Publications by authors named "Henry Brem"

230 Publications

The safety and efficacy of dexamethasone in the perioperative management of glioma patients.

J Neurosurg 2021 Sep 24:1-8. Epub 2021 Sep 24.

1Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection.

Methods: A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019.

Results: The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062).

Conclusions: Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone use.
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http://dx.doi.org/10.3171/2021.4.JNS204127DOI Listing
September 2021

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma.

Oncoimmunology 2021 29;10(1):1956142. Epub 2021 Aug 29.

Department of Neurosurgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, USA.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone ( = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ ( < .0001) and CD8+ IFN-γ ( = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain ( = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.
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http://dx.doi.org/10.1080/2162402X.2021.1956142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409779PMC
October 2021

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02.

J Neurosurg Pediatr 2021 Sep 3:1-10. Epub 2021 Sep 3.

Objective: Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi-CDK inhibitor, TG02.

Methods: Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software.

Results: TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs.

Conclusions: The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.
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http://dx.doi.org/10.3171/2021.5.PEDS20920DOI Listing
September 2021

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

J Neurosurg 2021 Aug 13:1-10. Epub 2021 Aug 13.

1Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

Objective: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM.

Methods: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry.

Results: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05).

Conclusions: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.
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http://dx.doi.org/10.3171/2021.1.JNS202482DOI Listing
August 2021

The Impact of Hydrocephalus Shunt Devices on Quality of Life.

J Craniofac Surg 2021 Jul-Aug 01;32(5):1746-1750

Section of Neuroplastic and Reconstructive Surgery, Department of Plastic and Reconstructive Surgery.

Background: Despite advances in hydrocephalus shunt technology and improvement in hydrocephalus management, many patients have chronic disability and require multiple surgeries throughout their lifetime. There is limited data from patients' perspective regarding the impact of shunt devices on quality-of-life.

Methods: A cross-sectional survey was developed to evaluate the impact of shunt devices on patient quality-of-life. The survey was distributed via social media platforms of the Hydrocephalus Association, and patients self-selected to anonymously complete the online questionnaire. A literature review was performed to contextualize the findings from the survey.

Results: A total of 562 survey responses were obtained from a network encompassing 35,000 members. The mean age was 30 years old (0.5-87), and 65% identified as female. Eighty one percent underwent at least 1 shunt revision surgery, with a reported average of 10 shunt revision surgeries per patient (1-200 surgeries). Occlusion, shunt migration and infection were the leading causes for revision at 60%, 47%, and 35%, respectively. In addition, 72% of patients reported pain and discomfort from the device, and 68% expressed avoidance of certain activities due to "fear of bumping shunt." Despite numerous articles discussing shunt technology, a review of the literature indicated a paucity of studies specifically evaluating the burden of shunt devices from a patient/caregiver perspective.

Conclusions: The findings from this study suggest long-term physical and psychosocial burden associated with shunt devices. Importantly, this study highlights the need for concerted efforts to develop validated tools to study patient reported outcomes as it relates to neurocranial implanted devices.
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http://dx.doi.org/10.1097/SCS.0000000000007579DOI Listing
July 2021

Impact of international research fellows in neurosurgery: results from a single academic center.

J Neurosurg 2021 Jul 23:1-11. Epub 2021 Jul 23.

Objective: International research fellows have been historically involved in academic neurosurgery in the United States (US). To date, the contribution of international research fellows has been underreported. Herein, the authors aimed to quantify the academic output of international research fellows in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.

Methods: Research fellows with Doctor of Medicine (MD), Doctor of Philosophy (PhD), or MD/PhD degrees from a non-US institution who worked in the Hopkins Department of Neurosurgery for at least 6 months over the past decade (2010-2020) were included in this study. Publications produced during fellowship, number of citations, and journal impact factors (IFs) were analyzed using ANOVA. A survey was sent to collect information on personal background, demographics, and academic activities.

