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Purpose:Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line.Patients and Methods:Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine.Results:For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay.Conclusions:In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

Supplementary Data from A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma

Supplementary Figure from A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma

BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

The surgical treatment of atrial meningiomas carries unique challenges. Recent advancements have aimed to optimize visualization and minimize insult to adjacent tissue. To investigate outcomes following resection of atrial meningiomas using an integrated tubular retraction system with neuro-navigated exoscope. A retrospective analysis of surgical outcomes in consecutive patients who underwent surgical resection of atrial meningiomas via an exoscopic tubular retraction system at three university hospital institutions. Four patients harboring intraventricular meningiomas in the atrium of the lateral ventricle were treated using an integrated navigation-assisted, channel-based trans-sulcal approach via a left temporal-occipital (1), right parieto-occipital (2), or left posterior-temporal (1) sulcal approach with exoscopic visualization. Indications for surgery included headaches (4/4, 100%), dizziness (1/4, 25%), or evidence of progression on imaging (3/4, 75%). Mean maximal tumor diameter was 25.5 mm (range 22–28 mm). No intraoperative complications were observed, and no conversion to a microscopic or open approach was required. Gross total resection (GTR) was obtained in all 4 cases. Median hospital length of stay was 3 days (range 3–4 days). Postoperative complications included homonymous hemianopsia (1) and transient bilateral lower extremity paresthesias (1). At 3-month follow up both complications had improved and all patients had returned to work. At last follow-up (3–24 months), 3 patients (75%) reported improvement of preoperative symptoms. Utilization of a channel-based, navigable retractor with the aid of an exoscope can be an excellent option for accessing the atrium of the lateral ventricles and for achieving complete surgical resection of atrial meningiomas.

Purpose: Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line. Patients and Methods: Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine. Results: For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay. Conclusions: In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

IntroductionThere is a wide variety in the timing of the first intraventricular chemotherapy dose after Ommaya reservoir placement. Given the rapid nature of leptomeningeal metastasis, it is important to avoid any delays in treatment in order to have the optimal therapeutic benefit. We present the first series of immediate intraoperative intraventricular infusion of chemotherapy after Ommaya placement.MethodsA single-institution, retrospective review of twenty patients who underwent surgical placement of an Ommaya reservoir from 2012 to 2020 and had intraoperative infusion of chemotherapy was conducted. Inclusion criteria consisted of patients 18 years and older with a diagnosis of leptomeningeal metastases, central nervous system lymphoma or leukemia. Outcomes such as leukoencephalopathy, wound healing, intracranial hemorrhage, catheter malfunction, Ommaya days, mortality, and other complications were reviewed.ResultsThe mean patient age was 55.1 years and the most common diagnosis was breast cancer (40%). All catheters were placed into the ventricular system, and there were no wound healing complications, infections or symptomatic leukoencephalopathy. Intraventricular chemotherapy was administered for a total of 201 cycles and a mean of 10 times per patient. The number of Ommaya days ranged from 7 to 2177, with a mean of 326.5 days, and 30-day mortality was 10%.Conclusions Ommaya reservoirs are effective intraventricular delivery mechanism for chemotherapy in patients with leptomeningeal metastases. Endoscopy-assisted placement of Ommaya catheters provides a real-time, visual confirmation of adequate placement. Immediate intraoperative intraventricular infusion of chemotherapy after Ommaya placement is safe, effective, and may increase efficiency in time to treatment for patients.

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

Meningiomas account for a significant proportion of all primary intracranial tumors; distant metastasis is quite rare. We report a patient with resected, atypical meningioma. The patient's clinical course over 5 years included two craniotomies, a course of radiation, and a shortened course of bevacizumab. Only 5 months after starting bevacizumab, the patient developed an isolated left clavicular pathological fracture attributable to metastatic anaplastic meningioma. This constitutes the first report of meningioma with isolated extracranial intraosseous metastasis in the modern English literature and highlights concerns associated with the use of anti-angiogenic agents in promoting more invasive tumor phenotypes upon disease recurrence.

