Bio

Clinical Focus


  • Cancer > Neuro Oncology
  • Minimally Invasive Surgical Procedures
  • Brain Tumors
  • radiosurgery
  • Neurosurgery

Academic Appointments


Honors & Awards


  • Stanford Spectrum-Medtech Translational Grant, Stanford Spectrum (2014)
  • Stanford Cancer Institute Bioscience Screening Award, Stanford Cancer Institute (2014)
  • K08 Mentored Research Grant: PI, NIH-KNS085333A (2013-2018)
  • Disease Team Therapy Development Planning Award (Planning Investigator), CIRM (DR2-05373) (2011-2012)
  • Center for Brain and Behavior Awards in Pediatric Neurosciences (co-investigator), Lucile Packard Children's Hospital (2009-2011)
  • Grand Opportunity Grant (co-investigator), NIH (RC2CA148491-01) (2009-2011)
  • Ruth L. Kirschstein National Research Service Award (PI), NIH-NCI (1F32CA132329-01) (2008-2010)
  • SANS Challenge Finalist, Congress of Neurological Surgeons (2008)
  • Junior AOA, University of California, Davis (2002)
  • Ernest Gold Award, University of California, Davis (2001)
  • Predoctoral Research Award, University of California, Davis (2001)
  • Plummer Linzy Scholarship, University of California, Davis (2000)

Professional Education


  • Medical Education:University of California Davis (2004) CA
  • Residency:Stanford University (2011) CA
  • Internship:Stanford University (2005) CA
  • Bachelor of Science, Brown University, Neuroscience (1999)

Research & Scholarship

Current Research and Scholarly Interests


1.) My laboratory studies the biology of brain tumors with the goal of developing novel therapeutics for the treatment of malignant brain tumors and translating that research into clinical trials.
2.) My clinical interests include improving surgical techniques for brain tumor surgery, immunotherapy for the treatment of glioblastoma, and novel uses for stereotactic radiosurgery.

Clinical Trials


  • A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma Recruiting

    The purpose of this research study is to find out whether adding an experimental vaccine called rindopepimut (also known as CDX-110) to the commonly used drug bevacizumab can improve progression free survival (slowing the growth of tumors) of patients with relapsed EGFRvIII positive glioblastoma.

    View full details

  • Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas Not Recruiting

    This is a research study of patients with diffuse intrinsic pontine gliomas. We hope to learn about the safety and efficacy of treating pediatric diffuse intrinsic pontine glioma patients with the EGFRvIII peptide vaccine after conventional radiation.

    Stanford is currently not accepting patients for this trial. For more information, please contact Christina Huang, 650-723-0574.

    View full details

Teaching

2013-14 Courses


Publications

Journal Articles


  • Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III. Cancer research Emlet, D. R., Gupta, P., Holgado-Madruga, M., Del Vecchio, C. A., Mitra, S. S., Han, S., Li, G., Jensen, K. C., Vogel, H., Xu, L. W., Skirboll, S. S., Wong, A. J. 2014; 74 (4): 1238-1249

    Abstract

    The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII- cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

    View details for DOI 10.1158/0008-5472.CAN-13-1407

    View details for PubMedID 24366881

  • Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Atalar, B., Modlin, L. A., Choi, C. Y., Adler, J. R., Gibbs, I. C., Chang, S. D., Harsh, G. R., Li, G., Nagpal, S., Hanlon, A., Soltys, S. G. 2013; 87 (4): 713-718

    Abstract

    We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients.We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other).With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004).In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.

    View details for DOI 10.1016/j.ijrobp.2013.07.034

    View details for Web of Science ID 000325763300022

    View details for PubMedID 24054875

  • Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. Journal of clinical neuroscience Chaichana, K. L., Pendleton, C., Chambless, L., Camara-Quintana, J., Nathan, J. K., Hassam-Malani, L., Li, G., Harsh, G. R., Thompson, R. C., Lim, M., Quinones-Hinojosa, A. 2013; 20 (10): 1422-1426

    Abstract

    Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p<0.0001), Karnofsky Performance Scale score ≤80 (p=0.03), motor deficit (p=0.02), language deficit (p=0.04), and periventricular tumor location (p=0.04). Patients possessing 0-1, 2, 3, and 4-5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3, 10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p<0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.

    View details for DOI 10.1016/j.jocn.2013.02.007

    View details for PubMedID 23928040

  • The invasive nature of glioblastoma. World neurosurgery Nitta, R. T., Li, G. 2013; 80 (3-4): 279-280

    View details for DOI 10.1016/j.wneu.2011.09.036

    View details for PubMedID 22120249

  • The incidence and significance of multiple lesions in glioblastoma JOURNAL OF NEURO-ONCOLOGY Thomas, R. P., Xu, L. W., Lober, R. M., Li, G., Nagpal, S. 2013; 112 (1): 91-97

    Abstract

    The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances.