Results: Sixty-four international research fellows were included, with 42 (65.6%) having MD degrees, 17 (26.6%) having PhD degrees, and 5 (7.8%) having MD/PhD degrees. During an average 27.9 months of fellowship, 460 publications were produced in 136 unique journals, with 8628 citations and a cumulative journal IF of 1665.73. There was no significant difference in total number of publications, first-author publications, and total citations per person among the different degree holders. Persons holding MD/PhDs had a higher number of citations per publication per person (p = 0.027), whereas those with MDs had higher total IFs per person (p = 0.048). Among the 43 (67.2%) survey responders, 34 (79.1%) had nonimmigrant visas at the start of the fellowship, 16 (37.2%) were self-paid or funded by their country of origin, and 35 (81.4%) had mentored at least one US medical student, nonmedical graduate student, or undergraduate student.

Conclusions: International research fellows at the authors' institution have contributed significantly to academic neurosurgery. Although they have faced major challenges like maintaining nonimmigrant visas, negotiating cultural/language differences, and managing self-sustainability, their scientific productivity has been substantial. Additionally, the majority of fellows have provided reciprocal mentorship to US students.
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http://dx.doi.org/10.3171/2021.1.JNS203824DOI Listing
July 2021

Patient-Specific Factors Drive Intensive Care Unit and Total Hospital Length of Stay in Operative Patients with Brain Tumor.

World Neurosurg 2021 Sep 2;153:e338-e348. Epub 2021 Jul 2.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Background: Hospital length of stay (LOS) is an important cost driver in neurosurgery. Broader surgical literature has shown that patient-related factors, including comorbidities, and procedure-related factors, such surgeon experience, may be associated with LOS. Because value optimization strategies may be targeted toward either domain, this study investigated the contributions of patient-related and procedure-related factors in predicting prolonged intensive care unit LOS (iLOS) and total hospital LOS (tLOS).

Methods: Data for adult patients undergoing brain tumor surgery (2017-2019) were collected. Bivariate analyses for iLOS and tLOS were performed using the Mann-Whitney U test and Fisher exact test. Variables associated with either outcome with P < 0.10 were included in patient-only, procedure-only, and patient+procedure factor multivariate linear regression models. Model discrimination was quantified using C-statistics.

Results: Our 654 patients had a mean age of 57.54 years (standard deviation, ± 14.34 years). For iLOS, the patient-only model significantly outperformed the procedure-only model (P < 0.0001) and performed similarly to the patient+procedure model (P = 0.50). Other than tumor diagnosis, 5-Factor Modified Frailty Index score was the only factor associated with iLOS (P < 0.001) and tLOS (P < 0.001) on multivariate analysis. When predicting prolonged tLOS, the patient-only model significantly outperformed the procedure-only model (P < 0.0001), and performed similarly to patient+procedure models (P = 0.49).

Conclusions: Patient-specific factors are the main drivers of prolonged iLOS and tLOS among patients with brain tumor. Frailty was significantly associated with both iLOS and tLOS on multivariate analysis. Efforts to improve care value should focus on strategies to optimize patient status, such as prehabilitation and enhanced recovery after surgery.
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http://dx.doi.org/10.1016/j.wneu.2021.06.114DOI Listing
September 2021

Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.

Clin Neurol Neurosurg 2021 08 22;207:106771. Epub 2021 Jun 22.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo.

Methods: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue.

Results: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively).

Conclusions: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.
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http://dx.doi.org/10.1016/j.clineuro.2021.106771DOI Listing
August 2021

Predictors of Academic Neurosurgical Career Trajectory among International Medical Graduates Training Within the United States.

Neurosurgery 2021 08;89(3):478-485

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Within the literature, there has been limited research tracking the career trajectories of international medical graduates (IMGs) following residency training.

Objective: To compare the characteristics of IMG and US medical school graduate (USMG) neurosurgeons holding academic positions in the United States and also analyze factors that influence IMG career trajectories following US-based residency training.

Methods: We collected data on 243 IMGs and 2506 USMGs who graduated from Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgery residency programs. We assessed for significant differences between cohorts, and a logistic regression model was used for the outcome of academic career trajectory.

