Publications from the Li Lab

Associate Professor of Neurosurgery and, by courtesy, of Neurology and of Otolaryngology-Head and Neck Surgery at the Stanford University Medical Center

Publications

  • Prognostic Factors and Treatment Patterns in the Management of Giant Cell Glioblastoma WORLD NEUROSURGERY Jin, M. C., Wu, A., Xiang, M., Azad, T. D., Soltys, S. G., Li, G., Pollom, E. L. 2019; 128: E217–E224
  • Facial Nerve Paralysis Occurring 4 Days following Stereotactic Radiosurgery for a Vestibular Schwannoma. Asian journal of neurosurgery Chow, K. K., Ajlan, A., Ho, A. L., Li, G., Soltys, S. G. ; 14 (1): 262–65

    Abstract

    Stereotactic radiosurgery (SRS) is commonly used for the treatment of vestibular schwannomas given its high rate of tumor control and low rate of complications. Facial nerve palsy has been reported several months after treatment as a rare late complication of SRS. Here, we report a case of facial weakness occurring only 4 days after treatment and discuss potential etiology and management considerations.

    View details for PubMedID 30937049

    View details for PubMedCentralID PMC6417297

  • Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study ONCOLOGIST Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2019; 24 (6): 836–43
  • Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases WORLD NEUROSURGERY Koenig, J. L., Shi, S., Sborov, K., Gensheimer, M. F., Le, G., Nagpal, S., Chang, S. D., Gibbs, I. C., Soltys, S. G., Pollom, E. L. 2019; 126: E1399–E1411
  • Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases. World neurosurgery Koenig, J. L., Shi, S., Sborov, K., Gensheimer, M. F., Li, G., Nagpal, S., Chang, S. D., Gibbs, I. C., Soltys, S. G., Pollom, E. L. 2019

    Abstract

    BACKGROUND: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies.METHODS: We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving 'concurrent' SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure (LF), distant intracranial failure (DIF), extracranial failure (EF), and adverse radiation effect (ARE) were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models.RESULTS: A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses demonstrated that concurrent SRS-ICI therapy is associated with higher rates of ARE (6.4% vs 2.0% at 1 year; multivariable HR 4.47; 95% CI, 1.57-12.73; p=0.005), lower rates of EF (69.7% vs 80.8% at 1 year; multivariable HR 0.60; 95% CI, 0.42-0.87; p=0.007), and better overall survival (48.6% vs 25.4% at 1 year; multivariable HR 0.57; 95% CI, 0.33-0.99; p=0.044) as compared to non-concurrent therapy. SRS-ICI timing was not associated with LF or DIF.CONCLUSIONS: Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.

    View details for PubMedID 30902777

  • Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide. Oncogene Nitta, R. T., Bolin, S., Luo, E., Solow-Codero, D. E., Samghabadi, P., Purzner, T., Aujla, P. S., Nwagbo, G., Cho, Y. J., Li, G. 2019

    Abstract

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a high-throughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the anti-tumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced β-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.

    View details for DOI 10.1038/s41388-019-0927-y

    View details for PubMedID 31406250

  • Lumboperitoneal and Ventriculoperitoneal Shunting for Idiopathic Intracranial Hypertension Demonstrate Comparable Failure and Complication Rates. Neurosurgery Azad, T. D., Zhang, Y., Varshneya, K., Veeravagu, A., Ratliff, J. K., Li, G. 2019

    Abstract

    Idiopathic intracranial hypertension results in increased intracranial pressure leading to headache and visual loss. This disease frequently requires surgical intervention through lumboperitoneal (LP) or ventriculoperitoneal (VP) shunting.To compare postoperative outcomes between LP and VP shunts, including failure and complication rates.A retrospective analysis was conducted using a national administrative database (MarketScan) to identify idiopathic intracranial hypertension (IIH) patients who underwent LP or VP shunting from 2007 to 2014. Multivariate logistic and Cox regressions were performed to compare rates of shunt failure and time to shunt failure between LP and VP shunts while controlling for demographics and comorbidities.The analytic cohort included 1082 IIH patients, 347 of whom underwent LP shunt placement at index hospitalization and 735 of whom underwent VP shunt placement. Rates of shunt failure were similar among patients with LP and VP shunt (34.6% vs 31.7%; P = .382). Among patients who experienced shunt failure, the mean number of shunt failures was 2.1 ± 1.6 and was similar between LP and VP cohorts. Ninety-day readmission rates, complication rates, and costs did not differ significantly between LP and VP shunts. Patients who experienced more than two shunt failures tended to have an earlier time to first shunt failure (hazard ratio 1.41; 95% confidence interval 1.08-1.85; P = .013).These findings suggest that LP and VP shunts may have comparable rates of shunt failure and complication. Regardless of shunt type, earlier time to first shunt failure may be associated with multiple shunt failures.

