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Adília Hormigo, David R. Friedlander, Perry A. Brittis, David Zagzag and Martin Grumet

Object. A variant of C6 glioma cells, C6R-G/H cells express hygromycin phosphotransferase (HPT) and appear to have reduced tumorigenicity in the embryonic brain. The goal of this study was to investigate their reduced capacity to generate tumors in the adult rat brain.

Methods. Cell lines were implanted into rat brains and tumorigenesis was evaluated. After 3 weeks, all rats with C6 cells showed signs of neurological disease, whereas rats with C6R-G/H cells did not and were either killed then or allowed to survive until later. Histological studies were performed to analyze tumor size, malignancy, angiogenesis, and cell proliferation. Cells isolated from rat brain tumors were analyzed for mutation to HPT by testing their sensitivity to hygromycin.

Conclusions. The results indicate that HPT suppresses tumor formation. Three weeks after implantation, only 44% of animals implanted with C6R-G/H cells developed tumors, whereas all animals that received C6 glioma cells developed high-grade gliomas. The C6R-G/H cells filled a 20-fold smaller maximal cross-sectional area than the C6 cells, and exhibited less malignant characteristics, including reduced angiogenesis, mitosis, and cell proliferation. Similar results were obtained in the brain of nude rats, indicating that the immune system did not play a significant role in suppressing tumor growth. The combination of green fluorescent protein (GFP) and HPT was more effective in suppressing tumorigenesis than either plasmid by itself, indicating that the GFP may protect against inactivation of the HPT. Interestingly, hygromycin resistance was lost in tumor cells that were recovered from a group of animals in which C6R-G/H cells formed tumors, confirming the correlation of HPT with reduced tumorigenicity.

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Conor Grady, Omar Tanweer, David Zagzag, Jafar J. Jafar, Paul P. Huang and Douglas Kondziolka

Stereotactic radiosurgery is widely used to treat cerebral arteriovenous malformations (AVMs), with the goal of complete angiographic obliteration. A number of case series have challenged the assumption that absence of residual AVM on follow-up angiograms is consistent with elimination of the risk of hemorrhage. The authors describe 3 cases in which patients who had angiographic evidence of AVM occlusion presented with late hemorrhage in the area of their prior lesions. They compare the radiographic, angiographic, and histological features of these patients with those previously described in the literature.

Delayed hemorrhage from the tissue of occluded AVMs has been reported as early as 4 and as late as 11 years after initial stereotactic radiosurgery. In all cases for which data are available, hemorrhage occurred in the area of persistent imaging findings despite negative findings on conventional angiography. The hemorrhagic lesions that were resected demonstrated a number of distinct histological findings.

While rare, delayed hemorrhage from the tissue of occluded AVMs may occur from a number of distinct, angiographically occult postirradiation changes. The hemorrhages in the authors' 3 cases were symptomatic and localized. The correlation of histological and imaging findings in delayed hemorrhage from occluded AVMs is an area requiring further investigation.

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Ashwatha Narayana, Deborah Gruber, Saroj Kunnakkat, John G. Golfinos, Erik Parker, Shahzad Raza, David Zagzag, Patricia Eagan and Michael L. Gruber

Object

The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM.

Methods

From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m2 daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m2 on Days 1–7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle.

Results

The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients.

Conclusions

The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

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Ali R. Rezai, Henry H. Woo, Mark Lee, Henry Cohen, David Zagzag and Fred J. Epstein