Chondromas are rare, benign tumors composed of cartilaginous tissue that mainly affect the metaphases of long tubular bones. Juxtacortical (periosteal) chondromas arise from the surface of periosteum and rarely affect the cervical spine. We present a patient with a spinal juxtacortical chondroma causing spinal cord compression and a cervical deformity treated with surgical resection and circumferential spinal fixation and stabilization. A 55-year-old female with past medical history of Crohn's disease with years of neck pain, balance issues, and left upper extremity radicular symptoms. Cervical spine x-rays show kyphosis with an apex at C5, degenerative changes of the endplates and facet joints, and grade 2 anterolisthesis C4 on C5 with no abnormal motion with flexion/extension. MRI showed a left sided C5-6 extramedullary mass measuring 11 x 11 x 15 mm causing spinal cord compression and neural foraminal narrowing. Her pain is worsening and refractory to physical therapy, gabapentin and methocarbamol. A C4-5 & C5-6 anterior cervical discectomy and fusion, C4-5 & C5-6 laminectomy for tumor resection, and C4-5 & C5-6 posterior fusion with instrumentation was performed. The tumor was completely removed in piecemeal fashion. Microscopic findings showed bland well differentiated cartilaginous neoplasm consistent with juxtacortical chondroma. Postoperative X-rays show partial reduction of C4-5 anterolisthesis and partial reversal of cervical kyphosis. The patient's radicular pain resolved and neck pain improved postoperatively but she still has some left sided neck pain and hand dysesthesias that are controlled with oral medication one year following surgery. Cervical chondromas are rare, benign cartilaginous tumors that may present with spinal cord or nerve root compression. They are more complex when they present in patients with co-existing spinal deformities. Maximal safe resection followed by spinal re-alignment and fixation without adjuvant chemotherapy or radiation is recommended in most cases. Close follow-up is recommended to monitor for recurrence.

Osteoid osteoma is a benign primary bone tumor of unknown etiology that occurs most commonly in males during adolescence and early adulthood. Osteoid osteoma affects the spine in 20% of cases, and may cause spinal deformity, stiffness, and pain that may sometimes be worst at night. We present a novel description of a partial laminectomy with cement augmentation after resection of an osteoid osteoma. A 22-year-old male with a past medical history of Hodgkin's lymphoma status post chemotherapy and radiation to the mediastinum, and right hip osteoblastoma treated with surgery and radiofrequency ablation presented with low back pain for five years with a recent onset of severe radicular symptoms. The pain was described as shooting and radiating laterally down the right leg to the mid-calf without bowel or bladder incontinence. He has a known right L5 laminar sclerotic lesion measuring 11 x 10 mm causing neuroforaminal narrowing and it kept increasing in size despite previous treatment with stereotactic radiosurgery and radiofrequency ablation. This lesion was metabolically active on positron emission tomography-computed tomography (PET-CT) imaging. His pain was worsening and was refractory to physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and radiation therapy. A right L5 partial laminectomy was performed to resect the abnormality in an en-bloc fashion. The lesion did not involve the inner cortex of the bone. Lamina reconstruction was achieved with bone cement augmentation for the preservation of vertebral column strength. Pathology was consistent with osteoid osteoma with marrow edema. Microscopic findings include bony trabeculae associated with prominent rimming and hypercellular fibroblastic stroma. No nuclear atypia, necrosis or appreciable mitotic activity was observed. The patient remains neurologically intact with significantly improved radicular symptoms and low back pain. Osteoid osteoma of the lamina may be resected using a partial laminectomy and cement augmentation done to preserve the integrity of the posterior ligamentous complex, prevent potential fracture of the pars interarticularis, and avoid the need for lumbar fusion in younger patients in whom this pathology is commonly found.