    View details for PubMedID 30937428

  • Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nature communications Kahn, S. A., Wang, X., Nitta, R. T., Gholamin, S., Theruvath, J., Hutter, G., Azad, T. D., Wadi, L., Bolin, S., Ramaswamy, V., Esparza, R., Liu, K., Edwards, M., Swartling, F. J., Sahoo, D., Li, G., Wechsler-Reya, R. J., Reimand, J., Cho, Y., Taylor, M. D., Weissman, I. L., Mitra, S. S., Cheshier, S. H. 2018; 9 (1): 4651

    Abstract

    The original version of this Article omitted Suzana A. Kahn, Siddhartha S. Mitra & Samuel H. Cheshier as jointly supervising authors. This has now been corrected in both the PDF and HTML versions of the Article.

    View details for PubMedID 30389946

  • TREATMENT WITH THE CASEIN KINASE 2 INHIBITOR, CX-4945, SENSITIZES MEDULLOBLASTOMA TO TEMOZOLOMIDE Nitta, R., Li, G. OXFORD UNIV PRESS INC. 2018: 52–53
  • How Intraoperative Tools and Techniques Have Changed the Approach to Brain Tumor Surgery. Current oncology reports Fatemi, P., Zhang, M., Miller, K. J., Robe, P., Li, G. 2018; 20 (11): 89

    Abstract

    PURPOSE OF REVIEW: Surgical treatment of brain tumors remains an integral part of a comprehensive treatment plan. Here, we review technological advances that have enhanced what surgeons are capable of doing within and outside the traditional operating room.RECENT FINDINGS: Extent of surgical resection has improved with the use of MRI and fluorescent dyes intraoperatively. Neurological injury during brain tumor surgery has decreased with appropriate use of neurophysiological monitoring. New operative scopes have enhanced ability of surgeons to visualize tissues during dissection. Laser interstitial therapy and radiation treatment have made possible the treatment of previously considered non-operable brain tumors in addition to replacing or serving as adjunct to surgical treatment of brain tumors. Surgery remains an important pillar in treatment of most brain tumors. Ongoing technological advances have augmented extent of what is possible in this realm.

    View details for PubMedID 30259202

  • Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. Science signaling Purzner, T., Purzner, J., Buckstaff, T., Cozza, G., Gholamin, S., Rusert, J. M., Hartl, T. A., Sanders, J., Conley, N., Ge, X., Langan, M., Ramaswamy, V., Ellis, L., Litzenburger, U., Bolin, S., Theruvath, J., Nitta, R., Qi, L., Li, X., Li, G., Taylor, M. D., Wechsler-Reya, R. J., Pinna, L. A., Cho, Y., Fuller, M. T., Elias, J. E., Scott, M. P. 2018; 11 (547)

    Abstract

    A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

    View details for PubMedID 30206138

  • Casein kinase 2 is a major regulator of medulloblastoma growth Nitta, R., Bolin, S., Nwagbo, G., Purzner, T., Kahn, S., Cho, Y., Li, G. AMER ASSOC CANCER RESEARCH. 2018
  • In Reply: The Use of Vancomycin Powder for Surgical Prophylaxis Following Craniotomy NEUROSURGERY Ho, A. L., Li, G. H. 2018; 82 (2): E71

    View details for DOI 10.1093/neuros/nyx537

    View details for Web of Science ID 000424225800017

    View details for PubMedID 29149292

  • Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study. The oncologist Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2018

    Abstract

    Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting.Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

    View details for PubMedID 30126856

  • Multiple Extradural Spinal Meningiomas in a Patient with Acquired Immunodeficiency Syndrome: Case Report and Literature Review. World neurosurgery Ghanchi, H., Hariri, O. R., Takayanagi, A., Li, G. 2018

    View details for PubMedID 29966786

  • Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer. Journal of neuro-oncology Kakusa, B., Han, S., Aggarwal, S., Liu, B., Li, G., Soltys, S., Hayden Gephart, M. 2018

