Hemorrhagic vestibular schwannomas are rare entities, with only a few case reports in the literature during the last 25 years. The authors review the literature on vestibular schwannoma hemorrhage and the presenting symptoms of this entity, which include headache, nausea, vomiting, sudden cranial nerve dysfunction, and ataxia. A very unusual case is presented of a 36-year-old man, who unlike most of the patients reported in the literature, had clinically silent vestibular schwannoma hemorrhage. The authors also discuss the management issues involved in more than 1000 vestibular schwannomas treated at their institution during a 25-year period.
Hemorrhagic vestibular schwannoma: an unusual clinical entity
Dean Chou, Prakash Sampath, and Henry Brem
Heterotransplantation of malignant human gliomas in neonatal rats
Rafael J. Tamargo, Jonathan I. Epstein, and Henry Brem
✓ Three human glioma cell lines (TE-671 medulloblastoma, U-87 MG glioblastoma, and U-373 MG glioblastoma) were transplanted to the quadrigeminal cistern of the brain in 37 newborn Sprague-Dawley rats and to the subcutaneous space in 30 of their siblings. Two of the three gliomas (the TE-671 medulloblastoma and the U-87 MG glioblastoma) grew both intracranially and subcutaneously. The U-373 MG glioblastoma did not grow in either site. The resulting tumors expressed unique morphological features characteristic of their tissue of origin. The newborn rat represents a model for the heterologous transplantation of human gliomas, providing a biological window for the study of these lesions.
The role of minocycline in the treatment of intracranial 9L glioma
Jon D. Weingart, Eric P. Sipos, and Henry Brem
✓ This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection.
Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.
The 5-factor modified frailty index: an effective predictor of mortality in brain tumor patients
Adham M. Khalafallah, Sakibul Huq, Adrian E. Jimenez, Henry Brem, and Debraj Mukherjee
Health measures such as the Charlson Comorbidity Index (CCI) and the 11-factor modified frailty index (mFI-11) have been employed to predict general medical and surgical mortality, but their clinical utility is limited by the requirement for a large number of data points, some of which overlap or require data that may be unavailable in large datasets. A more streamlined 5-factor modified frailty index (mFI-5) was recently developed to overcome these barriers, but it has not been widely tested in neuro-oncology patient populations. The authors compared the utility of the mFI-5 to that of the CCI and the mFI-11 in predicting postoperative mortality in brain tumor patients.
The authors retrospectively reviewed a cohort of adult patients from a single institution who underwent brain tumor surgery during the period from January 2017 to December 2018. Logistic regression models were used to quantify the associations between health measure scores and postoperative mortality after adjusting for patient age, race, ethnicity, sex, marital status, and diagnosis. Results were considered statistically significant at p values ≤ 0.05. Receiver operating characteristic (ROC) curves were used to examine the relationships between CCI, mFI-11, and mFI-5 and mortality, and DeLong’s test was used to test for significant differences between c-statistics. Spearman’s rho was used to quantify correlations between indices.
The study cohort included 1692 patients (mean age 55.5 years; mean CCI, mFI-11, and mFI-5 scores 2.49, 1.05, and 0.80, respectively). Each 1-point increase in mFI-11 (OR 4.19, p = 0.0043) and mFI-5 (OR 2.56, p = 0.018) scores independently predicted greater odds of 90-day postoperative mortality. Adjusted CCI, mFI-11, and mFI-5 ROC curves demonstrated c-statistics of 0.86 (CI 0.82–0.90), 0.87 (CI 0.83–0.91), and 0.87 (CI 0.83–0.91), respectively, and there was no significant difference between the c-statistics of the adjusted CCI and the adjusted mFI-5 models (p = 0.089) or between the adjusted mFI-11 and the adjusted mFI-5 models (p = 0.82). The 3 indices were well correlated (p < 0.01).
The adjusted mFI-5 model predicts 90-day postoperative mortality among brain tumor patients as well as our adjusted CCI and adjusted mFI-11 models. The simplified mFI-5 may be easily integrated into clinical workflows to predict brain tumor surgery outcomes in real time.
A novel intramedullary spinal cord tumor model: functional, radiological, and histopathological characterization
Gaurav Mavinkurve, Gustavo Pradilla, Federico G. Legnani, Betty M. Tyler, Carlos A. Bagley, Henry Brem, and George Jallo
Survival rates for high-grade intramedullary spinal cord tumors (IMSCTs) are approximately 30%, and optimal therapy has yet to be determined. Development of a satisfactory intramedullary tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel intramedullary model in rabbits.
