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Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema

Rafael J. Tamargo, Allen K. Sills Jr., Carla S. Reinhard, Michael L. Pinn, Donlin M. Long, and Henry Brem

✓ Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically.

Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 µg of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections.

The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.

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Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain

Henry Brem, Rafael J. Tamargo, Alessandro Olivi, Michael Pinn, Jon D. Weingart, Moody Wharam, and Jonathan I. Epstein

✓ Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomologus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.

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The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

Stuart A. Grossman, Carla Reinhard, O. Michael Colvin, Mark Chasin, Robert Brundrett, Rafael J. Tamargo, and Henry Brem

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time.

The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

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Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres

Laboratory investigation

Patrik Gabikian, Betty M. Tyler, Irma Zhang, Khan W. Li, Henry Brem, and Kevin A. Walter

Object

The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo.

Methods

The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival.

Results

Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6–12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6–12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001).

Conclusions

These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.

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Impact of master’s degree attainment upon academic career placement in neurosurgery

Adham M. Khalafallah, Adrian E. Jimenez, Rafael J. Tamargo, Timothy Witham, Judy Huang, Henry Brem, and Debraj Mukherjee

OBJECTIVE

Previous authors have investigated many factors that predict an academic neurosurgical career over private practice, including attainment of a Doctor of Philosophy (PhD) and number of publications. Research has yet to demonstrate whether a master’s degree predicts an academic neurosurgical career. This study quantifies the association between obtaining a Master of Science (MS), Master of Public Health (MPH), or Master of Business Administration (MBA) degree and pursuing a career in academic neurosurgery.

METHODS

Public data on neurosurgeons who had graduated from Accreditation Council for Graduate Medical Education (ACGME)–accredited residency programs in the period from 1949 to 2019 were collected from residency and professional websites. Residency graduates with a PhD were excluded to isolate the effect of only having a master’s degree. A position was considered “academic” if it was affiliated with a hospital that had a neurosurgery residency program; other positions were considered nonacademic. Bivariate analyses were performed with Fisher’s exact test. Multivariate analysis was performed using a logistic regression model.

RESULTS

Within our database of neurosurgery residency alumni, there were 47 (4.1%) who held an MS degree, 31 (2.7%) who held an MPH, and 10 (0.9%) who held an MBA. In bivariate analyses, neurosurgeons with MS degrees were significantly more likely to pursue academic careers (OR 2.65, p = 0.0014, 95% CI 1.40–5.20), whereas neurosurgeons with an MPH (OR 1.41, p = 0.36, 95% CI 0.64–3.08) or an MBA (OR 1.00, p = 1.00, 95% CI 0.21–4.26) were not. In the multivariate analysis, an MS degree was independently associated with an academic career (OR 2.48, p = 0.0079, 95% CI 1.28–4.93). Moreover, postresidency h indices of 1 (OR 1.44, p = 0.048, 95% CI 1.00–2.07), 2–3 (OR 2.76, p = 2.01 × 10−8, 95% CI 1.94–3.94), and ≥ 4 (OR 4.88, p < 2.00 × 10−16, 95% CI 3.43–6.99) were all significantly associated with increased odds of pursuing an academic career. Notably, having between 1 and 11 months of protected research time was significantly associated with decreased odds of pursuing academic neurosurgery (OR 0.46, p = 0.049, 95% CI 0.21–0.98).

CONCLUSIONS

Neurosurgery residency graduates with MS degrees are more likely to pursue academic neurosurgical careers relative to their non-MS counterparts. Such findings may be used to help predict residency graduates’ future potential in academic neurosurgery.

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Which medical schools produce the most neurosurgery residents? An analysis of the 2014–2020 cohort

Albert Antar, James Feghali, Elizabeth E. Wicks, Shahab Aldin Sattari, Sean Li, Timothy F. Witham, Henry Brem, and Judy Huang

OBJECTIVE

In this study, the authors sought to determine which US medical schools have produced the most neurosurgery residents and to evaluate potential associations between recruitment and medical school characteristics.

METHODS

Demographic and bibliometric characteristics were collected for 1572 residents in US-based and Accreditation Council for Graduate Medical Education (ACGME)–accredited neurosurgery programs over the 2014 to 2020 match period using publicly available websites. US medical school characteristics were collected, including class size, presence of a home neurosurgery program, number of clinical neurosurgery faculty, research funding, presence of a neurosurgery interest group, and a top 10 ranking via U.S. News & World Report or Doximity. Correlations and associations were then evaluated using Pearson’s correlation coefficient (PCC), independent-samples t-test, and univariable or stepwise multivariable linear regression, as appropriate.