OBJECT Craniopharyngiomas and similar midline suprasellar tumors have traditionally been resected via transcranial approaches. More recently, expanded endoscopic endonasal transsphenoidal approaches have gained interest. Surgeons have advocated for both approaches, and at present there is no consensus whether one approach is superior to the other. The authors therefore compared surgical outcomes between craniotomy and endoscopic endonasal transsphenoidal surgery (EETS) for suprasellar tumors treated at their institution. METHODS A retrospective review of patients undergoing resection of suprasellar lesions at Cedars-Sinai Medical Center between 2000 and 2013 was performed. Patients harboring suspected craniopharyngioma were selected for extensive review. Other pathologies or predominantly intrasellar masses were excluded. Cases were separated into 2 groups, based on the surgical approach taken. One group underwent EETS and the other cohort underwent craniotomy. Patient demographic data, presenting symptoms, and previous therapies were tabulated. Preoperative and postoperative tumor volume was calculated for each case based on MRI. Student t-test and the chi-square test were used to evaluate differences in patient demographics, tumor characteristics, and outcomes between the 2 cohorts. To assess for selection bias, 3 neurosurgeons who did not perform the surgeries reviewed the preoperative imaging studies and clinical data for each patient in blinded fashion and indicated his/her preferred approach. These data were subject to concordance analysis using Cohen’s kappa test to determine if factors other than surgeon preference influenced the choice of surgical approach. RESULTS Complete data were available for 53 surgeries; 19 cases were treated via EETS, and 34 were treated via craniotomy. Patient demographic data, preoperative symptoms, and tumor characteristics were similar between the 2 cohorts, except that fewer operations for recurrent tumor were observed in the craniotomy cohort compared with EETS (17.6% vs 42.1%, p = 0.05). The extent of resection was similar between the 2 groups (85.6% EETS vs 90.7% craniotomy, p = 0.77). An increased rate of cranial nerve injury was noted in the craniotomy group (0% EETS vs 23.5% craniotomy, p = 0.04). Postoperative CSF leak rate was higher in the EETS group (26.3% EETS vs 0% craniotomy, p = 0.004). The progression-free survival curves (log-rank p = 0.99) and recurrence rates (21.1% EETS vs 23.5% craniotomy, p = 1.00) were similar between the 2 groups. Concordance analysis of cases reviewed by 3 neurosurgeons indicated that individual surgeon preference was the only factor that determined surgical approach (kappa coefficient −0.039, p = 0.762) CONCLUSIONS Surgical outcomes were similar for tumors resected via craniotomy or EETS, except that more CSF leaks occurred in the EETS cohort, whereas more neurological injuries occurred in the craniotomy cohort. Surgical approach appears to mostly reflect surgeon preference rather than specific tumor characteristics. These data support the view that EETS is a viable alternative to craniotomy, providing a similar extent of resection with less neurological injury.

Objective: Spontaneous spinal CSF leaks are an important cause of new-onset headaches. Such leaks are reported to be particularly common at the cervico-thoracic junction. The authors undertook a study to determine the significance of these cervico-thoracic CSF leaks. Methods: The patient population consisted of a consecutive group of 13 patients who underwent surgery for CSF leak repair based on CT myelography showing CSF extravasation at the cervico-thoracic junction but without any evidence of an underlying structural lesion. Results: The mean age of the 9 women and 4 men was 41.2 years. Extensive extrathecal longitudinal CSF collections were demonstrated in 11 patients. At surgery, small leaking arachnoid cysts were found in 2 patients. In the remaining 11 patients, no clear source of CSF leakage could be identified at surgery. Resolution of symptoms was achieved in both patients with leaking arachnoid cysts, but in only 3 of the 11 patients with negative intraoperative findings. Postoperative spinal imaging was performed in 9 of the 11 patients with negative intraoperative findings and showed persistence of the longitudinal intraspinal extradural CSF. Further imaging revealed the site of the CSF leak to be ventral to the thoracic spinal cord. Five of these patients underwent microsurgical repair of the ventral CSF leak with resolution of symptoms in all 5 patients. Conclusions: Cervico-thoracic extravasation of dye on myelography does not necessarily indicate the site of the CSF leak. Treatment directed at this site should not be expected to have a high probability of sustained improvement of symptoms.

Background: Multiple radiation-induced cavernous malformations of the cauda equina are extremely rare. A review of the literature suggested that the post-irradiation lumbosacral radiculopathy in our patient was most likely associated with a diagnosis of multiple radiation-induced cavernous malformations of the cauda equina. Case Description: A 76-year-old man with a remote history of abdominal radiation therapy presented with a 6-month history of progressively worsening right foot drop and balance impairment. Magnetic resonance imaging (MRI) revealed multiple enhancing areas of the cauda equina concerning for carcinomatous meningitis, however, cerebrospinal fluid (CSF) analysis was unrevealing. Intraoperative findings were consistent with multiple radiation-induced cavernous malformations of the cauda equina. Conclusions: Multiple radiation-induced cavernous malformations of the cauda equina may mimic carcinomatous or infectious meningitis. Clinicians should be suspicious of this diagnosis when CSF and MRI findings are inconsistent with metastatic disease or infectious meningitis in patients who present with radiculopathy and a history of radiation therapy.

