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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

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.

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.

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.

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.

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.