Results: Among the 2749 neurosurgeons in our study, IMGs were more likely to pursue academic neurosurgery careers relative to USMGs (59.7% vs 51.1%; P = .011) and were also more likely to complete a research fellowship before beginning residency (odds ratio [OR] = 9.19; P < .0001). Among current US academic neurosurgeons, USMGs had significantly higher pre-residency h-indices relative to IMGs (1.23 vs 1.01; P < .0001) with no significant differences between cohorts when comparing h-indices during (USMG = 5.02, IMG = 4.80; P = .67) or after (USMG = 14.05, IMG = 13.90; P = .72) residency. Completion of a post-residency clinical fellowship was the only factor independently associated with an academic career trajectory among IMGs (OR = 1.73, P = .046).

Conclusion: Our study suggests that while IMGs begin their US residency training with different research backgrounds and achievements relative to USMG counterparts, they attain similar levels of academic productivity following residency. Furthermore, IMGs are more likely to pursue academic careers relative to USMGs. Our work may be useful for better understanding IMG career trajectories following US-based neurosurgery residency training.
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http://dx.doi.org/10.1093/neuros/nyab194DOI Listing
August 2021

P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression.

Nat Commun 2021 03 26;12(1):1912. Epub 2021 Mar 26.

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.
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http://dx.doi.org/10.1038/s41467-021-22186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997963PMC
March 2021

Letter: Commentary: Costs and Their Predictors in Transsphenoidal Pituitary Surgery.

Neurosurgery 2021 04;88(5):E482-E483

Department of Neurosurgery Johns Hopkins Hospital Baltimore, Maryland, USA.

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http://dx.doi.org/10.1093/neuros/nyab027DOI Listing
April 2021

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

J Neurosurg Pediatr 2021 Feb 5:1-7. Epub 2021 Feb 5.

Objective: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.

Methods: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.

Results: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004).

Conclusions: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.
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http://dx.doi.org/10.3171/2020.8.PEDS20561DOI Listing
February 2021

Development of new brain metastases in triple negative breast cancer.

J Neurooncol 2021 Apr 29;152(2):333-338. Epub 2021 Jan 29.

Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, Institute of NanoBiotechnology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA.

Background: Brain metastases are common in patients with breast cancer, and those with triple negative status have an even higher risk. Triple negative status is currently not considered when managing brain metastases.

Objective: To determine whether triple negative breast cancer (TNBC) patients with brain metastases have a higher burden of intracranial disease and whether WBRT has a survival benefit in this cohort of patients.

Methods: We conducted a retrospective cohort study with 85 patients meeting the inclusion criteria.

Results: 25% of patients had TNBC. 95% of the patients in this study received SRS and 48% received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67 ± 1.1 in the non-TNBC status patients and 2.6 ± 3.7 in the triple negative status patients (p = 0.001). A cox proportional hazards model showed that WBRT does not significantly affect overall survival in patients with TNBC (HR 1.48; 95% CI 0.47-4.67; p = 0.50).

Conclusion: Our findings highlight the highly aggressive intracranial nature of TNBC. The rate of new brain metastasis formation is higher in TNBC patients compared to non-TNBC patients. Furthermore, there is no survival benefit for WBRT in TNBC patients. These findings are relevant for clinicians planning brain radiation for TNBC patients as they may find more brain metastases at the time of brain radiation than they anticipated based on initial brain imaging.
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http://dx.doi.org/10.1007/s11060-021-03702-0DOI Listing
April 2021

Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa154. Epub 2020 Nov 12.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers.

Methods: A single-center dose-escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose-escalation levels were 25, 50, 100, and 200 mg/kg/day of oral mebendazole. A total of 15 patients were enrolled at the highest dose studied of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8, and 16 weeks.

Results: Twenty-four patients (18 glioblastoma and 6 anaplastic glioma) were enrolled with a median age of 49.8 years. Four patients (at 200 mg/kg) developed elevated grade 3 alanine aminotransferase (ALT) and/or aspartate transaminase (AST) after 1 month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan-Meier analysis showed a 21-month median overall survival with 41.7% of patients alive at 2 years and 25% at 3 and 4 years. Median progression-free survival (PFS) from the date of diagnosis for 17 patients taking more than 1 month of mebendazole was 13.1 months (95% confidence interval [CI]: 8.8-14.6 months) but for 7 patients who received less than 1 month of mebendazole PFS was 9.2 months (95% CI: 5.8-13.0 months).