RESULTS

Vanderbilt University produced the most neurosurgery residents as a percentage of medical graduates at 3.799%. Case Western Reserve University produced the greatest absolute number of neurosurgery residents (n = 40). The following factors were shown to be associated with a higher mean percentage of graduates entering neurosurgery: number of clinical neurosurgery faculty (PCC 0.509, p < 0.001), presence of a neurosurgery interest group (1.022% ± 0.737% vs 0.351% ± 0.327%, p < 0.001) or home neurosurgery program (1.169% ± 0.766% vs 0.428% ± 0.327%, p < 0.001), allopathic compared with osteopathic school (0.976% ± 0.719% vs 0.232% ± 0.272%, p < 0.001), U.S. News top 10 ranking for neurology and neurosurgery (1.923% ± 0.924% vs 0.757% ± 0.607%, p < 0.001), Doximity top 10 residency program ranking (1.715% ± 0.803% vs 0.814% ± 0.688%, p < 0.001), and amount of NIH funding (PCC 0.528, p < 0.001).

CONCLUSIONS

The results of this study have delineated which medical schools produced the most neurosurgery residents currently in training, and the most important independent factors predicting the percentage of graduates entering neurosurgery and the preresidency h-index.

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Recruitment of women in neurosurgery: a 7-year quantitative analysis

James Feghali, Albert Antar, Elizabeth E. Wicks, Shahab Aldin Sattari, Sean Li, Timothy F. Witham, Henry Brem, and Judy Huang

OBJECTIVE

The authors aimed to characterize which US medical schools have the most female neurosurgery residents and to identify potential associations between medical school characteristics and successful recruitment of women pursuing a neurosurgery career.

METHODS

The authors evaluated a total of 1572 residents in US neurosurgery programs accredited by the Accreditation Council for Graduate Medical Education as of February 2021, representing match cohorts from 2014 to 2020. The authors extracted US medical school characteristics and ranked schools based on the percentages of women graduates entering neurosurgery. They additionally studied yearly trends of the percentage of women constituting incoming neurosurgery resident cohorts as well as associations between female recruitment percentage and medical school characteristics using univariable and stepwise multivariable linear regression (including significant univariable factors).

RESULTS

The cohort consisted of 1255 male and 317 (20%) female residents. Yearly trends indicated a significant drop in incoming female residents in 2016, followed by significant increases in 2017 and 2019. On multivariable analysis, the following factors were associated with a higher average percentage of female graduates entering neurosurgery: total affiliated neurosurgery clinical faculty (β = 0.006, 95% CI 0.001–0.011, p = 0.01), allopathic versus osteopathic schools (β = 0.231, 95% CI 0.053–0.409, p = 0.01), and top 10 U.S. News & World Report ranking (β = 0.380, 95% CI 0.129–0.589, p < 0.01). When the number of female clinical faculty was added to the model, the variable was not statistically significant. Multivariable bibliometric analyses indicated a higher mean preresidency H-index for men, with an even greater gender difference identified in the 2021 H-index.

CONCLUSIONS

This study characterizes which medical schools are most successful at recruiting female students who constituted the total neurosurgery resident workforce of the 2020–2021 academic year. The overall number of clinical neurosurgery faculty rather than faculty gender was independently associated with female recruitment. Gender differences in research productivity persisted with control for confounders and increased between preresidency and 2021 time points. Such understanding of factors that influence the recruitment of women can help improve female representation in neurosurgery residency training moving forward.

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Factors involved in maintaining prolonged functional independence following supratentorial glioblastoma resection

Clinical article

Kaisorn L. Chaichana, Aditya N. Halthore, Scott L. Parker, Alessandro Olivi, Jon D. Weingart, Henry Brem, and Alfredo Quinones-Hinojosa

Object

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.

Methods

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.

Results

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).

Conclusions

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.

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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

Laboratory investigation

Rita Sattler, Betty Tyler, Benjamin Hoover, Luke T. Coddington, Violette Recinos, Lee Hwang, Henry Brem, and Jeffrey D. Rothstein

Object

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.

Methods

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.

Results

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.

Conclusions

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.

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Rhabdoid meningioma occurring in an unrelated resection cavity with leptomeningeal carcinomatosis

Case report

Matthew A. Koenig, Romergryko G. Geocadin, Piotr Kulesza, Alessandro Olivi, and Henry Brem

✓ Rhabdoid meningioma (RM) is a recently described, aggressive variant of meningioma. The authors report a case of RM occurring in the resection cavity of an unrelated neurosurgical procedure, temporal lobectomy for intractable seizures. The patient presented with intractable headache 10 years after the temporal lobectomy. Imaging revealed a dura-based, uniformly enhancing lesion within the resection cavity. She underwent gross-total resection and the findings of the surgical pathological report were consistent with an RM, with a dramatically elevated MIB-1 index of approximately 50%. The patient's clinical course was complicated by severe pain and communicating hydrocephalus secondary to rapid dissemination of malignant cells throughout the CSF pathways. Despite aggressive measures, including tumor resection, ventriculoperitoneal shunt placement, and the initiation of conventional radiation therapy, the ensuing leptomeningeal carcinomatosis proved to be rapidly fatal.