    View details for DOI 10.1007/s11060-012-1030-1

    View details for Web of Science ID 000315487900011

    View details for PubMedID 23354652

  • Neurosurgery concepts: Key perspectives on regulatory proteins, management of ossification of the posterior longitudinal ligament, and radiosurgery for intracranial lesions. Surgical neurology international Sherman, J. H., Smith, Z. A., Cho, J. M., Lim, M., Colen, C. B., Kim, C., Wang, V. Y., Zada, G., Li, G., Yang, I. 2013; 4: 35-?

    View details for DOI 10.4103/2152-7806.109525

    View details for PubMedID 23607057

  • The predictive value of serum myeloperoxidase for vasospasm in patients with aneurysmal subarachnoid hemorrhage NEUROSURGICAL REVIEW Lim, M., Bower, R. S., Wang, Y., Sims, L., Bower, M. R., Camara-Quintana, J., Li, G., Cheshier, S., Harsh, G. R., Steinberg, G. K., Guccione, S. 2012; 35 (3): 413-419

    Abstract

    Vasospasm is a major contributor to morbidity and mortality in aneurysmal subarachnoid hemorrhage (SAH), with inflammation playing a key role in its pathophysiology. Myeloperoxidase (MPO), an inflammatory marker, was examined as a potential marker of vasospasm in patients with SAH. Daily serum samples from patients with aneurysmal SAH were assayed for MPO, and transcranial Doppler (TCDs) and neurological exams were assessed to determine vasospasm. Suspected vasospasm was confirmed by angiography. Peak MPO levels were then compared with timing of onset of vasospasm, based on clinical exams, TCDs and cerebral angiography. Patients with vasospasm had a mean MPO level of 115.5 ng/ml, compared to 59.4 ng/ml in those without vasospasm, 42.0 ng/ml in those with unruptured aneurysms, and 4.3 ng/ml in normal controls. In patients who experienced vasospasm, MPO was elevated above the threshold on the day of, or at any point prior to, vasospasm in 10 of 15 events (66.7%), and on the day of, or within 2 days prior to, vasospasm in 8 of 15 events (53.3%). Elevated serum MPO correlates with clinically evident vasospasm following aneurysmal SAH. The potential utility of MPO as a marker of vasospasm is discussed.

    View details for DOI 10.1007/s10143-012-0375-4

    View details for Web of Science ID 000305230000023

    View details for PubMedID 22370810

  • Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas JOURNAL OF NEURO-ONCOLOGY Li, G., Mitra, S. S., Monje, M., Henrich, K. N., Bangs, C. D., Nitta, R. T., Wong, A. J. 2012; 108 (3): 395-402

    Abstract

    Despite numerous clinical trials over the past 2 decades, the overall survival for children diagnosed with diffuse intrinsic pontine glioma (DIPG) remains 9-10 months. Radiation therapy is the only treatment with proven effect and novel therapies are needed. Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the epidermal growth factor receptor and is expressed in many tumor types but is rarely found in normal tissue. A peptide vaccine targeting EGFRvIII is currently undergoing investigation in phase 3 clinical trials for the treatment of newly diagnosed glioblastoma (GBM), the tumor in which this variant receptor was first discovered. In this study, we evaluated EGFRvIII expression in pediatric DIPG samples using immunohistochemistry with a double affinity purified antibody raised against the EGFRvIII peptide. Staining of pediatric DIPG histological samples revealed expression in 4 of 9 cases and the pattern of staining was consistent with what has been seen in EGFRvIII transfected cells as well as GBMs from adult trials. In addition, analysis of tumor samples collected immediately post mortem and of DIPG cells in culture by RT-PCR, western blot analysis, and flow cytometry confirmed EGFRvIII expression. We were therefore able to detect EGFRvIII expression in 6 of 11 DIPG cases. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors.

    View details for DOI 10.1007/s11060-012-0842-3

    View details for Web of Science ID 000305123800007

    View details for PubMedID 22382786

  • Arachnoid ossificans containing metaplastic hematopoietic marrow resulting in diffuse thoracic intrathecal cysts and severe myelopathy. European spine journal Abrams, J., Li, G., Mindea, S. A., Haynes, C. M., Cheng, I. 2012; 21: S436-40

    Abstract

    To present a rare case of multiple compressive thoracic intradural cysts with pathologic arachnoid ossification, review the literature and present the surgical options. Few reports have identified the existence of arachnoid calcifications and intrathecal cysts causing progressive myelopathy. The literature regarding each of these pathologies is limited to case reports. Their clinical significance is not well studied, although known to cause neurologic sequelae.An 81-year-old female clinically presents with rapidly progressive myelopathy. Pre-operative magnetic resonance imaging identified multiple compressive thoracic intrathecal cysts. Surgical exploration and decompression of these cysts identified calcified plaques within the arachnoid. Histopathologic examination revealed fibrocalcific tissue undergoing ossification with bone marrow elements.Due to progressive myelopathy, the thoracic cysts were decompressed and calcified plaques were excised, once identified intra-operatively.On last examination, the patient's neurologic status had not improved, but had stabilized. The rate of neurologic improvement from excision and decompression is variable, but it may still be warranted in the face of progressive neurologic deficits.