We have developed and tested a system for real-time intra-operative optical identification and classification of brain tissues using time-resolved fluorescence spectroscopy (TRFS). A supervised learning algorithm using linear discriminant analysis (LDA) employing selected intrinsic fluorescence decay temporal points in 6 spectral bands was employed to maximize statistical significance difference between training groups. The linear discriminant analysis on in vivo human tissues obtained by TRFS measurements (N = 35) were validated by histopathologic analysis and neuronavigation correlation to pre-operative MRI images. These results demonstrate that TRFS can differentiate between normal cortex, white matter and glioma.

Background This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). Methods TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. Results Twenty-one patients were enrolled with 17 newly diagnosed (ND-GBM) and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33 % responders. TAA expression by qRT-PCR from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. Conclusions Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumors.

Adult, malignant brainstem gliomas are rare entities that often cause treatment conundrums due to the difficulty of surgical resection and, therefore, the absence of pathological diagnosis. This leads to a reliance on radiological imaging for diagnosis, which can often be unreliable. These shortcomings have made the treatment of brainstem gliomas challenging with unpredictable outcomes. The mainstay of treatment consists of chemotherapy and radiation; however, recurrence is inevitable. Predicting outcomes has been the major difficulty in treating these patients as adult malignant brainstem gliomas Grade II have a median survival between five to seven years while Grades III and IV are between 10-17 months (with some studies showing significantly longer survival in Grade III). Here, we present the case of a patient with the pathologic diagnosis of a right brachium pontis glioblastoma who had a remarkable survival of 73 months, whereas the expected median survival for these patients is 10-17 months.

The use of immunotherapy, specifically immune checkpoint inhibitors, is a rapidly emerging and evolving treatment modality for many solid tumor types. In this abstract, we describe a case of a 70 year old male with history of PD-L1 expressing metastatic poorly differentiated NSCLC treated with anti-PD-L1 therapy who was subsequently diagnosed with a glioblastoma with evidence of unexpected tumor infiltrating lymphocytes (TILs). The lung cancer was initially treated with combination chemotherapy with excellent response. This regimen was stopped prematurely due to significant treatment-related side effects. He then received the investigational anti-PD-L1 monoclonal antibody, MPDL3280A (Roche), under the Phase II Trial of MPDL3280A for PD-L1 positive locally advanced or metastatic NSCLC (NCT02031458). He experienced partial response without significant treatment-related side effects. Two weeks after completion of his 9th cycle of the study drug, he experienced altered mental status, personality changes, and confusion. A contrast brain MRI demonstrated a multifocal, rim-enhancing, left frontal lobe lesion with corpus callosal involvement. Of note, CT brain imaging prior to anti-PD-L1 study enrollment showed no evidence of abnormal enhancement. Stereotactic biopsy was performed with pathology showing glioblastoma with significant reactive lymphoid component noted (majority of lymphoid cells CD20 positive, scattered lymphocytes CD3 positive). He then underwent near image complete resection with pathology again demonstrating glioblastoma with 20-70% tumor necrosis, with 3 genomic alterations (CDKN2A/B loss; APCI1307K; TERT promoter – 124C > T) identified on Foundation One (Cambridge, MA) Next Generation Sequencing. This is the first reported case of a patient treated with anti-PD-L1 therapy for a high grade malignancy, who then developed a de novo glioblastoma with unusual biopsy findings of CD20 and CD3 positive TILs. Although more correlative studies are currently being performed, the immune implications for the use of immunotherapy for pre-treatment of glioblastomas may correspond to improved treatment response and patient outcomes.

BACKGROUND: Standards for residual tumor detection after resection of brain tumors with have not been established. In the postoperative period presence of contrast enhancement is suggestive of residual tumor. METHODS: We report a case of radiological postoperative metastatic tumor residual, which upon repeat resection was found to negative for presence of tumor. RESULTS: We report a case of a patient with metastatic tumor whose immediate postoperative MRI revealed enhancement in the peritumoral resection area which was suspicious for residual tumor. Repeat craniotomy for residual tumor was offered the following day after the first resection and the enhancing area was resected. Repeat postoperative MRI did not reveal any enhancing lesion. Final pathology revealed features of gliosis without any residual tumor. A follow up MRI 4 weeks later did not show any enhancing lesion either. This report suggests that the sensitivity of MRI may allow for detection of new lesions which are not tumor. CONCLUSIONS: Our results suggest that not all enhancing lesion in the immediate postoperative period represent tumors. Repeat surgery may be warranted only in those patients in whom the enhancement fails to subside with time.