Ten New Zealand white rabbits were randomized to receive an intramedullary injection of either 25 µl of VX2 carcinoma cells (500,000 cells; six rabbits) or 25 ml of medium (Dulbecco modified Eagle medium; four rabbits) into the midthoracic spinal cord. Postoperatively the rabbits were evaluated twice daily for neurological deficits. High-resolution magnetic resonance (MR) images were acquired preoperatively and weekly postoperatively until onset of paraparesis, at which point the animals were killed, and the midthoracic spines were processed for histopathological examination.
The VX2-carcinoma cells grew in 100% of animals injected and resulted in a statistically significant mean onset of paraparesis of 16.8 ± 1.7 days (p = 0.0035, log-rank test), compared with animals in the control group in which neurological deficits were absent by Day 45. Contrast-enhanced T1-weighted MR imaging best demonstrated space-occupying intramedullary lesions and histopathological findings confirmed the intramedullary location of the tumor. Animals in the control group exhibited no functional, radiographic, or pathological signs of tumor.
Progression to paraparesis was consistent in all the VX2-injected animals, with predictable onset of paraparesis occurring approximately 17 days postinjection. Histopathological and radiological characteristics of the VX2 intramedullary tumor are comparable with those of aggressive primary human IMSCTs. Establishment of this novel animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of IMSCTs.
Late-onset facial nerve degeneration after vestibular schwannoma surgery: incidence, putative mechanisms, and prevention
Prakash Sampath, Laurence D. Rhines, Michael J. Holliday, Henry Brem, and Donlin M. Long
Delayed facial nerve dysfunction after vestibular schwannoma surgery is a poorly understood phenomenon that has been reported to occur in 15 to 29% of patients undergoing microsurgery. It is a condition characterized by spontaneous deterioration of facial nerve function in a patient who has otherwise normal or near-normal facial function in the immediate postoperative period. This delayed paralysis is generally reported to occur in the first few days postsurgery, with the majority of patients eventually recovering their immediate postoperative facial function. However, infrequently, it can also occur more than 1 week after surgery (so-called late-onset facial nerve palsy).
The authors reviewed facial nerve outcome in 611 patients who underwent microsurgery between 1973 and 1994. The facial nerve was anatomically preserved in 596 patients (97.5%), and 90% of patients had House-Brackmann Grade 1 or 2 function 1 year after surgery. Late-onset facial dysfunction was seen in 13 patients (2.1%). All of these had significant deterioration in facial nerve function between 1 and 4 weeks postoperatively, and all showed improvement by 1 year. In this study, the focus on these patients who developed late-onset facial palsy. The incidence, treatment strategies, and outcomes will be discussed with emphasis on possible pathophysiological mechanisms that contribute to this relatively rare condition.
Facial nerve injury in acoustic neuroma (vestibular schwannoma) surgery: etiology and prevention
Prakash Sampath, Michael J. Holliday, Henry Brem, John K. Niparko, and Donlin M. Long
Facial nerve injury associated with acoustic neuroma surgery has declined in incidence but remains a clinical concern. A retrospective analysis of 611 patients surgically treated for acoustic neuroma between 1973 and 1994 was undertaken to understand patterns of facial nerve injury more clearly and to identify factors that influence facial nerve outcome.
Anatomical preservation of the facial nerve was achieved in 596 patients (97.5%). In the immediate postoperative period, 62.1% of patients displayed normal or near-normal facial nerve function (House-Brackmann Grade 1 or 2). This number rose to 85.3% of patients at 6 months after surgery and by 1 year, 89.7% of patients who had undergone acoustic neuroma surgery demonstrated normal or near-normal facial nerve function.
The surgical approach appeared to have no effect on the incidence of facial nerve injury. Poor facial nerve outcome (House-Brackmann Grade 5 or 6) was seen in 1.58% of patients treated via the suboccipital approach and in 2.6% of patients treated via the translabyrinthine approach. When facial nerve outcome was examined with respect to tumor size, there clearly was an increased incidence of facial nerve palsy seen in the immediate postoperative period in cases of larger tumors: 60.8% of patients with tumors smaller than 2.5 cm had normal facial nerve function, whereas only 37.5% of patients with tumors larger than 4 cm had normal function. This difference was less pronounced, however, 6 months after surgery, when 92.1% of patients with tumors smaller than 2.5 cm had normal or near normal facial function, versus 75% of patients with tumors larger than 4 cm.