    View details for DOI 10.1007/s00586-011-2005-1

    View details for PubMedID 21892775

  • The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. B., Alizadeh, A. A., Clarke, M. F., Weissman, I. L. 2012; 109 (17): 6662-6667

    Abstract

    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRP?, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

    View details for DOI 10.1073/pnas.1121623109

    View details for Web of Science ID 000303249100065

    View details for PubMedID 22451913

  • Pathology: Commonly Monitored Glioblastoma Markers: EFGR, EGFRvIII, PTEN, and MGMT NEUROSURGERY CLINICS OF NORTH AMERICA Camara-Quintana, J. Q., Nitta, R. T., Li, G. 2012; 23 (2): 237-?

    Abstract

    The purpose of this article is to update the neurosurgical field on current molecular markers important to glioblastoma biology, treatment, and prognosis. The highlighted biologic markers in this article include epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O6-methylguanine-DNA methyltransferase (MGMT).

    View details for DOI 10.1016/j.nec.2012.01.011

    View details for Web of Science ID 000303282100006

    View details for PubMedID 22440867

  • Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas EXPERT REVIEW OF VACCINES Del Vecchio, C. A., Li, G., Wong, A. J. 2012; 11 (2): 133-144

    Abstract

    Glioblastoma multiforme (GBM) is the most common and deadly of the human brain cancers. The EGF receptor is often amplified in GBM and provides a potential therapeutic target. However, targeting the normal receptor is complicated by its nearly ubiquitous and high level of expression in certain tissues. A naturally occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively active variant originally identified in a high percentage of brain cancer cases, and more importantly is rarely found in normal tissue. A peptide vaccine, rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon 1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy in preclinical models. Recent Phase II clinical trials in patients with newly diagnosed GBM have shown EGFRvIII-specific immune responses and significantly increased time to progression and overall survival in those receiving vaccine therapy, as compared with published results for standard of care. Rindopepimut therefore represents a very promising therapy for patients with GBM.

    View details for DOI 10.1586/ERV.11.177

    View details for Web of Science ID 000300758700009

    View details for PubMedID 22309662

  • Perspectives on key articles in neurosurgery. Surgical neurology international Lim, M., Sherman, J. H., Wang, V. Y., Smith, Z. A., Cho, J. M., Colen, C. B., Kim, C. Y., Zada, G., Li, G., Yang, I. 2012; 3: 58-?

    View details for DOI 10.4103/2152-7806.96869

    View details for PubMedID 22754723

  • RADIOSURGERY OF GLOMUS JUGULARE TUMORS: A META-ANALYSIS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Guss, Z. D., Batra, S., Limb, C. J., Li, G., Sughrue, M. E., Redmond, K., Rigamonti, D., Parsa, A. T., Chang, S., Kleinberg, L., Lim, M. 2011; 81 (4): E497-E502

    Abstract

    During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors.To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta-analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data when Cochrane's statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test.Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control.The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors.

    View details for DOI 10.1016/j.ijrobp.2011.05.006

    View details for Web of Science ID 000309412300039

    View details for PubMedID 21703782

  • Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Monje, M., Mitra, S. S., Freret, M. E., Raveh, T. B., Kim, J., Masek, M., Attema, J. L., Li, G., Haddix, T., Edwards, M. S., Fisher, P. G., Weissman, I. L., Rowitch, D. H., Vogel, H., Wong, A. J., Beachy, P. A. 2011; 108 (11): 4453-4458

    Abstract

    Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.

    View details for DOI 10.1073/pnas.1101657108

    View details for Web of Science ID 000288450900040

    View details for PubMedID 21368213

  • Neurosurgery concepts. Surgical neurology international Yang, I., Cho, J. M., Colen, C. B., Li, G., Lim, M., Sherman, J. H., Wang, V. Y. 2011; 2: 173-?

    View details for DOI 10.4103/2152-7806.90444

    View details for PubMedID 22259751

  • Development of an EGFRvIII specific recombinant antibody BMC BIOTECHNOLOGY Gupta, P., Han, S., Holgado-Madruga, M., Mitra, S. S., Li, G., Nitta, R. T., Wong, A. J. 2010; 10