Subdural empyema (SDE) is generally a disease of children and adolescents. The lack of specific findings in a child with SDE may lead to a rapidly fatal outcome as the result of a delay in diagnosis and treatment. The advent of newer imaging modalities, such as magnetic resonance imaging (MRI), and antibiotics has resulted in improved outcomes. This article reviews the current strategies for diagnosis and treatment of this condition. Current articles on SDE were reviewed and summarized. An overview is presented, followed by an emphasis on causation, pathogenesis, patient presentation, differential diagnosis, and treatment. The approach currently used at this institution for the management of pediatric patients with SDE is also described. Sinus and ear infections, trauma, intracranial surgery, and dental caries account for most cases of SDE. The clinician must be highly suspicious of SDE in the febrile child with neurologic signs and a recent history of ear or paranasal sinus infections. Aerobic and anaerobic streptococci are the most frequent causative organisms cultured from this infection. No definitive guidelines exist regarding duration of treatment, but most series report 2 to 6 weeks of intravenous antibiotics. Arguments have persisted over the use of burr hole drainage versus craniotomy for evacuation of subdural pus. The type of surgical procedure has little impact on the outcome, provided that it is performed early and allows for complete evacuation of the pus. The preoperative neurologic status, age of the patient, and time from presentation to treatment are the most significant determinants of outcome. Early diagnosis, early evacuation, and early use of antibiotics are the fundamental principles of SDE management.

Interventional magnetic resonance imaging (MRI) continues to make a profound impact on the practice of neurosurgery. We describe a new MRI modality, diffusion tensor imaging (DTI), which uses the diffusion energy of water to map white matter fibers. DTI has been established in other disorders such as metabolic, demyelinating and ischemic diseases. We describe the use of DTI in identifying white matter tracts such as optic radiations and avoiding them intraoperatively in 2 children with low-grade glial tumors.

Magnetic resonance imaging (MRI) has had a tremendous impact on neurosurgery, particularly for patients with brain tumors. Originally a diagnostic instrument, MRI technology recently has been incorporated into the neurosurgical operative setting. High-field (1.5-Tesla) systems offer imaging

OBJECTIVE AND IMPORTANCE Except for its role in shunt infections, Propionibacterium acnes has been of little interest to neurosurgeons. The rarity and indolent nature of focal intracranial infections by P. acnes limit their recognition. Three cases of serious intracranial infection due to this organism are described. CLINCAL PRESENTATION Three patients with histories of immunosuppression and neurosurgical procedures developed nonspecific, delayed presentations (5 wk to 5 yr after surgery) of intracranial infections. In two patients, radiological investigations showed enhancing lesions that were later found to be brain abscesses. A subdural empyema was found in the third patient. INTERVENTION All three patients underwent surgical drainage of the purulent collections. P. acnes was isolated in each case, and each patient was treated with a 6-week course of intravenous penicillin. All three patients made good recoveries, and subsequent imaging showed no recurrence of the infectious collections. CONCLUSION P. acnes is an indolent organism that may rarely cause severe intracranial infections. This organism should be suspected when an intracranial purulent collection is discovered in a patient with a history of neurosurgical procedures. Immunosuppressed patients may be susceptible to this otherwise benign organism. Surgical drainage and treatment with intravenous penicillin should be considered standard therapy.

The purpose of this study was to conduct a randomized clinical trial to assess whether a self-management group intervention can improve mood, self-efficacy, and activity in people with central vision loss due to age-related macular degeneration (AMD). Ninety-two elderly patients with AMD (average age=79) from a university ophthalmology clinic were randomly assigned to the self-management intervention (n=44) or to a wait-list (n=48). All patients were legally blind in at least one eye. The intervention consisted of 6 weekly 2-hour group sessions providing education about the disease, group discussion, and behavioral and cognitive skills training to address barriers to independence. All participants eventually completed the intervention allowing pre-post comparisons for all patients. The battery of measures included the Profile of Mood States (POMS); Quality of Well-Being Scale; and assessments of self-efficacy, participation in activities, and use of vision aids. Participants' initial psychological distress was high (mean total POMS=59.72) and similar to distress experienced by other serious chronic illness populations (e.g. cancer, bone marrow transplant). Analysis of covariance testing the primary hypothesis revealed that intervention participants experienced significantly (p=.04) reduced psychological distress (pre $$\bar x = 61.45$$ ; post $$\bar x = 51.14$$ ) in comparison with wait-list controls (pre $$\bar x = 57.72$$ ; post $$\bar x = 62.32$$ ). Intervention participants also experienced improved (p=.02) self-efficacy (pre $$\bar x = 70.16$$ ; post $$\bar x = 77.27$$ ) in comparison with controls (pre $$\bar x = 67.71$$ ; post $$\bar x = 69.07$$ ). Further, intervention participants increased their use of vision aids (p

