Michael Lim, M.D.

All Publications

• The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function. Immunity Jackson, C. M., Pant, A., Dinalankara, W., Choi, J., Jain, A., Nitta, R., Yazigi, E., Saleh, L., Zhao, L., Nirschl, T. R., Kochel, C. M., Hwa-Lin Bergsneider, B., Routkevitch, D., Patel, K., Cho, K. B., Tzeng, S., Neshat, S. Y., Kim, Y. H., Smith, B. J., Ramello, M. C., Sotillo, E., Wang, X., Green, J. J., Bettegowda, C., Li, G., Brem, H., Mackall, C. L., Pardoll, D. M., Drake, C. G., Marchionni, L., Lim, M. 2024

  Abstract

  Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

  View details for DOI 10.1016/j.immuni.2024.07.003

  View details for PubMedID 39111315

• Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain. Science advances Vasavda, C., Xu, R., Liew, J., Kothari, R., Dhindsa, R. S., Semenza, E. R., Paul, B. D., Green, D. P., Sabbagh, M. F., Shin, J. Y., Yang, W., Snowman, A. M., Albacarys, L. K., Moghekar, A., Pardo-Villamizar, C. A., Luciano, M., Huang, J., Bettegowda, C., Kwatra, S. G., Dong, X., Lim, M., Snyder, S. H. 2022; 8 (31): eabo5633

  Abstract

  Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

  View details for DOI 10.1126/sciadv.abo5633

  View details for PubMedID 35921423

• Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma The CheckMate 143 Phase 3 Randomized Clinical Trial JAMA ONCOLOGY Reardon, D. A., Brandes, A. A., Omuro, A., Mulholland, P., Lim, M., Wick, A., Baehring, J., Ahluwalia, M. S., Roth, P., Baehr, O., Phuphanich, S., Sepulveda, J., De Souza, P., Sahebjam, S., Carleton, M., Tatsuoka, K., Taitt, C., Zwirtes, R., Sampson, J., Weller, M. 2020; 6 (7): 1003–10

  Abstract

  Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.The primary end point was overall survival (OS).A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.ClinicalTrials.gov Identifier: NCT02017717.

  View details for DOI 10.1001/jamaoncol.2020.1024

  View details for Web of Science ID 000552068600008

  View details for PubMedID 32437507

  View details for PubMedCentralID PMC7243167

• Retrosigmoid approach for glycerin rhizotomy in the treatment of trigeminal neuralgia without overt arterial compression: updated case series JOURNAL OF NEUROSURGERY Kim, T. Y., Jackson, C. M., Xia, Y., Mashouf, L. A., Patel, K. K., Kim, E. S., Hung, A. L., Wu, A., Garzon-Muvdi, T., Bender, M. T., Bettegowda, C., Lee, J. K., Lim, M. 2020; 132 (4): 1227–33

  Abstract

  OBJECTIVETrigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe, lancinating facial pain that is commonly treated with neuropathic medication, percutaneous rhizotomy, and/or microvascular decompression (MVD). Patients who are not found to have distinct arterial compression during MVD present a management challenge. In 2013, the authors reported on a small case series of such patients in whom glycerin was injected intraoperatively into the cisternal segment of the trigeminal nerve. The objective of the authors' present study was to report their updated experience with this technique to further validate this novel approach.METHODSThe authors performed a retrospective analysis of data obtained in patients in whom glycerin was directly injected into the inferior third of the cisternal portion of the trigeminal nerve. Seventy-four patients, including 14 patients from the authors' prior study, were identified, and demographic information, intraoperative findings, postoperative course, and complications were recorded. Fisher's exact test, unpaired t-tests, and Kaplan-Meier survival curves using Mantel log-rank test were used to compare the 74 patients with a cohort of 476 patients who received standard MVD by the same surgeon.RESULTSThe 74 patients who underwent MVD and glycerin injection had an average follow-up of 19.1 ± 18.0 months, and the male/female ratio was 1:2.9. In 33 patients (44.6%), a previous intervention for TN had failed. On average, patients had an improvement in the Barrow Neurological Institute Pain Intensity score from 4.1 ± 0.4 before surgery to 2.1 ± 1.2 after surgery. Pain improvement after the surgery was documented in 95.9% of patients. Thirteen patients (17.6%) developed burning pain following surgery. Five patients developed complications (6.7%), including incisional infection, facial palsy, CSF leak, and hearing deficit, all of which were minor.CONCLUSIONSIntraoperative injection of glycerin into the trigeminal nerve is a generally safe and potentially effective treatment for TN when no distinct site of arterial compression is identified during surgery or when decompression of the nerve is deemed to be inadequate.