The etiology of facial nerve injury is discussed with emphasis on the pathophysiology of facial nerve palsy. In addition, on the basis of the authors' experience with these complex tumors, techniques of preventing facial nerve injury are discussed.
Improvement in the standard treatment for experimental glioma by fusing antibody Fc domain to endostatin
Rachel Grossman, Betty Tyler, Lee Hwang, Patti Zadnik, Bachchu Lal, Kashi Javaherian, and Henry Brem
Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods.
Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect.
Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post–tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5–9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors.
Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.
Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma
Rita Sattler, Betty Tyler, Benjamin Hoover, Luke T. Coddington, Violette Recinos, Lee Hwang, Henry Brem, and Jeffrey D. Rothstein
Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well.
In this study 9L gliosarcoma cells were treated with a glutamate transporter upregulating agent, thiamphenicol, an antibiotic approved in Europe, which has been shown previously to increase glutamate transporter expression and has recently been validated in a human Phase I biomarker trial for glutamate transporter upregulation. Cells were monitored in vitro for glutamate transporter levels and cell proliferation. In vivo, rats were injected intracranially with 9L cells and were treated with increasing doses of thiamphenicol. Animals were monitored for survival. In addition, postmortem brain tissue was analyzed for tumor size, glutamate transporter levels, and neuron count.
Thiamphenicol showed little effects on proliferation of 9L gliosarcoma cells in vitro and did not change glutamate transporter levels in these cells. However, when delivered locally in an experimental glioma model in rats, thiamphenicol dose dependently (10–5000 μM) significantly increased survival up to 7 days and concomitantly decreased tumor size from 46.2 mm2 to 10.2 mm2 when compared with lesions in nontreated controls. Furthermore, immunohistochemical and biochemical analysis of peritumoral tissue confirmed an 84% increase in levels of glutamate transporter protein and a 72% increase in the number of neuronal cells in the tissue adjacent to the tumor.
These results show that increasing glutamate transporter expression in peritumoral tissue is neuroprotective. It suggests that glutamate transporter upregulation for the treatment of gliomas should be further investigated and potentially be part of a combination therapy with standard chemotherapeutic agents.
Factors involved in maintaining prolonged functional independence following supratentorial glioblastoma resection
Kaisorn L. Chaichana, Aditya N. Halthore, Scott L. Parker, Alessandro Olivi, Jon D. Weingart, Henry Brem, and Alfredo Quinones-Hinojosa
The median survival duration for patients with glioblastoma is approximately 12 months. Maximizing quality of life (QOL) for patients with glioblastoma is a priority. An important, yet understudied, QOL component is functional independence. The aims of this study were to evaluate functional outcomes over time for patients with glioblastoma, as well as identify factors associated with prolonged functional independence.
All patients who underwent first-time resection of either a primary (de novo) or secondary (prior lower grade glioma) glioblastoma at a single institution from 1996 to 2006 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score ≥ 80 were included. Kaplan-Meier, log-rank, and multivariate proportional hazards regression analyses were used to identify associations (p < 0.05) with functional independence (KPS score ≥ 60) following glioblastoma resection.
The median follow-up duration time was 10 months (interquartile range [IQR] 5.6–17.0 months). A patient's preoperative (p = 0.02) and immediate postoperative (within 2 months) functional status was associated with prolonged survival (p < 0.0001). Of the 544 patients in this series, 302 (56%) lost their functional independence at a median of 10 months (IQR 6–16 months). Factors independently associated with prolonged functional independence were: preoperative KPS score ≥ 90 (p = 0.004), preoperative seizures (p = 0.002), primary glioblastoma (p < 0.0001), gross-total resection (p < 0.0001), and temozolomide chemotherapy (p < 0.0001). Factors independently associated with decreased functional independence were: older age (p < 0.0001), coexistent coronary artery disease (p = 0.009), and incurring a new postoperative motor deficit (p = 0.009). Furthermore, a decline in functional status was independently associated with tumor recurrence (p = 0.01).
The identification and consideration of these factors associated with prolonged functional outcome (preoperative KPS score ≥ 90, seizures, primary glioblastoma, gross-total resection, temozolomide) and decreased functional outcome (older age, coronary artery disease, new postoperative motor deficit) may help guide treatment strategies aimed at improving QOL for patients with glioblastoma.