

BACKGROUND: CT angiography (CTA) is widely used for the detection of vascular lesions in patients with non-traumatic subarachnoid hemorrhage (ntSAH); however, digital subtraction angiography (DSA) remains the gold standard for diagnosis. Our aim was to analyze the diagnostic yield of DSA after negative high-resolution CTA findings. METHODS: Records of patients with a CTA-negative ntSAH at a single institution from 2014 to 2018 were retrospectively analyzed. ntSAH patterns were categorized as cortical, perimesencephalic, or diffuse. Subsequent DSA findings were compared across the three cohorts. RESULTS: A total of 186 patients had CTA-negative ntSAH. The ntSAH pattern was identified as cortical (n=77, 41.4%), diffuse (n=60, 32.3%), or perimesencephalic (n=49, 26.3%). In eight patients (4%), DSA revealed a vascular lesion (one cervical arteriovenous fistula and seven atypical aneurysms) after negative CTA findings. All eight patients with positive DSA findings had diffuse SAH (13% of patients with a diffuse pattern). The seven aneurysms included four blister or dissecting (two basilar artery, one superior cerebellar artery, and one dorsal wall internal carotid artery), two fusiform (one posterior communicating artery and one anterior spinal artery), and one saccular aneurysm (middle cerebral artery). CONCLUSION: DSA identified a causative lesion in 4% of patients with CTA-negative ntSAH, but only in patients with diffuse ntSAH. Most of the lesions detected were atypical aneurysms and were found on delayed angiograms. These results suggest that DSA can help to diagnose CTA-negative ntSAH caused by unusual aneurysms, and repeat DSA may be needed only for patients with diffuse ntSAH.

Laparoscopic-Assisted Ventriculoperitoneal Shunt Placement and Reduction in Operative Time and Total Hospital Charges.

OBJECTIVE: In ventriculoperitoneal shunt (VPS) placement, distal placement of the peritoneal catheter will typically be performed by a neurosurgeon. More recently, laparoscopic-assisted (LA) placement of the distal peritoneal catheter by general surgeons has become common. The present study examined whether LA placement of a VPS (LAVPS) is associated with a reduced operative time, lower hospital costs, and fewer distal revisions. METHODS: A retrospective review was performed of the data from all patients who had received a new VPS at our institution from 2013 to 2016. Age, sex, diagnosis, previous abdominal surgery, operative time, anesthesia grade, incidence of 30-day shunt failure, and total hospital charges were analyzed. RESULTS: A total of 680 patients had undergone first-time VPS placement, including 199 with LAVPS and 481 with non-LAVPS placement (non-LAVPS). The mean age of the LAVPS patients was significantly older than that of the non-LAVPS patients (64.1 vs. 59.3 years; P = 0.002). The mean operative time was shorter in the LAVPS group than in the non-LAVPS group (55 vs. 75 minutes; P < 0.001). Distal shunt revision within 30 days occurred more often for the non-LAVPS patients (6 of 481 [1.2%]) than for the LAVPS patients (0 of 199 [0%]). A subset analysis of patients with normal-pressure hydrocephalus found decreased total hospital charges in the LAVPS group ($67,124 vs. $80,890; P = 0.009). CONCLUSIONS: Compared with non-LAVPS, LAVPS was associated with significantly shorter operative times and fewer distal shunt revisions within 30 days. The findings from a subset analysis supported a decrease in total hospital charges. Additional studies are needed; however, these data suggest that LAVPS is a safer, less-expensive alternative to non-LAVPS.

The Barrow Biomimetic Spine: Face, Content, and Construct Validity of a 3D-Printed Spine Model for Freehand and Minimally Invasive Pedicle Screw Insertion.

STUDY DESIGN: Description and evaluation of a novel surgical training platform. OBJECTIVES: The purpose of this study was to investigate the face, content, and construct validity of 5 novel surgical training models that simulate freehand and percutaneous (minimally invasive surgery [MIS]) pedicle screw placement. METHODS: Five spine models were developed by residents: 3 for freehand pedicle screw training (models A-C) and 2 for MIS pedicle screw training (models D and E). Attending spine surgeons evaluated each model and, using a 20-point Likert-type scale, answered survey questions on model face, content, and construct validity. Scores were statistically evaluated and compared using means, standard deviations, and analysis of variance between models and between surgeons. RESULTS: Among the freehand models, model C demonstrated the highest overall validity, with mean face (15.67 ± 5.49), content (19.17 ± 0.59), and construct (18.83 ± 0.24) validity all measuring higher than the other freehand models. For the MIS models, model D had the highest validity scores (face, content, and construct validity of 11.67 ± 3.77, 18.17 ± 2.04, and 17.00 ± 3.46, respectively). The 3 freehand models differed significantly in content validity scores (P = .002) as did the 2 MIS models (P < .001). The testing surgeons' overall validity scores were significantly different for models A (P = .005) and E (P < .001). CONCLUSIONS: A 3-dimensional-printed spine model with incorporated bone bleeding and silicone rubber soft tissue was scored as having very high content and construct validity for simulating freehand pedicle screw insertion. These data has informed the further development of several surgical training models that hold great potential as educational adjuncts in surgical training programs.

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.

Thirty-day readmission rate and risk factors for patients undergoing single level elective anterior lumbar interbody fusion (ALIF).