    Abstract

    EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor observed in human tumors. It results from the in frame deletion of exons 2-7 and the generation of a novel glycine residue at the junction of exons 1 and 8. This novel juxtaposition of amino acids within the extra-cellular domain of the EGF receptor creates a tumor specific and immunogenic epitope. EGFRvIII expression has been seen in many tumor types including glioblastoma multiforme (GBM), breast adenocarcinoma, non-small cell lung carcinoma, ovarian adenocarcinoma and prostate cancer, but has been rarely observed in normal tissue. Because this variant is tumor specific and highly immunogenic, it can be used for both a diagnostic marker as well as a target for immunotherapy. Unfortunately many of the monoclonal and polyclonal antibodies directed against EGFRvIII have cross reactivity to wild type EGFR or other non-specific proteins. Furthermore, a monoclonal antibody to EGFRvIII is not readily available to the scientific community.In this study, we have developed a recombinant antibody that is specific for EGFRvIII, has little cross reactivity for the wild type receptor, and which can be easily produced. We initially designed a recombinant antibody with two anti-EGFRvIII single chain Fv's linked together and a human IgG1 Fc component. To enhance the specificity of this antibody for EGFRvIII, we mutated tyrosine H59 of the CDRH2 domain and tyrosine H105 of the CDRH3 domain to phenylalanine for both the anti-EGFRvIII sequence inserts. This mutated recombinant antibody, called RAb(DMvIII), specifically detects EGFRvIII expression in EGFRvIII expressing cell lines as well as in EGFRvIII expressing GBM primary tissue by western blot, immunohistochemistry (IHC) and immunofluorescence (IF) and FACS analysis. It does not recognize wild type EGFR in any of these assays. The affinity of this antibody for EGFRvIII peptide is 1.7 × 10? M?¹ as determined by enzyme-linked immunosorbent assay (ELISA).This recombinant antibody thus holds great potential to be used as a research reagent and diagnostic tool in research laboratories and clinics because of its high quality, easy viability and unique versatility. This antibody is also a strong candidate to be investigated for further in vivo therapeutic studies.

    View details for DOI 10.1186/1472-6750-10-72

    View details for Web of Science ID 000283354200001

    View details for PubMedID 20925961

  • Pineal Parenchymal Tumor of Intermediate Differentiation: Clinicopathological Report and Analysis of Epidermal Growth Factor Receptor Variant III Expression NEUROSURGERY Li, G., Mitra, S., Karamchandani, J., Edwards, M. S., Wong, A. J. 2010; 66 (5): 963-968

    Abstract

    Epidermal growth factor receptor (EGF) receptor gene amplification is commonly seen in cancer and is the target of many therapies. EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor and has been detected in a large percentage of patients with glioblastoma multiforme but not in normal brain. Therapies targeting EGFRvIII are currently being investigated in clinical and preclinical trials.A 14-year-old girl who presented with headaches was found to have a pineal parenchymal tumor of intermediate differentiation. We review the histopathological properties that led to the diagnosis of this tumor. EGF receptor gene amplification and EGFRvIII expression have not been analyzed in pineal tumors. We investigated EGF receptor gene status and EGFRvIII expression in this patient's tumor.Tumor tissue was obtained and analyzed with flow cytometry, reverse-transcriptase polymerase chain reaction, and Western blot analysis. EGFRvIII was detected by all 3 methods. The tumor was further analyzed by fluorescence in situ hybridization, which did not reveal EGF receptor gene amplification.This is the first report of EGFRvIII expression in a pineal tumor. It is interesting that this variant is detected in the absence of EGF receptor gene amplification. A larger study evaluating the presence of EGFRvIII in pineal tumors is needed.

    View details for DOI 10.1227/01.NEU.0000367726.49003.F1

    View details for Web of Science ID 000276970800026

    View details for PubMedID 20404701

  • Passive Antibody-Mediated Immunotherapy for the Treatment of Malignant Gliomas NEUROSURGERY CLINICS OF NORTH AMERICA Mitra, S., Li, G., Harsh, G. R. 2010; 21 (1): 67-?

    Abstract

    Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

    View details for DOI 10.1016/j.nec.2009.08.010

    View details for Web of Science ID 000278059500007

    View details for PubMedID 19944967

  • The Epidermal Growth Factor Variant III Peptide Vaccine for Treatment of Malignant Gliomas NEUROSURGERY CLINICS OF NORTH AMERICA Li, G., Mitra, S., Wong, A. J. 2010; 21 (1): 87-?

    Abstract

    Epidermal growth factor variant III (EGFRvIII) is the most common alteration of the epidermal growth factor (EGF) receptor found in human tumors. It is commonly expressed in glioblastoma multiforme (GBM), where it was initially identified. This constitutively active mutant receptor leads to unregulated growth, survival, invasion, and angiogenesis in cells that express it. EGFRvIII results from an in-frame deletion of exons 2 to 7 resulting in the fusion of exon 1 to exon 8 of the EGF receptor gene creating a novel glycine at the junction in the extracellular amino terminal domain. The juxtaposition of ordinarily distant amino acids in combination with the glycine that forms at the junction leads to a novel tumor-specific epitope that would make an ideal tumor-specific target. A peptide derived from the EGFRvIII junction can be used as a vaccine to prevent or induce the regression of tumors. This peptide vaccine has now proceeded to phase 1 and 2 clinical trials where it has been highly successful and is now undergoing investigation in a larger human clinical trial for patients who have newly diagnosed GBM. In this article, the authors discuss the preclinical data that led to the human trials and the exciting preliminary data from the clinical trials.