Conclusion: Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole's efficacy in patients with malignant glioma.
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http://dx.doi.org/10.1093/noajnl/vdaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817892PMC
November 2020

PD-1+ Monocytes Mediate Cerebral Vasospasm Following Subarachnoid Hemorrhage.

Neurosurgery 2021 03;88(4):855-863

Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options.

Objective: To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm.

Methods: Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm.

Results: We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm.

Conclusion: Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy.
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http://dx.doi.org/10.1093/neuros/nyaa495DOI Listing
March 2021

Effect of radiation therapy on overall survival following subtotal resection of adult pilocytic astrocytoma.

J Clin Neurosci 2020 Nov 21;81:340-345. Epub 2020 Oct 21.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States. Electronic address:

Objective: Pilocytic astrocytoma (PCA) is a low-grade glioma that primarily presents in children, but can also present in adulthood. Ideal primary treatment for PCA is gross total resection. However, for patients who are only able to undergo subtotal resection, the optimal course of post-operative therapy remains unclear. We investigated the association of patient characteristics and radiation therapy (RT) with overall survival specifically for adult PCA patients who underwent subtotal tumor resection.

Methods: Information on adult patients (age ≥18 years old) who underwent subtotal PCA resection between 2004 and 2016 was collected from the National Cancer Database (NCDB). A multivariate Cox proportional hazards model was utilized to determine factors associated with overall survival.

Results: A total of 451 patients were identified. The mean age of our patient cohort was 36.8 years old, and the majority of patients (83.4%) did not receive RT following subtotal PCA resection. Overall median survival was >93.8 months. On multivariate analysis, patients who were older at diagnosis (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.02-1.06, p < 0.01), black (HR = 2.35, CI = 1.05-5.23, p = 0.037), had a Charlson/Deyo comorbidity score ≥ 1 (HR = 2.27, CI = 1.00-5.14, p = 0.049), or received RT during their initial treatment (HR = 3.77, CI = 1.77-8.03, p < 0.01) had a significantly higher risk of death following subtotal PCA resection.

Conclusion: Post-operative RT was associated with a significantly higher risk of death among adults who underwent subtotal PCA resection. Our findings provide support for further inquiry into the efficacy of RT within this patient population.
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http://dx.doi.org/10.1016/j.jocn.2020.10.020DOI Listing
November 2020

Translucent Customized Cranial Implants Made of Clear Polymethylmethacrylate: An Early Outcome Analysis of 55 Consecutive Cranioplasty Cases.

Ann Plast Surg 2020 12;85(6):e27-e36

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Large skull reconstruction, with the use of customized cranial implants, restores cerebral protection, physiologic homeostasis, and one's preoperative appearance. Cranial implants may be composed of either bone or a myriad of alloplastic biomaterials. Recently, patient-specific cranial implants have been fabricated using clear polymethylmethacrylate (PMMA), a visually transparent and sonolucent variant of standard opaque PMMA. Given the new enhanced diagnostic and therapeutic applications of clear PMMA, we present here a study evaluating all outcomes and complications in a consecutive patient series.

Methods: A single-surgeon, retrospective, 3-year study was conducted on all consecutive patients undergoing large cranioplasty with clear PMMA implants (2016-2019). Patients who received clear PMMA implants with embedded neurotechnologies were excluded due to confounding variables. All outcomes were analyzed in detail and compared with previous studies utilizing similar alloplastic implant materials.

Results: Fifty-five patients underwent cranioplasty with customized clear PMMA implants. Twenty-one (38%) were performed using a single-stage cranioplasty method (ie, craniectomy and cranioplasty performed during the same operation utilizing a prefabricated, oversized design and labor-intense, manual modification), whereas the remaining 34 (62%) underwent a standard, 2-stage reconstruction (craniectomy with a delayed surgery for cranioplasty and minimal-to-no implant modification necessary). The mean cranial defect size was 101.8 cm. The mean follow-up time was 9 months (range, 1.5-39). Major complications requiring additional surgery occurred in 7 patients (13%) consisting of 2 (4%) cerebrospinal fluid leaks, 2 (4%) epidural hematomas, and 3 (4%) infections. In addition, 3 patients developed self-limiting or nonoperative complications including 2 (4%) with new onset seizures and 1 (2%) with delayed scalp healing.