    Abstract

    Routine brain MRI surveillance frequently diagnoses small, asymptomatic brain metastases from non-small cell lung cancer (NSCLC) that are effectively treated with stereotactic radiosurgery (SRS). A subset of patients, however, may die prior to the onset of symptoms. This study identifies clinical features that distinguish neurologically-asymptomatic NSCLC brain metastases patients that die prior to routine 3 month follow-up after SRS.Retrospective chart review from 2007 to 2017 identified 18 patients with neurologically-asymptomatic NSCLC brain metastases who died < 3 months after SRS. Twenty-eight additional patients meeting criteria and surviving > 6 months after SRS were identified. Clinical factors were examined to determine characteristics correlated with survival using cox proportional hazards and nominal logistic regression models. Logistic regression models using salient factors were trained with 10-fold cross-validation and compared to the graded prognostic assessment (GPA) and score index of radiosurgery (SIR) using the AUC from receiver operant characteristic curves.The median survival following SRS was 1.4 and 9.2 months for the < 3 months and > 6 months groups, respectively. Age, number of brain metastases, and Karnofsky performance status were associated with overall survival while gender and interval between primary cancer and first brain metastasis diagnoses were associated with < 3 months and > 6 months survival, respectively. Models using GPA and SIR performed poorly compared to preliminary metrics generated in this study for prognosis of both < 3 months and > 6 months survival.Physicians require data to provide high-value, cost-conscious health care. Clinical metrics can screen patients with asymptomatic NSCLC brain metastases likely to die prior to the standard screening interval and observation could be considered.

    View details for PubMedID 30460628

  • Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors. Neurosurgery Chin, A. L., Fujimoto, D., Kumar, K. A., Tupper, L., Mansour, S., Chang, S. D., Adler, J. R., Gibbs, I. C., Hancock, S. L., Dodd, R., Li, G., Gephart, M. H., Ratliff, J. K., Tse, V., Usoz, M., Sachdev, S., Soltys, S. G. 2018

    Abstract

    Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data.To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors.We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy.Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed.Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

    View details for PubMedID 30445557

  • Topical vancomycin surgical prophylaxis in pediatric open craniotomies: an institutional experience. Journal of neurosurgery. Pediatrics Ho, A. L., Cannon, J. G., Mohole, J., Pendharkar, A. V., Sussman, E. S., Li, G., Edwards, M. S., Cheshier, S. H., Grant, G. A. 2018: 1–6

    Abstract

    OBJECTIVE Topical antimicrobial compounds are safe and can reduce cost and complications associated with surgical site infections (SSIs). Topical vancomycin has been an effective tool for reducing SSIs following routine neurosurgical procedures in the spine and following adult craniotomies. However, widespread adoption within the pediatric neurosurgical community has not yet occurred, and there are no studies to report on the safety and efficacy of this intervention. The authors present the first institution-wide study of topical vancomycin following open craniotomy in the pediatric population. METHODS In this retrospective study the authors reviewed all open craniotomies performed over a period from 05/2014 to 12/2016 for topical vancomycin use, SSIs, and clinical variables associated with SSI. Topical vancomycin was utilized as an infection prophylaxis and was applied as a liquid solution following replacement of a bone flap or after dural closure when no bone flap was reapplied. RESULTS Overall, 466 consecutive open craniotomies were completed between 05/2014 and 12/2016, of which 43% utilized topical vancomycin. There was a 1.5% SSI rate in the nontopical cohort versus 0% in the topical vancomycin cohort (p = 0.045). The number needed to treat was 66. There were no significant differences in risk factors for SSI between cohorts. There were no complications associated with topical vancomycin use. CONCLUSIONS Routine topical vancomycin administration during closure of open craniotomies can be a safe and effective tool for reducing SSIs in the pediatric neurosurgical population.

    View details for PubMedID 30141749

  • First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. Journal of neuro-oncology Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018

    Abstract

    Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

    View details for PubMedID 29623552

  • Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nature communications Kahn, S. A., Wang, X., Nitta, R. T., Gholamin, S., Theruvath, J., Hutter, G., Azad, T. D., Wadi, L., Bolin, S., Ramaswamy, V., Esparza, R., Liu, K. W., Edwards, M., Swartling, F. J., Sahoo, D., Li, G., Wechsler-Reya, R. J., Reimand, J., Cho, Y. J., Taylor, M. D., Weissman, I. L., Mitra, S. S., Cheshier, S. H. 2018; 9 (1): 4121

    Abstract

    Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

    View details for PubMedID 30297829

  • Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. Radiology Iv, M., Samghabadi, P., Holdsworth, S., Gentles, A., Rezaii, P., Harsh, G., Li, G., Thomas, R., Moseley, M., Daldrup-Link, H. E., Vogel, H., Wintermark, M., Cheshier, S., Yeom, K. W. 2018: 181204

    Abstract

    Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32-65 years]; mean age of all participants, 58 years ± 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.