    View details for DOI 10.1016/j.nec.2009.08.004

    View details for Web of Science ID 000278059500009

    View details for PubMedID 19944969

  • Radiosurgery for glomus jugulare: history and recent progress NEUROSURGICAL FOCUS Guss, Z. D., Batra, S., Li, G., Chang, S. D., Parsa, A. T., Rigamont, D., Kleinberg, L., Lim, M. 2009; 27 (6)

    Abstract

    In this article the authors review the literature for recent studies of radiosurgical treatment for glomus jugulare. These studies demonstrate that radiosurgery results in similar glomus jugulare tumor control and a superior morbidity profile compared with surgical treatment. In addition, patients treated with radiosurgery usually remain stable clinically or improve. Given the indolent nature of these tumors, however, more follow-up is required to ensure that the immediate benefits are lasting. These preliminary reports demonstrate that the use of radiosurgery as a primary treatment for glomus jugulare should be extended to encompass more of the patients who are currently assigned to microsurgical treatment.

    View details for DOI 10.3171/2009.9.FOCUS09195

    View details for Web of Science ID 000272301500007

    View details for PubMedID 19951058

  • CYBERKNIFE FOR BRAIN METASTASES OF MALIGNANT MELANOMA AND RENAL CELL CARCINOMA NEUROSURGERY Hara, W., Tran, P., Li, G., Su, Z., Puataweepong, P., Adler, J. R., Soltys, S. G., Chang, S. D., Gibbs, I. C. 2009; 64 (2): A26-A32

    Abstract

    To evaluate the efficacy of CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS) for patients with brain metastases of malignant melanoma and renal cell carcinoma.We conducted a retrospective review of all patients treated by image-guided radiosurgery at our institution between March 1999 and December 2005. Sixty-two patients with 145 brain metastases of renal cell carcinoma or melanoma were identified.The median follow-up period was 10.5 months. Forty-four patients had malignant melanoma, and 18 patients had renal cell carcinoma. The median age was 57 years, and patients were classified as recursive partitioning analysis Class 1 (6 patients), 2 (52 patients) or 3 (4 patients). Thirty-three patients had been treated systemically with either chemotherapy or immunotherapy, and 33 patients were taking corticosteroids at the time of treatment. The mean tumor volume was 1.47 mL (range, 0.02-35.7 mL), and the mean prescribed dose was 20 Gy (range, 14-24 Gy). The median survival after SRS was 8.3 months. Actuarial survival at 6 and 12 months was 57 and 37%, respectively. On multivariate analysis, Karnofsky Performance Scale score (P < 0.01) and previous immunotherapy/clinical trial (P = 0.01) significantly affected overall survival. One-year intracranial progression-free survival was 38%, and local control was 87%. Intracranial control was impacted by whole-brain radiotherapy (P = 0.01), previous chemotherapy (P = 0.01), and control of the primary at the time of SRS (P = 0.02). Surgical resection had no effect on intracranial or local control. Radiographic evidence of radiation necrosis developed in 4 patients (6%).CyberKnife radiosurgery provided excellent local control with acceptable toxicity in patients with melanoma or renal cell brain metastases. Initial SRS alone appeared to be a reasonable option, as survival was dictated by systemic disease.

    View details for DOI 10.1227/01.NEU.0000339118.55334.EA

    View details for Web of Science ID 000262797700009

    View details for PubMedID 19165071

  • Perioperative management of ventriculoperitoneal shunts during abdominal surgery SURGICAL NEUROLOGY Li, G., Dutta, S. 2008; 70 (5): 492-497

    Abstract

    Patients with ventriculoperitoneal shunts (VPSs) inserted for a variety of disorders may subsequently undergo gastrointestinal or urologic operations, and surgeons must determine the appropriate perioperative management to minimize the risk for shunt malfunction or infection. There is currently no established set of guidelines for this scenario. The objective of this study was to determine the risks and standard of practice for patients with VPSs undergoing abdominal surgery.A retrospective review of the charts of patients with VPSs who underwent abdominal or urologic surgery at the Stanford University Medical Center between 1995 and 2003 was performed. Data regarding type of abdominal surgery, level of contamination, choice of antibiotic therapy, perioperative management of the VPS, and outcomes were obtained.Twenty-six patient charts were reviewed, for a total of 39 operations (5 urologic, 23 upper gastrointestinal, and 11 lower gastrointestinal). Of these, 3 were clean, 34 were clean-contaminated, and 2 were dirty operations. Seven cases were laparoscopic, whereas 32 were open. Thirty-four cases required opening the bowel or urologic system. No patient had preoperative shunt externalization. All except one patient received pre- and postoperative antibiotics, but the duration and type of antibiotics were widely variable. The remaining patient had an inguinal hernia repair and received only one preoperative dose of cephalexin. Purulent fluid was found in 2 cases. One VPS found lying in purulent material next to an anastomotic leak was externalized and subsequently revised. However, in another patient, a VPS found lying next to a purulent jejunal tear was not externalized. This patient returned 2 months later with a VPS malfunction. In the remaining 35 cases, no VPS infection or malfunction was noted over 2 to 10 years of follow-up.The data suggest that there is minimal risk for VPS malfunction or infection among patients undergoing routine clean and clean-contaminated abdominal and urologic surgeries. Patients with VPSs undergoing these operations do not need externalization of their shunt. None of the patients in this study had a contaminated procedure. For dirty procedures, surgeons should opt to externalize the shunt. Future studies will aim to better standardize the perioperative management of VPSs during abdominal surgery.