Asymptomatic intracranial abnormalities are increasingly becoming a focus of attention with the utilization of high-resolution imaging. The concurrence of tumor and aneurysm has been described, largely, by case reports and single-surgeon experiences. Recent papers have outlined the ethics of incidental findings and possible treatment algorithms. Incidental finding of an aneurysm occurs most commonly in patients with meningiomas, pituitary adenomas, and gliomas. Such an association may explain the mechanisms of aneurysm formation, growth, and rupture in acromegalic patients; however, insufficient data are available to link aneurysm with either glioma or meningioma.

The goal of the study was to elucidate the spinal manifestations of spontaneous intracranial hypotension.The authors reviewed the medical records and imaging studies of 338 consecutive patients with spontaneous intracranial hypotension who were evaluated at their institution between 2001 and 2010.Twenty patients (6%; mean age 35.8 [range 16 to 60 years]; 5 males and 15 females) had convincing signs or symptoms referable to the spinal cord or spinal nerve roots. The spinal manifestations consisted of radiculopathy in 11 patients (unilateral in 8 and bilateral in 3), myelopathy in 8 patients, and bibrachial amyotrophy in 1 patient. The cervical spine was involved in 12 patients, the thoracic spine in 5, and the lumbosacral spine in 3. The spinal symptoms were positional in only 3 patients. The spinal manifestations occurred around the time of the headache onset in 16 patients, and months to years after the positional headache had resolved in 4 patients. A large extrathecal CSF collection causing compression of the spinal cord or nerve root was responsible for the spinal manifestations in the majority of patients. Treatment of the spinal CSF leak resulted in resolution of the spinal manifestations along with the headache, except for those in the patient with bibrachial amyotrophy.Spinal manifestations are uncommon in cases of spontaneous intracranial hypotension, occurring in about 6% of patients, but myelopathy and radiculopathy involving all spinal segments do occur. Unlike the headache, the spinal manifestations usually are not positional and are caused by mass effect from an extradural CSF collection.

High-resolution neuroimaging modalities are used often in studies involving healthy volunteers. Subsequently, a significant increase in the incidental discovery of asymptomatic intracranial abnormalities raised the important ethical issues of when follow-up and treatment may be necessary. We examined the literature to establish a practical set of criteria for approaching incidental findings. Our objective is to develop an algorithm for when follow-up may be important and to provide recommendations that would increase the likelihood of follow-up. A systematic literature search was performed using the PubMed and MEDLINE databases to identify articles describing brain tumors and intracranial aneurysms. The treatment algorithm we present suggests that incidental intracranial masses suspicious for glioma should be biopsied or resected, while other masses are to be followed with serial imaging based on the expected growth pattern. Lack of follow-up can result in adverse outcomes that can be mitigated by using technology to facilitate communication and improve follow-up care. The importance of training physicians to be good communicators is also stressed. New technology including automated telephone systems, texting and email will improve access to patients and hopefully encourage compliance and follow-up.

BACKGROUND: For patients with carcinomatous meningitis, treatment needs to be expedited, especially for patients with hematologic malignancies. Using neuroendoscopy as an adjunct at the time of ventricular reservoir placement allows immediate confirmation of catheter placement rather than waiting for a post-operative CT scan and waiting for contact from the surgeon. This confirmation allows delivery of intrathecal chemotherapy at the time of surgery saving the patient delays in chemotherapy delivery and potential side effects of the first chemotherapy delivery, as they are still under general anesthesia. Delay in confirmation of appropriate catheter placement or poor catheter placement delays treatment; this technique also allows the surgeon and oncologist to know definitively that the reservoir is properly positioned and functional at the time of surgery. METHODS: Five patients with carcinomatous meningitis who were candidates for intrathecal chemotherapy were prospectively followed. All of them had a ventricular reservoir placed with neuroendoscopy and immediate delivery of intrathecal chemotherapy. RESULTS: All five of the patients had a reservoir placed without incident. Four of the patients had chemotherapy delivered during surgery without incident. For one patient, there was a pharmacy delay, but the chemotherapy was delivered while the patient was still recovering from anesthesia. There were no complications related to the treatment. CONCLUSIONS: Neuroendoscopy has the power to immediately confirm proper ventricular placement of an Ommaya reservoir and to safely allow the delivery of intrathecal chemotherapy in the operating room. This technique eliminates delays in chemotherapy delivery and is safe.

