Browse

You are looking at 1 - 10 of 41 items for

  • By Author: Brem, Henry x
Clear All
Restricted access

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.

Restricted access

Tushar Garg and Apurva Shrigiriwar

Restricted access

Daniel Lubelski, Roy Xiao, Debraj Mukherjee, William W. Ashley, Timothy Witham, Henry Brem, Judy Huang and Stacey Quintero Wolfe

OBJECTIVE

Neurosurgery seeks to attract the best and brightest medical students; however, there is often a lack of early exposure to the field, among other possible barriers. The authors sought to identify successful practices that can be implemented to improve medical student recruitment to neurosurgery.

METHODS

United States neurosurgery residency program directors were surveyed to determine the number of medical student rotators and medical students matching into a neurosurgery residency from their programs between 2010 and 2016. Program directors were asked about the ways their respective institutions integrated medical students into departmental clinical and research activities.

RESULTS

Complete responses were received from 30/110 institutions. Fifty-two percent of the institutions had neurosurgery didactic lectures for 1st- and 2nd-year medical students (MS1/2), and 87% had didactics for MS3/4. Seventy-seven percent of departments had a neurosurgery interest group, which was the most common method used to integrate medical students into the department. Other forms of outreach included formal mentorship programs (53%), lecture series (57%), and neurosurgery anatomy labs (40%). Seventy-three percent of programs provided research opportunities to medical students, and 57% indicated that the schools had a formal research requirement. On average, 3 medical students did a rotation in each neurosurgery department and 1 matched into neurosurgery each year. However, there was substantial variability among programs. Over the 2010–2016 period, the responding institutions matched as many as 4% of the graduating class into neurosurgery per year, whereas others matched 0%–1%. Departments that matched a greater (≥ 1% per year) number of medical students into neurosurgery were significantly more likely to have a neurosurgery interest group and formal research requirements. A greater percentage of high-matching programs had neurosurgery mentorship programs, lecture series, and cadaver training opportunities compared to the other institutions.

CONCLUSIONS

In recent decades, the number of applicants to neurosurgery has decreased. A major deterrent may be the delayed exposure of medical students to neurosurgery. Institutions with early preclinical exposure, active neurosurgery interest groups, research opportunities, and strong mentorship recruit and match more students into neurosurgery. Implementing such initiatives on a national level may increase the number of highly qualified medical students pursuing neurosurgery.

Restricted access

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.

Restricted access

Kaleb Yohay, Betty Tyler, Kyle D. Weaver, Andrea C. Pardo, Dan Gincel, Jaishri Blakeley, Henry Brem and Jeffrey D. Rothstein

Object

The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models.

Methods

In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT).

Results

In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival.

Conclusions

Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

Restricted access

Hansen Bow, Lee S. Hwang, Noam Schildhaus, Joanna Xing, Luke Murray, Quinn Salditch, Xiaobu Ye, Yonggang Zhang, Jon Weingart, Henry Brem and Betty Tyler

Object

Over the past several years, there has been increasing interest in combining angiogenesis inhibitors with radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma. Although the US FDA approved bevacizumab for the treatment of glioblastoma in 2009, the European Medicines Agency rejected its use due to its questionable impact on patient survival. One factor contributing to the failure of angiogenesis inhibitors to increase overall patient survival may be their inability to cross the blood-brain barrier. Here the authors examined in a 9L glioma model whether intracranial polymer-based delivery of the angiogenesis inhibitor minocycline potentiates the effects of both radiotherapy and temozolomide chemotherapy in increasing median survival. The authors also investigated whether the relative timing of minocycline polymer implantation with respect to radiotherapy affects the efficacy of radiotherapy.

Methods

Minocycline was incorporated into the biodegradable polymer polyanhydride poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]) (CPP:SA) at a ratio of 50:50 by weight. Female Fischer 344 rats were implanted with 9L glioma on Day 0. The minocycline polymer was then implanted on either Day 3 or Day 5 posttumor implantation. Cohorts of rats were exposed to 20 Gy focal radiation on Day 5 or were administered oral temozolomide (50 mg/kg daily) on Days 5–9.

Results

Both minocycline polymer implantations on Days 3 and 5 increased survival from 14 days to 19 days (p < 0.001 vs control). Treatment with a combination of both minocycline polymer and radiotherapy on Day 5 resulted in a 139% increase in median survival compared with treatment with radiotherapy alone (p < 0.005). There was not a statistically significant difference in median survival between the group that received minocycline implanted on the same day as radiotherapy and the group that received minocycline polymer 2 days prior to radiotherapy. Lastly, treatment with a combination of minocycline polymer with oral temozolomide resulted in a 38% extension of median survival compared with treatment of oral temozolomide alone (p < 0.001).

Conclusions

These results show that minocycline delivered locally potentiates the effects of both radiotherapy and oral temozolomide in increasing median survival in a rodent glioma model. More generally, these results suggest that traditional therapy in combination with local, as opposed to systemic, delivery of angiogenesis inhibitors may be able to increase median survival for patients with glioblastoma.

Restricted access

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.

Restricted access

Kaisorn L. Chaichana, Patricia Zadnik, Jon D. Weingart, Alessandro Olivi, Gary L. Gallia, Jaishri Blakeley, Michael Lim, Henry Brem and Alfredo Quiñones-Hinojosa

Object

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival.

Methods

The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis.

Results

Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423–4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525–0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388–0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238–0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05).

Conclusions

Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.

Restricted access

Rachel Grossman, Betty Tyler, Lee Hwang, Patti Zadnik, Bachchu Lal, Kashi Javaherian and Henry Brem

Object

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.

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.

Results

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.

Conclusions

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.