    View details for PubMedID 30398435

  • Cranioplasty Complications and Costs: A National Population-Level Analysis Using the MarketScan Longitudinal Database. World neurosurgery Li, A., Azad, T. D., Veeravagu, A., Bhatti, I., Long, C., Ratliff, J. K., Li, G. 2017; 102: 209-220

    Abstract

    To characterize cranioplasty complications and costs at a population level using a longitudinal national claims database.We identified cranioplasty patients between 2007-2014 in the MarketScan national database. We evaluated age, autograft usage, cranioplasty size, and cranioplasty timing on postoperative outcomes. We further analyzed associated costs. A subset analysis of adult cranioplasty patients with emergent indications, including stroke and trauma, was also performed.We identified 8,275 patients (mean 44.0±20.0 years, 45.2% male) consisting of 13.8% pediatric (<18 years), 76.0% adults (18-64 years), and 10.2% elderly adults (>65 years). Overall complication rate was 36.6%, mortality rate 0.5%, and 30-day readmission rate 12.0%. Elderly patients had the highest complication rate (p<0.0001). Overall, large cranioplasties (>5 cm) saw higher complication rates than small cranioplasties (≤5 cm, p=0.047). In those with emergent indications only(N=1,282), size did not influence complications-though large cranioplasties showed higher infection risk (p=0.02). Overall, autograft use did not affect outcomes, but was associated with higher complication risk-including infections-in the subset with only emergent indications (p<0.001, p=0.001). Late (>90 days) cranioplasty timing had higher complication rates in both the overall cohort and subset with emergent indications (p<0.001, p<0.001). Index costs of care were mainly driven by hospital payments in both the overall cohort and those with emergent indications.We found a high complication rate associated with cranioplasty in the U.S.A. Older age, large cranioplasties, and delayed cranioplasties increased complication risk overall. Among those with only emergent indications, complications were associated with a delayed time to cranioplasty and autograft usage.

    View details for DOI 10.1016/j.wneu.2017.03.022

    View details for PubMedID 28315803

  • Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results. International journal of radiation oncology, biology, physics Pollom, E. L., Fujimoto, D., Wynne, J., Seiger, K., Modlin, L. A., Jacobs, L. R., Azoulay, M., von Eyben, R., Tupper, L., Gibbs, I. C., Hancock, S. L., Li, G., Chang, S. D., Adler, J. R., Harsh, G. R., Harraher, C., Nagpal, S., Thomas, R. P., Recht, L. D., Choi, C. Y., Soltys, S. G. 2017; 98 (1): 123-130

    Abstract

    We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide.HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point.With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01).On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.

    View details for DOI 10.1016/j.ijrobp.2017.01.242

    View details for PubMedID 28586949

  • History and current state of immunotherapy in glioma and brain metastasis THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY McGranahan, T., Li, G., Nagpal, S. 2017; 9 (5): 347-368

    Abstract

    Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

    View details for DOI 10.1177/1758834017693750

    View details for Web of Science ID 000400896200004

    View details for PubMedID 28529551

    View details for PubMedCentralID PMC5424864

  • The Use of Vancomycin Powder for Surgical Prophylaxis Following Craniotomy. Neurosurgery Ravikumar, V., Ho, A. L., Pendhakar, A. V., Sussman, E. S., Kwong-Hon Chow, K., Li, G. 2017; 80 (5): 754-758

    Abstract

    Intrawound vancomycin powder has been studied extensively in spinal fusion surgeries and been found to reduce rates of surgical site infections (SSIs) significantly. Despite its success in spinal surgeries, topical vancomycin has not been extensively studied with respect to cranial neurosurgery.To evaluate the efficacy of intrawound topical vancomycin for prevention of SSIs following open craniotomies.We retrospectively analyzed a large series of 350 patients from 2011 to 2015 in a pre/postintervention study of use of topical vancomycin to reduce postoperative craniotomy infection rates. We had a preintervention control group of 225 patients and a postintervention group of 125 patients that received intrawound topical vancomycin.Our preintervention incidence of SSI was 2.2% and this was significantly reduced to 0% following introduction of topical vancomycin ( P < .5). An ad hoc cost analysis suggested a cost savings of

  • Neurosurgery concepts: Key perspectives on endoscopic versus microscopic resection for pituitary adenomas, surgical decision-making in tuberculum sellae meningiomas, optic nerve mobilization during resection of craniopharyngiomas, and evaluation of headache and quality of life after endoscopic transphenoidal surgery for pituitary adenomas. Surgical neurology international Germanwala, A. V., Hofler, R., Lagman, C., Chung, L. K., Khalessi, A. A., Zada, G., Smith, Z. A., Dahdaleh, N. S., Bohnen, A. M., Cho, J. M., Colen, C. B., Duckworth, E., Kan, P., Lam, S., Kim, C. Y., Li, G., Lim, M., Sherman, J. H., Wang, V. Y., Yang, I. 2017; 8: 52