Conclusions: This is the first reported consecutive case series of cranioplasty reconstruction using customized clear PMMA implants, demonstrating excellent results with regard to ease of use, safety, and complication rates well below published rates when compared with other alloplastic materials. Clear PMMA also provides additional benefits, such as visual transparency and sonolucency, which is material specific and unavailable with autologous bone. Although these early results are promising, further studies with multicenter investigations are well justified to evaluate long-term outcomes.
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http://dx.doi.org/10.1097/SAP.0000000000002441DOI Listing
December 2020

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 11 2;18(11):1537-1570. Epub 2020 Nov 2.

5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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http://dx.doi.org/10.6004/jnccn.2020.0052DOI Listing
November 2020

The Neuroplastic Surgery Fellowship Experience: Where Tradition Meets Innovation.

J Craniofac Surg 2021 Jan-Feb 01;32(1):12-14

Section of Neuroplastic and Reconstructive Surgery, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine.

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http://dx.doi.org/10.1097/SCS.0000000000007201DOI Listing
May 2021

Mechanisms underlying the generation of autonomorespiratory coupling amongst the respiratory central pattern generator, sympathetic oscillators, and cardiovagal premotoneurons.

J Integr Neurosci 2020 Sep;19(3):521-560

Department of Neurosurgery, University Hospital, Zurich, Rämistrasse Zurich, 100, 8091, Switzerland.

The respiratory rhythm and pattern and sympathetic and parasympathetic outflows are generated by distinct, though overlapping, propriobulbar arrays of neuronal microcircuit oscillators constituting networks utilizing mutual excitatory and inhibitory neuronal interactions, residing principally within the metencephalon and myelencephalon, and modulated by synaptic influences from the cerebrum, thalamus, hypothalamus, cerebellum, and mesencephalon and ascending influences deriving from peripheral stimuli relayed by cranial nerve afferent axons. Though the respiratory and cardiovascular regulatory effector mechanisms utilize distinct generators, there exists significant overlap and interconnectivity amongst and between these oscillators and pathways, evidenced reciprocally by breathing modulation of sympathetic oscillations and sympathetic modulation of neural breathing. These coupling mechanisms are well-demonstrated coordinately in sympathetic- and respiratory-related central neuronal and efferent neurogram recordings and quantified by the findings of cross-correlation, spectra, and coherence analyses, combined with empirical interventions including lesioning and pharmacological agonist and antagonist microinjection studies, baroloading, barounloading, and hypoxic and/or hypercapnic peripheral and/or central chemoreceptor stimulation. Sympathetic and parasympathetic central neuronal and efferent neural discharge recordings evidence classic fast rhythms produced by propriobulbar neuronal networks located within the medullary division of the lateral tegmental field, coherent with cardiac sympathetic nerve discharge. These neural efferent nerve discharges coordinately evidence slow synchronous oscillations, constituted by Traube Hering (i.e., high frequency), Mayer wave (i.e., medium or low frequency), and vasogenic autorhythmicity (i.e., very low frequency) wave spectral bands. These oscillations contribute to coupling neural breathing, sympathetic oscillations, and parasympathetic cardiovagal premotoneuronal activity. The mechanisms underlying the origins of and coupling amongst, these waves remains to be unresolved.
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http://dx.doi.org/10.31083/j.jin.2020.03.0196DOI Listing
September 2020

Quantifying the utility of a multidisciplinary neuro-oncology tumor board.

J Neurosurg 2020 Sep 18:1-6. Epub 2020 Sep 18.

1Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore.

Objective: There has been limited research on the efficacy of multidisciplinary tumor boards (MDTBs) in improving the treatment of patients with tumors affecting the nervous system. The objective of the present study was to quantify the utility of MDTBs in providing alternative diagnostic interpretations and treatment plans for this patient population.

Methods: The authors performed a prospective study of patients in 4 hospitals whose cases were discussed at MDTBs between July and November 2019. Patient demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables.

