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BACKGROUND: The National Institutes of Health has developed a new metric, the Relative Citation Ratio (RCR), to assess the impact of research articles and compare academic productivity across different fields. Global surgery, obstetrics, trauma, and anesthesia (SOTA) are young and increasingly popular fields attracting researchers and funding. This study analyzed the RCR of global neurosurgery; compared it with other global SOTA specialties; and discussed the implications for researchers, academic institutions, and aspiring global neurosurgeons. METHODS: Metadata were downloaded from the National Institutes of Health RCR website for 12 established global surgery specialties, including global neurosurgery. The authors performed descriptive and bivariable inferential analyses to evaluate differences in the number of total publications, median number of citations per year, and median RCR for each specialty for which data were available. RESULTS: Global pediatric surgery had the highest median citations per year (2.00, interquartile range: 0.63-3.50; P = 0.048) and median relative citation ratio (1.36, interquartile range: 0.33-1.95; P = 0.693). In comparison, global neurosurgery articles had 0.20 median citations per year (IQR: 0-1.5) and 0.54 (IQR: 0.12-1.30) median relative citations. The median expected citations per year for all SOTA articles was 1.77. CONCLUSIONS: We observed strong development of global neurosurgery and SOTA research. Overall, the use of the RCR will facilitate standardized interfield and intrafield academic productivity comparisons. Based on the results presented in this study, global neurosurgery is a promising career route for young and aspiring academic neurosurgeons.

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BACKGROUND: Glomus jugulare tumors (GJTs) are benign paragangliomas of the jugular foramen. Traditional management of these tumors involves surgical resection; however, considering the proximity of these tumors to important neurovasculature, stereotactic radiosurgery (SRS) may be an appropriate noninvasive treatment to consider. The aim of this meta-analysis was to evaluate SRS as a treatment option for GJTs. METHODS: An online search using PubMed, Web of Science, Scopus, and Cochrane databases was performed in March 2019 for articles on radiosurgery treatment of GJTs. The screening process followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: The final analysis comprised 23 studies including 460 patients. Average rates of tinnitus, hearing loss, and lower cranial nerve deficit as presenting symptoms were 56% (95% confidence interval [CI], 46%-66%), 56% (95% CI, 44%-68%), and 42% (95% CI, 31%-54%), respectively. Overall clinical status improvement rate after treatment was 47% (95% CI, 37%-57%). Rates of tinnitus, hearing loss, and lower cranial nerve improvement after treatment were 54% (95% CI, 44%-63%), 28% (95% CI, 19%-40%), and 22% (95% CI, 11%-39%), respectively. The mean follow-up time across studies was 47 months (range, 4-268 months). The aggregate tumor control rate at the time of follow-up was 95% (95% CI, 93%-97%). CONCLUSIONS: The tumor control rate of 95% and 47% symptomatic improvement suggest that SRS may be a suitable treatment modality for these hypervascular skull base tumors. Future studies are warranted to further evaluate the potential role of SRS in management of GJTs.

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INTRODUCTION: Global surgery is a growing movement worldwide, but its expansion has not been quantified. Google Search is the most popular search engine worldwide, and Google Trends analyzes its queries to determine popularity trends. We used Google Trends to analyze the regional and temporal popularity of global surgery (GS). Furthermore, we compared GS with global health (GH) to understand if the two were correlated. METHODS: This is a retrospective cross-sectional study examining Google Trends of GS and GH. We searched the terms "global surgery" and "global health" on Google Trends (Google Inc., CA, USA) from January 2004 to May 2021. We identified time trends and compared the two search terms using SPSS v26 (IBM, WA, USA) to run summary descriptive analyses and Wilcoxon rank-sum tests. RESULTS: The ten countries most interested in GS were India (5.0%), the United Kingdom (5.0%), Ireland (4.0%), the United States (4.0%), Australia (3.0%), Canada (3.0%), New Zealand (3.0%), Germany (2.0%), South Africa (2.0%), and Nigeria (1.0%). GS became more popular after 2015 (2.3% vs. 1.3%, P < 0.001) and was consistently less popular than GH (1.6% vs. 45.3%, P = 0.04). The difference between GS and GH interest levels increased after 2015 (45.4% vs. 42.9%, P = 0.04). CONCLUSION: GS is less popular than GH, more popular in high-income countries, and has become more popular after 2015 when the Lancet Commission on Global Surgery published its seminal report. The World Health Organization passed resolution WHA 68.15. Future advocacy efforts should target low- and middle-income countries primarily.