Object The role of cerebral revascularization remains unclear in symptomatic occlusive cerebrovascular disease refractory to medical therapy. Despite the disappointing findings of the Cooperative Study on Extracranial–Intracranial Bypass, a subpopulation of patients with ischemic cerebrovascular disease and poor hemodynamic reserve may benefit from extracranial–intracranial (EC–IC) bypass. The authors reviewed the records of 65 patients who underwent 71 EC–IC bypass procedures at their institution over the past 6 years. Methods All patients except one presented with repeated transient ischemic attacks (TIAs) that were referable to the involved vascular region. Eight patients underwent EC–IC bypass urgently for “crescendo” TIAs refractory to anti-platelet and anticoagulation therapy. Indications for surgery included cervical internal carotid artery (ICA) occlusion in 28, supraclinoid ICA stenosis in two, middle cerebral artery stenosis or occlusion in 14, moyamoya disease in 18, and ICA dissection in three. Cerebral angiography demonstrated poor collateral flow to the involved region in each case. There were no postoperative strokes or deaths in this series. Following EC–IC bypass, the vast majority (95.4%) of patients experienced cessation of their ischemic events and stabilization of preexisting neurological dysfunction. Of the eight patients who underwent EC–IC bypass urgently for crescendo TIAs, two awoke with increased neurological deficits that improved rapidly within 24 hours of surgery. Conclusions Although the Cooperative Study failed to show benefit from this treatment modality, the authors have continued to perform EC–IC bypass in certain cases. Carefully selected individuals with occlusive cerebrovascular disease and persistent ischemic symptoms refractory to maximal medical therapy appear to benefit from cerebral revascularization.

OBJECTIVE Therapy with intrathecal colloidal gold has been used in the past as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. We describe the long-term follow-up period of a series of patients treated with intrathecal colloidal gold and emphasize the high incidence of delayed cerebrovascular complications and their management. METHODS Between 1967 and 1970, 14 children with posterior fossa medulloblastoma underwent treatment at the University of Minnesota. Treatment consisted of surgical resection, external beam radiotherapy, and intrathecal colloidal gold. All patients underwent long-term follow-up periods. RESULTS Of the 14 original patients, 6 died within 2 years of treatment; all experienced persistent or recurrent disease. The eight surviving patients developed significant neurovascular complications 5 to 20 years after treatment. Three patients died as a result of aneurysmal subarachnoid hemorrhage, and five developed ischemic symptoms from severe vasculopathy that resembled moyamoya disease. CONCLUSION Although therapy with colloidal gold resulted in long-term survival in a number of cases of childhood medulloblastoma, our experience suggests that the severe cerebrovascular side effects fail to justify its use. The unique complications associated with colloidal gold therapy, as well as the management of these complications, are presented. We recommend routine screening of any long-term survivors to exclude the presence of an intracranial aneurysm and to document the possibility of moyamoya syndrome.

OBJECTIVE Intracranial aneurysm rupture during placement of Guglielmi detachable coils has been reported, but the management and consequences of this event have not been extensively described. We present our experience with this feared complication and report possible neuroradiological and neurosurgical interventions to improve outcomes. METHODS We retrospectively reviewed the records for 701 patients with 734 intracranial aneurysms that were treated with endovascular coiling, during a 6-year period, in the metropolitan Minneapolis-St. Paul (Minnesota) area. This analysis revealed 10 cases of perforation during coiling. The management and outcomes were recorded, and the pertinent literature was reviewed. RESULTS All 10 cases involved previously ruptured aneurysms. This complication occurred sporadically and was not observed in the first 100 cases. Perforation occurred during microcatheterization of the aneurysm in two cases and during coil deposition in eight cases. Seven of the perforated aneurysms were located in the anterior circulation and three in the posterior circulation. Six of the 10 patients made good or fair recoveries; all three patients with posterior circulation lesions died immediately after rehemorrhage. Elevated intracranial pressure (ICP) was noted for all five patients with intraventricular catheters in place. Bilateral pupil dilation and profound hemodynamic changes were noted for eight patients. Coiling was rapidly completed, and total or nearly total occlusion was achieved in all cases. Emergency ventriculostomy was performed to rapidly reduce increased ICP for two patients, both of whom made good recoveries. Hemodynamic and angiographic factors after perforation, such as prolonged systemic hypertension, persistent dye extravasation after deployment of the first Guglielmi detachable coil, and persistent prolongation of contrast dye transit time (suggesting ongoing ICP elevation), were correlated with poor outcomes. CONCLUSION Previously ruptured aneurysms seem to be more susceptible to endovascular treatment-related perforation than are unruptured lesions. Worse prognoses are associated with iatrogenic rupture during coiling of posterior circulation lesions, compared with those in the anterior circulation. When perforation is recognized, the definitive treatment seems to be reversal of anticoagulation therapy and completion of Guglielmi detachable coil embolization. Immediate neurosurgical intervention is limited in these cases and focuses on decreasing ICP via emergency ventriculostomy. However, these measures may be life-saving, and neurosurgical assistance must be readily available during treatment of these cases.