Results: A total of 176 cases met eligibility criteria for study inclusion. The majority (53%) of patients were male, and the mean patient age was 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times than patients whose cases were not discussed (p = 0.024).

Conclusions: MDTB discussions led to significant numbers of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.
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http://dx.doi.org/10.3171/2020.5.JNS201299DOI Listing
September 2020

The 5-factor modified frailty index: an effective predictor of mortality in brain tumor patients.

J Neurosurg 2020 Aug 14:1-9. Epub 2020 Aug 14.

Objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.3171/2020.5.JNS20766DOI Listing
August 2020

Predictors of Nonroutine Discharge Disposition Among Patients with Parasagittal/Parafalcine Meningioma.

World Neurosurg 2020 10 9;142:e344-e349. Epub 2020 Jul 9.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Objective: Discharge disposition is an important outcome for neurosurgeons to consider in the context of high-quality, value-based care. There has been limited research into how the unique anatomic considerations associated with parasagittal/parafalcine meningioma resection may influence discharge disposition. We investigated the effects of various predictors on discharge disposition within a cohort of patients with parasagittal/parafalcine meningioma.

Methods: A total of 154 patients treated at a single institution were analyzed (2016-2019). Bivariate analysis was conducted using the Mann-Whitney U and Fisher exact tests. Multivariate analysis was conducted using logistic regression. An optimism-corrected C-statistic was calculated using 2000 bootstrap samples to assess logistic regression model performance.

Results: Our cohort was mostly female (67.5%) and white (72.7%), with a mean age of 57.29 years. Most patients had tumors associated with the middle third of the superior sagittal sinus (SSS) (60.4%) and had tumors that were not fully occluding the SSS (74.0%). In multivariate analysis, independent predictors of nonroutine discharge disposition included 5-factor Modified Frailty Index score (odds ratio [OR], 2.06; P = 0.0088), Simpson grade IV resection (OR, 4.22; P = 0.0062), and occurrence of any postoperative complication (OR, 2.89; P = 0.031). The optimism-corrected C-statistic of our model was 0.757.

Conclusions: In our single-institution experience, neither extent of SSS invasion nor location along the SSS predicted nonroutine discharge, suggesting that tumor invasion and posterior location along the SSS are not necessarily contraindications to surgery. Our results also highlight the importance of frailty and tumor size in stratifying patients at risk of nonroutine discharge disposition.
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http://dx.doi.org/10.1016/j.wneu.2020.06.239DOI Listing
October 2020

Minimally invasive therapeutic ultrasound: Ultrasound-guided ultrasound ablation in neuro-oncology.

Ultrasonics 2020 Dec 20;108:106210. Epub 2020 Jun 20.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

Introduction: To improve patient outcomes (eg, reducing blood loss and infection), practitioners have gravitated toward noninvasive and minimally invasive surgeries (MIS), which demand specialized toolkits. Focused ultrasound, for example, facilitates thermal ablation from a distance, thereby reducing injury to surrounding tissue. Focused ultrasound can often be performed noninvasively; however, it is more difficult to carry out in neuro-oncological tumors, as ultrasound is dramatically attenuated while propagating through the skull. This shortcoming has prompted exploration of MIS options for intracranial placement of focused ultrasound probes, such as within the BrainPath™ (NICO Corporation, Indianapolis, IN). Herein, we present the design, development, and in vitro testing of an image-guided, focused ultrasound prototype designed for use in MIS procedures. This probe can ablate neuro-oncological lesions despite its small size.

Materials & Methods: Preliminary prototypes were iteratively designed, built, and tested. The final prototype consisted of three 8-mm-diameter therapeutic elements guided by an imaging probe. Probe functionality was validated on a series of tissue-mimicking phantoms.

Results: Lesions were created in tissue-mimicking phantoms with average dimensions of 2.5 × 1.2 × 6.5 mm and 3.4 × 3.25 × 9.36 mm after 10- and 30-second sonification, respectively. 30 s sonification with 118 W power at 50% duty cycle generated a peak temperature of 68 °C. Each ablation was visualized in real time by the built-in imaging probe.