    View details for DOI 10.1016/j.surneu.2007.08.050

    View details for Web of Science ID 000270846100009

    View details for PubMedID 18207538

  • EGF receptor variant III as a target antigen for tumor immunotherapy EXPERT REVIEW OF VACCINES Li, G., Wong, A. J. 2008; 7 (7): 977-985

    Abstract

    The EGF receptor (EGFR) is the first tyrosine kinase receptor ever cloned and remains at the forefront of targeted therapies against cancer. Currently, there are four US FDA-approved drugs and several more in Phase III studies that target the EGFR. These drugs, while resulting in some dramatic remissions, have not resulted in strong nor consistent improvements in survival. EGFR variant III (EGFRvIII) is the most common variant of the EGFR and is present in many different cancer types but not in normal tissue. It results from the fusion of exon 1 to exon 8 of the EGFR gene, which results in a novel glycine at the junction. This mutant receptor is constitutively active in these tumors and can lead directly to cancer phenotypes due to its oncogenic properties. EGFRvIII is an attractive target antigen for cancer immunotherapy because it is not expressed in normal tissue and because cells producing EGFRvIII have an enhanced capacity for dysregulated growth, survival, invasion and angiogenesis. In this review, we will discuss preclinical and clinical data from studies using EGFRvIII as the target antigen for immunotherapy, with a focus on the potential for greatly improved survival for patients diagnosed with glioblastoma multiforme.

    View details for DOI 10.1586/14760584.7.7.977

    View details for Web of Science ID 000259334600016

    View details for PubMedID 18767947

  • Effects of age and Comorbidities on complication rates and adverse outcomes after lumbar laminectomy in elderly patients SPINE Li, G., Patil, C. G., Lad, S. P., Ho, C., Tian, W., Boakye, M. 2008; 33 (11): 1250-1255

    Abstract

    This is a retrospective cohort study using the National Inpatient Sample database.The objective is to report mortality and complications after lumbar laminectomy in the elderly.As the population continues to age in the United States, it is important to consider the surgical complications and outcomes in the elderly. A review of the literature reveals controversy over the safety of lumbar laminectomy in the elderly and disagreement over estimates of risks in this population.Outcome measures were abstracted from the National Inpatient Sample. Multivariate analysis was performed to analyze the effect of patient and hospital characteristics on outcome measures.A total of 471,215 patients underwent lumbar laminectomy without fusion for lumbar stenosis from 1993 to 2002. The in-hospital mortality rate was 0.17%, and the complication rate was 12.17%. Postoperative hemorrhage or hematoma (5.2%) and nonspecific renal complications (2.8%) were the most common complications. Complication and mortality rates increased with age and comorbidities with an 18.9% complication rate and 1.4% mortality rate in patients over the age of 85 with 3 or more comorbidities, 14.7% complication rate and 0.22% mortality rate in patients over 85 with no comorbidities, and only a 6% complication rate and 0.05% mortality rate in patient between 18 and 44 with no comorbidities. Multivariate analysis revealed increased odds of mortality with increasing number of comorbidities and complications in the greater than 85 year age group. Increasing age, number of comorbidities, complication rate, and female sex also increased the odds of discharge to institution other than home.Elderly patients with comorbidities are at a higher risk for complications and adverse outcome after lumbar spine surgery. The effects of age and comorbidities on patient outcomes have been quantified. This information is critical in counseling elderly patients about the risk of surgery in their age group.

    View details for Web of Science ID 000255829200014

    View details for PubMedID 18469700

  • Intracranial hypotension from intrathecal baclofen pump insertion STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Lad, S. P., Li, G., Lin, S., Henderson, J. M. 2008; 86 (2): 75-79

    Abstract

    Intracranial hypotension is a syndrome of low cerebrospinal fluid pressure with a variable clinical presentation ranging from postural headaches to coma. A number of neuroradiologic techniques are now available to aid in the diagnosis of this syndrome (CT, MRI, radioisotope cisternography and CT myelography), each showing specific radiographic abnormalities. In this report, we present a case of intracranial hypotension secondary to baclofen pump placement. We review the major clinical findings, neuroimaging abnormalities, key diagnostic features as well as treatment options.

    View details for DOI 10.1159/000112427

    View details for Web of Science ID 000253247300002

    View details for PubMedID 18073519

  • CyberKnife radiosurgical rhizotomy for the treatment of atypical trigeminal nerve pain. Neurosurgical focus Patil, C. G., Veeravagu, A., Bower, R. S., Li, G., Chang, S. D., Lim, M., Adler, J. R. 2007; 23 (6): E9-?