2087 Background: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1 and/or HLA-A2 positive glioblastoma (GBM) patients with gross total resection were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals in the axilla region after a standard treatment with concurrent temozolomide (TMZ) and radiation therapy for newly diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 ND-GBM and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33% responders. TAA expression by qRT-PCR showed all patient tumors expressed at least three TAA with 75% expressing all six. Correlations of increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and HER2 were observed. A decrease or absence of CD133 expression was seen in five patients who underwent a second resection. As of February 1, 2012, six of 16 ND-GBM patients showed no evidence of tumor recurrence (44-63 months). Median progressive free survival (PFS) in newly diagnosed patients was 16.9 months with a two-year PFS rate was 43.8% (95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumor.

2084 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers and have a modest impact to extend overall survival. We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu, and this is a presentation of the final results of our clinical trial. Methods: Patients with glioblastoma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Twenty three patient with glioblastoma received therapy including 8 with newly diagnosed disease (35%) and 15 with recurrent disease (65%) were evaluable. Immune response data is available for 20/23 patients although survival data is present for all. One grade 3 SAE of fever and chills was noted otherwise therapy was well tolerated. Within the newly diagnosed GBM cohort the median overall survival (OS) was 25.5 months (15,31+), and within the recurrent GBM cohort, the median OS was 16 months (8,23+). Among the recurrent GBM an increase of >1.5 X baseline interferon gamma production post vaccination was associated with a prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months (9,27) in 8/12 patients. Conclusions: We were able to generate an immune response in 25% of patients which is lower than what we have seen in previous trials and suggests a limited synergy with local control. However, within the recurrent GBM cohort we did find prolonged survival in both groups with an increased survival noted in immune responders demonstrating the potential for this therapy.

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.

2032 Background: Previous immunotherapy trials for malignant glioma (Yu, J.,et al, Cancer Res. 2001;61:842–7 and 2004;64;4973–9) have demonstrated efficacy in generating a tumor specific immune response. Here we set out to determine feasibility and immunogenecity of dendritic vaccination with specific glioma-associated antigens. Methods: The goal of this study is to use tumor associated antigens (TAA) known to be expressed on gliomas and pulse dendritic cells with these antigens in an MHC compatible fashion using epitopes of HER-2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, HLA-A1 and/or HLA-A2-positive patients with newly diagnosed or recurrent glioblastoma were eligible. Leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells in culture, pulsed with tumor peptide, and then administered intradermally three times at 2-week intervals. Results: Twenty patients, 15 males and five females, were enrolled between November 2006 and December 2008 with one screen failure. The median patient age was 47 years (range: 26–65) and patients had a median Karnofsky performance status of 90% (range: 90–100). There were 16 newly diagnosed and three recurrent glioblastoma multiforme (GBM) patients, who underwent surgery prior to vaccination. Our data on 19 patients and 54 courses of dendritic cell vaccines demonstrate zero grade 3 /4 toxicities that were attributable to the vaccination. Thirteen patients continue to have stable disease (ranging from 15 to 115 weeks), six patients have demonstrated tumor progression. Median survival from surgery was 60 weeks (ranging from 26 to 115 weeks). Of 15 patients tested to date, six patients demonstrated an antigen-specific cytotoxic T-cell response to at least one antigen after vaccination. Only 17% of CTL responders (1/6) demonstrated tumor progression compared to 56% (5/9) of nonresponders to date. Conclusions: This phase I study demonstrated the feasibility, safety, and bioactivity of a TAA-pulsed dendritic cell vaccine for patients with glioblastoma progression free survival correlated with CTL response. [Table: see text]

2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of ra...