Anterior lumbar interbody fusion (ALIF) represents a common interbody fusion technique and is advantageous given reduced risk of damage to the paraspinal muscles, posterior ligaments, and neural elements. In this study, we identified the readmission rate, common causes, and risk factors associated with single level ALIF 30-day readmission. Patients who underwent elective single level ALIF surgery from 2011 to 2013 were identified in the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database. Segmental fusion, emergency, and trauma cases were excluded. A total of 2,042 patients were identified from the ACS-NSQIP database from 2011 to 2013. The proportion of patients readmitted was 5.19% (106/2,042) and approximately 59.81% (64/106) had a reportable cause. The top three causes were poor post-operative pain control (11%), deep (9%) and superficial (9%) surgical site infections. Risk factors associated with 30-day readmission included age (odds ratio (OR)=1.02, 95% confidence interval (CI): 1.00-1.03, p value=0.05), history of severe chronic obstructive pulmonary disease (COPD), (OR=2.11, 95% CI: 0.95-4.70, p value=0.08), post-operative pneumonia (OR=6.58, 95% CI: 2.36-18.30, p value<0.001), and presence of superficial surgical site infection (OR=11.68, 95% CI: 4.88-27.95, p value<0.001). Bleeding disorders, anemia, and perioperative blood loss was not associated with 30-day readmission. Limitations include retrospective level 3 data, and missing data. This study represents the first nation-wide descriptive evaluation of 30-day readmission causes and risk factors for patients undergoing an ALIF procedure.

Clinical attributes and surgical outcomes of angiocentric gliomas.

Angiocentric gliomas (AG) are exceedingly rare low-grade neoplasms which often present in the form of intractable epilepsy within younger patients. The current study extensively reviews all reported cases which were pathologically verified as AG in the literature to analyze clinical attributes and surgical outcomes of this neoplasm. There were 88 patients with AG reported in the literature consisting mostly of pediatric cases. The sex distribution consisted of 45 males and 36 females with the remaining seven cases not documenting sex. The average age of initial diagnosis was 16years with almost half of all diagnosed patients being within the first decade of life. In cases where extent of resection was reported, gross total resection (GTR) was achieved in 54 patients, subtotal resection (STR) in 16, and biopsy only in three. Post-operative complications were transient and only occurred in three patients with no reports of death following surgery. Only five cases reported tumor recurrence on follow-up. Eight patients had seizure recurrence post-operatively and GTR offered improved rates of seizure control when compared to STR (p=0.0005). Nearly half of the cases of AG are diagnosed within the first decade of life and they usually manifest with intractable seizures. GTR appears to offer better seizure control in the post-operative period. Surgical resection is the mainstay therapy for AG as post-operative complications and tumor recurrence remain uncommon. Since the number of reported cases is limited, future studies with longer follow-up periods will help elaborate more long-term outcomes.

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.

YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context.

Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited cell growth and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. While U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC(50) of 10 to 75 nmol/L, A172 cells were resistant (IC(50) ∼ 250 nmol/L). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGF receptor (EGFR) activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737-induced cytotoxicity and caspase-dependent apoptosis. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737 inversely correlated with EGFR activation status. However, sensitivity could be restored in highly resistant U87-EGFRvIII cells by inhibition of EGFR or its downstream pathways, highlighting the impact of EGFR signaling on Mcl-1 expression and the relevance of combined targeted therapies to overcome the multiple resistance mechanisms of these aggressive tumors.

Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage.

Glioblastomas are invasive tumors with poor prognosis despite current therapies. Histone deacetylase inhibitors (HDACIs) represent a class of agents that can modulate gene expression to reduce tumor growth, and we and others have noted some antiglioma activity from HDACIs, such as vorinostat, although insufficient to warrant use as monotherapy. We have recently demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics. In this study, we examined whether bortezomib could enhance response to HDAC inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with vorinostat treatment alone, the combination of vorinostat plus bortezomib significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib with vorinostat enhanced apoptosis by increasing Mcl-1 cleavage, Noxa upregulation, Bak and Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/vorinostat combination. Vorinostat induced a rapid and sustained phosphorylation of histone H2AX in primary GBM and T98G cells, and this effect was significantly enhanced by co-administration of bortezomib. Vorinostat/bortezomib combination also induced Rad51 downregulation, which plays an important role in the synergistic enhancement of DNA damage and apoptosis. The significantly enhanced antitumor activity that results from the combination of bortezomib and HDACIs offers promise as a novel treatment for glioma patients.

ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines.

We observed that glioma cells are differentially sensitive to N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide (ABT-737) and administration of ABT-737 at clinically achievable doses failed to induce apoptosis. Although elevated Bcl-2 levels directly correlated with sensitivity to ABT-737, overexpression of Bcl-2 did not influence sensitivity to ABT-737. To understand the molecular basis for variable and relatively modest sensitivity to the Bcl-2 homology domain 3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of glioma cell lines. Bcl-2 family member proteins, Bcl-xL, Bcl-w, Mcl-1, Bax, Bak, Bid, and Noxa, were found to be expressed ubiquitously at similar levels in all cell lines tested. We then examined the contribution of other apoptosis-resistance pathways to ABT-737 resistance. Bortezomib, an inhibitor of nuclear factor-kappaB (NF-κB), was found to enhance sensitivity of ABT-737 in phosphatase and tensin homolog on chromosome 10 (PTEN)-wild type, but not PTEN-mutated glioma cell lines. We therefore investigated the association between phosphatidylinositol 3-kinase (PI3K)/Akt activation and resistance to the combination of ABT-737 and bortezomib in PTEN-deficient glioma cells. Genetic and pharmacological inhibition of PI3K inhibition sensitized PTEN-deficient glioma cells to bortezomib- and ABT-737-induced apoptosis by increasing cleavage of Bid protein, activation and oligomerization of Bax, and loss of mitochondrial membrane potential. Our data further suggested that PI3K/Akt-dependent protection may occur upstream of the mitochondria. This study demonstrates that interference with multiple apoptosis-resistance signaling nodes, including NF-κB, Akt, and Bcl-2, may be required to induce apoptosis in highly resistant glioma cells, and therapeutic strategies that target the PI3K/Akt pathway may have a selective role for cancers lacking PTEN function.