    Abstract

    Patients with atypical trigeminal neuralgia (TN) have unilateral pain in the trigeminal distribution that is dull, aching, or burning in nature and is constant or nearly constant. Studies of most radiosurgical and surgical series have shown lower response rates in patients with atypical TN. This study represents the first report of the treatment of atypical TN with frameless CyberKnife stereotactic radiosurgery (SRS).Between 2002 and 2007, 7 patients that satisfied the criteria for atypical TN and underwent SRS were included in our study. A 6-8-mm segment of the trigeminal nerve was targeted, excluding the proximal 3 mm at the brainstem. All patients were treated in a single session with a median maximum dose of 78 Gy and a median marginal dose of 64 Gy.Outcomes in 7 patients with a mean age of 61.6 years and a median follow-up of 20 months are reported. Following SRS, 4 patients had complete pain relief, 2 had minimal pain relief with some decrease in the intensity of their pain, and 1 patient experienced no pain relief. Pain relief was reported within 1 week of SRS in 4 patients and at 4 months in 2 patients. After a median follow-up of 28 months, pain did not recur in any of the 4 patients who had reported complete pain relief. Complications after SRS included bothersome numbness in 3 patients and significant dysesthesias in 1 patient.The authors have previously reported a 90% rate of excellent pain relief in patients with classic TN treated with CyberKnife SRS. Compared with patients with classic TN, patients with atypical TN have a lower rate of pain relief. Nevertheless, the nearly 60% rate of success after SRS achieved in this study is still comparable to or better than results achieved with any other treatment modality for atypical TN.

    View details for PubMedID 18081486

  • Irradiation of glomus jugulare tumors: a historical perspective. Neurosurgical focus Li, G., Chang, S., Adler, J. R., Lim, M. 2007; 23 (6): E13-?

    Abstract

    Glomus jugulare tumors are rare, slow-growing vascular lesions that arise from the chief cells of the paraganglia within the jugular bulb. They can be associated with the tympanic branch of the glossopharyngeal nerve (Jacobsen nerve) or the auricular branch of the vagus nerve (Arnold nerve) and are also referred to as chemodectomas or nonchromaffin paragangliomas. Optimal treatment of these histologically benign tumors remains controversial. Surgery remains the treatment of choice, but can carry high morbidity rates. External-beam radiation was originally used for subtotal resections and in patients who were poor surgical candidates; however, radiosurgery has recently been introduced as an effective and safe treatment option for patients with these tumors. In this article the authors discuss the history of radiation therapy for glomus jugulare tumors, focusing on recent radiosurgical results.

    View details for PubMedID 18081478

  • CyberKnife rhizotomy for facetogenic back pain: a pilot study. Neurosurgical focus Li, G., Patil, C., Adler, J. R., Lad, S. P., Soltys, S. G., Gibbs, I. C., Tupper, L., Boakye, M. 2007; 23 (6): E2-?

    Abstract

    By targeting the medial branches of the dorsal rami, radiofrequency ablation and facet joint injections can provide temporary amelioration of facet joint-producing (or facetogenic) back pain. The authors used CyberKnife radiosurgery to denervate affected facet joints with the goal of obtaining a less invasive yet more thorough and durable antinociceptive rhizotomy.Patients with refractory low-back pain, in whom symptoms are temporarily resolved by facet joint injections, were eligible. The patients were required to exhibit positron emission tomography-positive findings at the affected levels. Radiosurgical rhizotomy, targeting the facet joint, was performed in a single session with a marginal prescription dose of 40 Gy and a maximal dose of 60 Gy.Seven facet joints in 5 patients with presumptive facetogenic back pain underwent CyberKnife lesioning. The median follow-up was 9.8 months (range 3-16 months). The mean planning target volume was 1.7 cm(3) (range 0.9-2.7 cm(3)). A dose of 40 Gy was prescribed to a mean isodose line of 79% (range 75-80%). Within 1 month of radiosurgery, improvement in pain was observed in 3 of the 5 patients with durable responses at 16, 12, and 6 months, respectively, of follow-up. Two patients, after 12 and 3 months of follow-up, have neither improved nor worsened. No patient has experienced acute or late-onset toxicity.These preliminary results suggest that CyberKnife radiosurgery could be a safe, effective, and non-invasive alternative to radiofrequency ablation for managing facetogenic back pain. No patient suffered recurrent symptoms after radiosurgery. It is not yet known whether pain relief due to such lesions will be more durable than that produced by alternative procedures. A larger series of patients with long-term follow-up is ongoing.