Conclusion: We developed and validated an ultrasound-guided focused ultrasound probe for use in MIS procedures. The dimensional constraints of the prototype were designed to reflect those of BrainPath trocars, which are MIS tools used to create atraumatic access to deep-seated brain pathologies.
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http://dx.doi.org/10.1016/j.ultras.2020.106210DOI Listing
December 2020

Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Mol Cancer Ther 2020 09 30;19(9):1797-1808. Epub 2020 Jun 30.

Hunterian Neurosurgical Research Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both and Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0572DOI Listing
September 2020

Scalp Invasion by Atypical or Anaplastic Meningioma Is a Risk Factor for Development of Systemic Metastasis.

World Neurosurg 2020 10 26;142:e133-e139. Epub 2020 Jun 26.

Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland, USA. Electronic address:

Background: Atypical and anaplastic meningiomas (AAMs) are rare and comprise approximately 5% of all meningiomas. Extracranial metastases in meningioma patients occur in 0.1% of all cases, but these lesions are difficult to treat and may be a poor prognostic factor.

Methods: We conducted a retrospective chart review between 1990 and 2016 of patients who had surgical resection of AAM. In a cohort of 149 patients, 6 had metastatic lesions that were histologically confirmed to be meningioma. We compared baseline characteristics between patients with and without metastasis and performed a multivariate Cox regression analysis to assess risk factors for the development of systemic metastasis.

Results: Six patients had histologically confirmed meningioma metastasis. We hypothesized that the presence of scalp invasion in patients could be a potential risk factor for the development of systemic meningioma metastasis. Nine out of the 149 patients without metastasis had scalp invasion, whereas 4 out of the 6 patients with metastasis had scalp invasion. Patients with metastasis had a median age of 62 ± 20. Patients without metastasis had a median age of 59 ± 15 years. Gender distribution was similar; approximately 50% of patients in each group were female. Eighty-five percent of patients with metastatic disease were white, and 65% of patients without metastatic disease were white. Among patients without metastatic disease, 77% had World Health Organization II tumors, whereas 50% of patients with metastatic disease had World Health Organization II tumors. In multivariate analysis including age, tumor grade, size, location, extent of resection, sex, and scalp invasion, the only significant predictor of systemic metastasis was scalp invasion (odds ratio = 39.67; 95% confidence interval = 3.74-421.12; P = 0.0023). Median overall survival (OS) with metastasis was 126 months, and median OS without metastasis was 158 months. Having metastatic disease was not significantly associated with worse OS (P = 0.33).

Conclusions: Metastasis development from AAM is a rare but serious event. Because scalp invasion is a strongly associated predictive factor for development of systemic metastasis in patients with AAM, it is necessary to consider strategies to prevent and to be vigilant of the development of scalp invasion.
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http://dx.doi.org/10.1016/j.wneu.2020.06.148DOI Listing
October 2020

A systematic review and meta-analysis of supratotal versus gross total resection for glioblastoma.

J Neurooncol 2020 Jul 19;148(3):419-431. Epub 2020 Jun 19.

Department of Neurosurgery, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, 21287, USA.

Purpose: Due to the infiltrative nature of glioblastoma (GBM) outside of the contrast-enhancing region on MRI, there is interest in exploring supratotal resections (SpTR) that extend beyond the contrast-enhancing portion of the tumor. However, there is currently no consensus on the potential survival benefit of SpTR in GBM compared to gross total resection (GTR). In this study, we compare the impact of SpTR versus GTR on overall survival (OS) of GBM patients.

Methods: We performed a systematic review and meta-analysis of literature published on PubMed, Embase, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov, from inception to August 16, 2018, to identify articles comparing OS after SpTR versus GTR.

Results: We identified 8902 unique citations, of which 11 articles met study inclusion criteria. 810 patients underwent SpTR out of a total of 2056 patients. 9 of 11 studies demonstrated improved outcomes with SpTR compared to GTR (median improvement in OS of 10.5 months), with no significant difference in postoperative complication rate. Overall study quality was variable, with ten studies presenting level IV evidence and one study presenting level IIIb evidence. Subgroup meta-analysis based on SpTR definition demonstrated a statistically significant 35% lower risk of mortality in patients who underwent anatomical SpTR compared to patients who underwent GTR (Hazard ratio = 0.65, 95% CI 0.47- 0.91, p = 0.003).