✓ Ependymomas are rare central nervous system (CNS) neoplasms that occasionally disseminate along the neuraxis or to extraneural sites. Definitive criteria predictive of dissemination have yet to be determined. One hundred forty patients with CNS ependymoma (88 primary spinal and 52 primary intracranial tumors) were surgically treated by the senior author (F.J.E.) between 1986 and 1994. Sixteen patients (11.4%) demonstrated tumor dissemination. The disseminated group consisted of 11 (12.5%) of 88 primary spinal and five (9.6%) of 52 primary intracranial ependymomas. The authors retrospectively reviewed the patients with CNS ependymoma and have identified several characteristics associated with dissemination from the primary tumor site. The mean time from diagnosis to dissemination was 6.8 years. The patients with disseminated disease were younger (16.8 vs. 28.3 years old, p = 0.02), had fewer gross-total resections (29% vs. 68%, p = 0.015), and had tumors with higher proliferative indices (MIB-1 staining, 13.14% vs. 2.06%, p = 0.02). High-grade tumors had a mean proliferation index of 21%, versus 2.4% and 1.6% for myxopapillary and low-grade tumors, respectively (p = 0.0003). In contrast to previous studies, tumor histology was the most significant variable for time to dissemination as determined by multivariate analysis (p = 0.008). Myxopapillary and high-grade tumors were 3.6 and 5.6 times more likely to have a shorter time to dissemination than low-grade tumors. In addition, dissemination is associated with a worse prognosis. At follow-up review, 31% of patients with disseminated disease had died compared to 7% of patients without dissemination (p = 0.04). It is concluded that younger patients with subtotal resections, myxopapillary or high-grade histology, and tumors with high proliferative indices are at substantial risk for the development of disseminated disease during their clinical course.

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Robert J. Bollo, Jonathan L. Berliner, Ingeborg Fischer, Daniel K. Miles, Elizabeth A. Thiele, David Zagzag and Howard L. Weiner

Subependymal giant cell tumors (SGCTs) are observed in 5–20% of patients with tuberous sclerosis complex (TSC) but account for ~ 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period.

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Joseph Haynes, Eytan Raz, Omar Tanweer, Maksim Shapiro, Rogelio Esparza, David Zagzag, Howard A. Riina, Christine Henderson, Kaitlyn Lillemoe, Cen Zhang, Sara Rostanski, Shadi Yaghi, Koto Ishida, Jose Torres, Brian Mac Grory and Erez Nossek

OBJECTIVE

The carotid web (CW) is an underrecognized source of cryptogenic, embolic stroke in patients younger than 55 years of age, with up to 37% of these patients found to have CW on angiography. Currently, there are little data detailing the best treatment practices to reduce the risk of recurrent stroke in these patients. The authors describe their institutional surgical experience with patients treated via carotid endarterectomy (CEA) for a symptomatic internal carotid artery web.

METHODS

A retrospective, observational cohort study was performed including all patients presenting to the authors’ institution with CW. All patients who were screened underwent either carotid artery stenting (CAS) or CEA after presentation with ischemic stroke from January 2019 to February 2020. From this sample, patients with suggestive radiological features and pathologically confirmed CW who underwent CEA were identified. Patient demographics, medical histories, radiological images, surgical results, and clinical outcomes were collected and described using descriptive statistics.

RESULTS

A total of 45 patients with symptomatic carotid lesions were treated at the authors’ institution during the time period. Twenty patients underwent CAS, 1 of them for a CW. Twenty-five patients were treated via CEA, and of these, 6 presented with ischemic strokes ipsilateral to CWs, including 3 patients who presented with recurrent strokes. The mean patient age was 55 ± 12.6 years and 5 of 6 were women. CT angiography or digital subtraction angiography demonstrated the presence of CWs ipsilateral to the stroke in all patients. All patients underwent resection of CWs using CEA. There were no permanent procedural complications and no patients had stroke recurrence following intervention at the latest follow-up (mean 6.1 ± 4 months). One patient developed mild tongue deviation most likely related to retraction, with complete recovery at follow-up.

CONCLUSIONS

CEA is a safe and feasible treatment for symptomatic carotid webs and should be considered a viable alternative to CAS in this patient population.

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Ashwatha Narayana, Patrick Kelly, John Golfinos, Erik Parker, Glyn Johnson, Edmond Knopp, David Zagzag, Ingeborg Fischer, Shahzad Raza, Praveen Medabalmi, Patricia Eagan and Michael L. Gruber

Object

Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas.

Methods

Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/ kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy.

Results

At a median follow-up of 7.5 months (range 1–19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1–7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval [CI] 2.3–7.7) and 9 (95% CI 7.6–10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease.

Conclusions

Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.