    View details for PubMedID 18081475

  • Carotid and vertebral rete mirabile in man presenting with intraparenchymal hemorrhage: a case report. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Li, G., Jayaraman, M. V., Lad, S. P., Adler, J., Do, H., Steinberg, G. K. 2006; 15 (5): 228-231

    Abstract

    Carotid and vertebral rete mirabile is an unusual segmental regression of both the cavernous carotid artery and transdural vertebral arteries with a network of collateral vessels seen rarely in human beings. We present a 57-year-old woman with carotid and vertebral rete mirabile who presented with an acute intraparenchymal hemorrhage. The majority of patients present with subarachnoid hemorrhage or ischemic stroke. This is the first case of a non-Asian patient presenting with an intraparenchymal hemorrhage. In this case report, we describe the clinical and angiographic features of this unusual entity.

    View details for PubMedID 17904080

  • Cerebral perfusion imaging in vasospasm. Neurosurgical focus Lad, S. P., Guzman, R., Kelly, M. E., Li, G., Lim, M., Lovbald, K., Steinberg, G. K. 2006; 21 (3): E7-?

    Abstract

    Vasospasm following cerebral aneurysm rupture is one of the most devastating sequelae and the most common cause of delayed ischemic neurological deficit (DIND). Because vasospasm also is the most common cause of morbidity and mortality in patients who survive the initial bleeding episode, it is imperative not only to diagnose the condition but also to predict which patients are likely to become symptomatic. The exact pathophysiology of vasospasm is complex and incompletely elucidated. Early recognition of vasospasm is essential because the timely use of several therapeutic interventions can counteract this disease and prevent the occurrence of DIND. However, the prompt implementation of these therapies depends on the ability to predict impending vasospasm or to diagnose it at its early stages. A number of techniques have been developed during the past several decades to evaluate cerebral perfusion, including positron emission tomography, xenon-enhanced computed tomography, single-photon emission computed tomography, perfusion- and diffusion-weighted magnetic resonance imaging, and perfusion computed tomography. In this article, the authors provide a general overview of the currently available perfusion imaging techniques and their applications in treating vasospasm after a patient has suffered a subarachnoid hemorrhage. The use of cerebral perfusion imaging techniques for the early detection of vasospasm is becoming more common and may provide opportunities for early therapeutic intervention to counteract vasospasm in its earliest stages and prevent the occurrence of DINDs.

    View details for PubMedID 17029346

  • Surfactant protein-A-deficient mice display an exaggerated early inflammatory response to a beta-resistant strain of influenza A virus AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Li, G., Siddiqui, J., Hendry, M., Akiyama, J., Edmondson, J., Brown, C., Allen, L., Levitt, S., Poulain, F., Hawgood, S. 2002; 26 (3): 277-282

    Abstract

    Surfactant protein (SP)-A is a member of the collectin family of proteins. In vitro, SP-A binds influenza A virus (IAV), neutralizes infectivity, and enhances uptake by macrophages. SP-D also binds and neutralizes certain strains of IAV. To determine if SP-A has a role in protecting the intact animal against IAV infection, we inoculated gene-targeted SP-A-deficient mice (-/-) and littermate controls (+/+) with either saline or increasing doses of an IAV strain that binds SP-A but not SP-D. IAV was more virulent in SP-A-/- compared with +/+ mice, with a significantly lower mean lethal dose (LD(50)) and significantly greater weight loss during infection. SP-A-/- mice also had increased airway epithelial injury and more alveolar cellular infiltrates than +/+ mice. On Day 2, SP-A-/- mice had more neutrophils and higher MIP-2 levels in the lung than +/+ mice. We conclude the altered host response and increased susceptibility to X-79Delta167 infection in SP-A-/- mice reflects a protective role for SP-A in regulating the host response to IAV. Because the recovery of virus from lung homogenates on Days 2 and 6 after inoculation was comparable in -/- and +/+ mice, we speculate SP-A reduces IAV virulence independently of direct viral neutralization.

    View details for Web of Science ID 000174222800006

    View details for PubMedID 11867335

  • GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D gene-targeted mice AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Hawgood, S., Akiyama, J., Brown, C., Allen, L., Li, G., Poulain, F. R. 2001; 280 (6): L1148-L1156

    Abstract

    Mice deficient in surfactant protein (SP) D develop increased surfactant pool sizes and dramatic changes in alveolar macrophages and type II cells. To test the hypothesis that granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates alveolar macrophage proliferation and activation and the type II cell hypertrophy seen in SP-D null mice, we bred SP-D and GM-CSF gene-targeted mice to obtain littermate double null, single null, and wild-type mice. Bronchoalveolar lavage levels of phospholipid, protein, SP-D, SP-A, and GM-CSF were measured from 1 to 4 mo. There was an approximately additive accumulation of phospholipid, total protein, and SP-A at each time point. Microscopy showed normal macrophage number and morphology in GM-CSF null mice, numerous giant foamy macrophages and hypertrophic type II cells in SP-D null mice, and large but not foamy macrophages and mostly normal type II cells in double null mice. These results suggest that the mechanisms underlying the alveolar surfactant accumulation in the SP-D-deficient and GM-CSF-deficient mice are different and that GM-CSF mediates some of the macrophage and type II cell changes seen in SP-D null mice.

    View details for Web of Science ID 000168621700009

    View details for PubMedID 11350793

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