Conclusion: Our systematic review indicates SpTR may be associated with improved OS compared to GTR for GBM, especially with anatomical SpTR. However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies. There is need for prospective clinical data to further guide parameters regarding the use of SpTR in GBM.
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http://dx.doi.org/10.1007/s11060-020-03556-yDOI Listing
July 2020

Impact of COVID-19 on an Academic Neurosurgery Department: The Johns Hopkins Experience.

World Neurosurg 2020 07 24;139:e877-e884. Epub 2020 May 24.

Department of Neurosurgery, The Johns Hopkins University School of Medicine, Bethesda, Maryland, USA; Department of Health Policy and Management, The Johns Hopkins Bloomberg School of Public Health, Bethesda, Maryland, USA. Electronic address:

Objective: Coronavirus disease 2019 (COVID-19) is a disruptive pandemic that has continued to test the limits of health care system capacities. It is important to highlight the specific challenges facing US neurosurgery during these difficult circumstances. In the present study, we have described our neurosurgery department's unique experience during the COVID-19 pandemic.

Methods: We analyzed the following data points both before and during the first months of the COVID-19 pandemic: the number of patients infected with COVID-19 at our institution, changes in neurosurgical operative workflow, changes in neurosurgical outpatient and inpatient clinic workflows, resident redeployment statistics and changes in call schedules, and changes in neurosurgical education.

Results: At our institution, the adult surgery numbers decreased from 120 during the week of March 4-11, 2020 (before the World Health Organization had classified the COVID-19 outbreak as a pandemic) to 17 during the week of April 13-17, 2020. The number of pediatric surgeries decreased from 15 to 3 during the same period. Significantly more surgeries were cancelled than were delayed (P < 0.0001). A drastic decline occurred in the number of in-person neurosurgery clinic visits (97.12%) between March and April 2020 (P = 0.0020). The inpatient census declined from mid-March to mid-April 2020 by 44.68% compared with a 4.26% decline during the same period in 2019 (P < 0.0001). Finally, neurosurgery education has largely shifted toward video-conferencing sessions rather than in-person sessions.

Conclusion: By detailing our experience during the COVID-19 pandemic, we hope to have provided a detailed picture of the challenges facing neurosurgery within an academic medical center.
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http://dx.doi.org/10.1016/j.wneu.2020.05.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245648PMC
July 2020

Intraoperative Laser Speckle Contrast Imaging For Real-Time Visualization of Cerebral Blood Flow in Cerebrovascular Surgery: Results From Pre-Clinical Studies.

Sci Rep 2020 05 6;10(1):7614. Epub 2020 May 6.

Vasoptic Medical, Inc., Baltimore, MD, United States.

Cerebrovascular surgery can benefit from an intraoperative system that conducts continuous monitoring of cerebral blood flow (CBF). Such a system must be handy, non-invasive, and directly integrated into the surgical workflow. None of the currently available techniques, considered alone, meets all these criteria. Here, we introduce the SurgeON™ system: a newly developed non-invasive modular tool which transmits high-resolution Laser Speckle Contrast Imaging (LSCI) directly onto the eyepiece of the surgical microscope. In preclinical rodent and rabbit models, we show that this system enabled the detection of acute perfusion changes as well as the recording of temporal response patterns and degrees of flow changes in various microvascular settings, such as middle cerebral artery occlusion, femoral artery clipping, and complete or incomplete cortical vessel cautery. During these procedures, a real-time visualization of vasculature and CBF was available in high spatial resolution through the eyepiece as a direct overlay on the live morphological view of the surgical field. Upon comparison with indocyanine green angiography videoangiography (ICG-VA) imaging, also operable via SurgeON, we found that direct-LSCI can produce greater information than ICG-VA and that continuous display of data is advantageous for performing immediate LSCI-guided adjustments in real time.
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http://dx.doi.org/10.1038/s41598-020-64492-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203106PMC
May 2020
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