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INTRODUCTION: Intracranial hemorrhage (ICH) is a devastating condition with a high rate of morbidity and mortality. Aneurysm or arteriovenous malformation (AVM) rupture are two common etiologies leading to ICH. Here we provide an update on ICH during pregnancy with a focus on those caused by aneurysm or AVM rupture. METHODS: Here we systematically review 25 studies reported in the literature to provide an update on ICH during pregnancy focusing on aneurysm or AVM rupture. We also reviewed the prognosis of ICH during puerperium. RESULTS: Discrepancies exist between studies supporting or refuting the hypothesis of a higher rate of ICH during pregnancy, obscuring the overall rate of aneurysm and AVM rupture in pregnant ICH patients. However, risk factors such as maternal age and hypertension have shown to increase the frequency of ICH in pregnant patients. We also show increased morbidity and mortality in patients suffering from preeclampsia/eclampsia. DISCUSSION: ICH is rare, but the various studies demonstrating its increased frequency, morbidity, and mortality during pregnancy should raise our awareness of this condition. The management and treatment decisions for a pregnant ICH patient should follow the same principles as nonpregnant patients, but with the knowledge that not all medications are appropriate for use in the pregnant patient. Although there seems to be a higher frequency of AVM rupture, further research must be conducted in order to fully determine the effects of pregnancy on aneurysm and AVM ruptures.

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OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.METHODSThe authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.RESULTSIL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.CONCLUSIONSThe current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

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BACKGROUND: The standard of care for glioblastoma is surgical resection followed by combination temozolomide and radiation. Magnetic resonance imaging (MRI) is used preoperatively for tumor resection planning. In some instances, MRI is also obtained postoperatively to assess for any complications and to determine extent of resection. There is some question whether early routine postoperative imaging of patients after tumor resection is beneficial to long-term outcomes, especially with the increased scrutiny of increasing health care costs. METHODS: In this study we retrospectively analyze patients with glioblastoma treated at our institution, comparing the difference in overall survival and treatment regimens between patients who had early postoperative MRI versus patients who did not. RESULTS: We determine that in our cohort of 125 patients, those with early postoperative MRI had no statistically significant overall survival difference compared with patients with no early postoperative MRI (P = 0.996). The median survival for the group with postoperative MRI was 378 days (95% confidence interval [CI], 242-443 days), and the median survival for the group without postoperative MRI was 308 days (95% CI, 203-445 days). Early postoperative MRI also did not significantly alter therapeutic regimens. CONCLUSIONS: Although early postoperative MRI may not significantly affect patient overall survival from a statistical standpoint or therapeutic regimens, this type of imaging may be important to hone resident and attending skill. We encourage other institutions to perform similar analyses to determine the overall survival benefit of early postoperative imaging after glioma resection for patients with glioblastoma.

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OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model.METHODSImmunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves.RESULTSImmunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134).CONCLUSIONSThe results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

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Glioblastoma is a devastating malignancy with a dismal survival rate. Currently, there are limited prognostic markers of glioblastoma including IDH1, ATRX, MGMT, PTEN, EGFRvIII, and others. Although these biomarkers for tumor prognosis are available, a surgical biopsy must be performed for these analyses, which has morbidity involved. A non-invasive and readily available biomarker is sought after which provides clinicians prognostic information. Sodium is an electrolyte that is easily and quickly obtained through analysis of a patient's serum. Hyponatremia has been shown to have a predictive and negative prognostic indication in multiple cancer types, but the role of glioblastoma patients' serum sodium at the time of diagnosis in predicting glioblastoma patient survival has not been determined. We assessed whether hyponatremia at the time of glioblastoma diagnosis correlates to patient survival and show that in our cohort of 200 glioblastoma patients, sodium, at any level, did not significantly correlate to glioblastoma survival, unlike what is seen in multiple other cancer types. We further demonstrate that inducing hyponatremia in an orthotopic murine model of glioblastoma has no effects on tumor progression and survival.

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Peripheral nerve sheath tumors are benign tumors that have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs). Interleukin-13 receptor alpha 2 (IL13Rα2) is a cancer associated receptor expressed in glioblastoma and other invasive cancers. We analyzed IL13Rα2 expression in several MPNST cell lines including the STS26T cell line, as well as in several peripheral nerve sheath tumors to utilize the IL13Rα2 receptor as a target for therapy. In our studies, we demonstrated the selective expression of IL13Rα2 in several peripheral nerve sheath tumors by immunohistochemistry (IHC) and immunoblots. We established a sciatic nerve MPNST mouse model in NIH III nude mice using a luciferase transfected STS26T MPNST cell line. Similarly, analysis of the mouse sciatic nerves after tumor induction revealed significant expression of IL13Rα2 by IHC when compared to a normal sciatic nerve. IL13 conjugated liposomal doxorubicin was formulated and shown to bind and internalized in the MPNST cell culture model demonstrating cytotoxic effect. Our subsequent in vivo investigation in the STS26T MPNST sciatic nerve tumor model indicated that IL13 conjugated liposomal doxorubicin (IL13LIPDXR) was more effective in inhibiting tumor progression compared to unconjugated liposomal doxorubicin (LIPDXR). This further supports that IL13 receptor targeted nanoliposomes is a potential approach for treating MPNSTs.

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