    View details for PubMedID 28480114

  • Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell reports Darmanis, S., Sloan, S. A., Croote, D., Mignardi, M., Chernikova, S., Samghababi, P., Zhang, Y., Neff, N., Kowarsky, M., Caneda, C., Li, G., Chang, S. D., Connolly, I. D., Li, Y., Barres, B. A., Gephart, M. H., Quake, S. R. 2017; 21 (5): 1399–1410

    Abstract

    Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor's genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.

    View details for PubMedID 29091775

  • Imaging changes over 18 months following stereotactic radiosurgery for brain metastases: both late radiation necrosis and tumor progression can occur. Journal of neuro-oncology Fujimoto, D., von Eyben, R., Gibbs, I. C., Chang, S. D., Li, G., Harsh, G. R., Hancock, S., Fischbein, N., Soltys, S. G. 2017

    Abstract

    Following stereotactic radiosurgery (SRS) for brain metastases, the median time range to develop adverse radiation effect (ARE) or radiation necrosis is 7-11 months. Similarly, the risk of local tumor recurrence following SRS is < 5% after 18 months. With improvements in systemic therapy, patients are living longer and are at risk for both late (defined as > 18 months after SRS) tumor recurrence and late ARE, which have not previously been well described. An IRB-approved, retrospective review identified patients treated with SRS who developed new MRI contrast enhancement > 18 months following SRS. ARE was defined as stabilization/shrinkage of the lesion over time or pathologic confirmation of necrosis, without tumor. Local failure (LF) was defined as continued enlargement of the lesion over time or pathologic confirmation of tumor. We identified 16 patients, with a median follow-up of 48.2 months and median overall survival of 73.0 months, who had 19 metastases with late imaging changes occurring a median of 32.9 months (range 18.5-63.2 months) after SRS. Following SRS, 12 lesions had late ARE at a median of 33.2 months and 7 lesions had late LF occurring a median of 23.6 months. As patients with cancer live longer and as SRS is increasingly utilized for treatment of brain metastases, the incidence of these previously rare imaging changes is likely to increase. Clinicians should be aware of these late events, with ARE occurring up to 5.3 years and local failure up to 3.8 years following SRS in our cohort.

    View details for PubMedID 29098569

  • Endoscopic vs. Microscopic Resection of Sellar Lesions-A Matched Analysis of Clinical and Socioeconomic Outcomes. Frontiers in surgery Azad, T. D., Lee, Y. J., Vail, D., Veeravagu, A., Hwang, P. H., Ratliff, J. K., Li, G. 2017; 4: 33

    Abstract

    Direct comparisons of microscopic and endoscopic resection of sellar lesions are scarce, with conflicting reports of cost and clinical outcome advantages.To determine if the proposed benefits of endoscopic resection are realized on a population level.We performed a matched cohort study of 9,670 adult patients in the MarketScan database who underwent either endoscopic or microscopic surgery for sellar lesions. Coarsened matching was applied to estimate the effects of surgical approach on complication rates, length of stay (LOS), costs, and likelihood of postoperative radiation.We found that LOS, readmission, and revision rates did not differ significantly between approaches. The overall complication rate was higher for endoscopy (47% compared to 39%, OR 1.37, 95% CI 1.22-1.53). Endoscopic approach was associated with greater risk of neurological complications (OR 1.32, 95% CI 1.11-1.55), diabetes insipidus (OR 1.65, 95% CI 1.37-2.00), and cerebrospinal fluid rhinorrhea (OR 1.83, 95% CI 1.07-3.13) compared to the microscopic approach. Although the total index payment was higher for patients receiving endoscopic resection (

  • Neurosurgery concepts: Key perspectives on imaging characteristics of spinal metastases, surgery for low back pain, anesthesia for disc surgery, and laminectomy versus laminectomy and fusion for lumbar spondylolisthesis. Surgical neurology international Lagman, C., Chung, L. K., Macyszyn, L., Choy, W., Smith, Z. A., Dahdaleh, N. S., Bohnen, A. M., Cho, J. M., Colen, C. B., Duckworth, E., Germanwala, A. V., Kan, P., Khalessi, A. A., Kim, C. Y., Lam, S., Li, G., Lim, M., Sherman, J. H., Wang, V. Y., Zada, G., Yang, I. 2017; 8: 9

    View details for PubMedID 28217388