  View details for DOI 10.3171/2018.12.JNS182572

  View details for Web of Science ID 000523185100282

  View details for PubMedID 30849763

• A Phase 2 Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Redmond, K. J., Sciubba, D., Khan, M., Gui, C., Lo, S., Gokaslan, Z. L., Leaf, B., Kleinberg, L., Grimm, J., Ye, X., Lim, M. 2020; 106 (2): 261–68

  Abstract

  In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates after conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of postoperative stereotactic body RT (SBRT) in patients who have undergone surgical intervention for spine metastases. We hypothesize that postoperative SBRT to the spine would be associated with higher local control than historical rates after conventional RT.Thirty-five adult patients with a Karnofsky Performance Status score ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. Thirty-three patients were treated. Two patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurological examinations and computed tomography and/or magnetic resonance imaging every 3 months. Neurologic function was assessed at the same time points using the American Spinal Injury Association (ASIA) impairment score. Pain was rated according to the 10-point visual analogue scale and MD Anderson Cancer Center brief pain index. Toxicity was recorded according to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4. The primary objective was the rate of radiographic local recurrence at 12 months after completion of SBRT.Patient characteristics were as follows: 34.3% had radioresistant primaries; 71.4% were ASIA E and the remainder ASIA D; and the median baseline Karnofsky Performance Status score was 70 (range, 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval, 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range, 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure, or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range, 0-9.4 months).This prospective study of postoperative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared with conventional RT; however, a formal comparative study is warranted.

  View details for DOI 10.1016/j.ijrobp.2019.10.011

  View details for Web of Science ID 000506573200010

  View details for PubMedID 31628959

• Carboxylated branched poly(beta-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing SCIENCE ADVANCES Rui, Y., Wilson, D. R., Choi, J., Varanasi, M., Sanders, K., Karlsson, J., Lim, M., Green, J. J. 2019; 5 (12): eaay3255

  Abstract

  Efficient cytosolic protein delivery is necessary to fully realize the potential of protein therapeutics. Current methods of protein delivery often suffer from low serum tolerance and limited in vivo efficacy. Here, we report the synthesis and validation of a previously unreported class of carboxylated branched poly(β-amino ester)s that can self-assemble into nanoparticles for efficient intracellular delivery of a variety of different proteins. In vitro, nanoparticles enabled rapid cellular uptake, efficient endosomal escape, and functional cytosolic protein release into cells in media containing 10% serum. Moreover, nanoparticles encapsulating CRISPR-Cas9 ribonucleoproteins (RNPs) induced robust levels of gene knock-in (4%) and gene knockout (>75%) in several cell types. A single intracranial administration of nanoparticles delivering a low RNP dose (3.5 pmol) induced robust gene editing in mice bearing engineered orthotopic murine glioma tumors. This self-assembled polymeric nanocarrier system enables a versatile protein delivery and gene editing platform for biological research and therapeutic applications.

  View details for DOI 10.1126/sciadv.aay3255

  View details for Web of Science ID 000505069600079

  View details for PubMedID 31840076

  View details for PubMedCentralID PMC6897553

• Mechanisms of immunotherapy resistance: lessons from glioblastoma NATURE IMMUNOLOGY Jackson, C. M., Choi, J., Lim, M. 2019; 20 (9): 1100–1109

  Abstract

  Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.

  View details for DOI 10.1038/s41590-019-0433-y

  View details for Web of Science ID 000482212600011

  View details for PubMedID 31358997

• Immediate and Long-Term Outcomes of Microvascular Decompression for Mixed Trigeminal Neuralgia WORLD NEUROSURGERY Wu, A., Doshi, T., Hung, A., Garzon-Muvdi, T., Bender, M. T., Bettegowda, C., Lim, M. 2018; 117: E300–E307

  Abstract

  Classic trigeminal neuralgia (TN) involves sharp, shooting pain in any trigeminal nerve distribution, whereas atypical TN presents with constant aching, numbness, or burning that can appear with classic features, leading to a mixed presentation. Microvascular decompression (MVD) is an effective treatment for classic TN, but its utility in treating mixed TN has been less well studied.We retrospectively studied 73 adult patients with mixed TN and 386 patients with classic TN who underwent MVD between December 2007 and October 2016. Recorded variables included demographic data, graded radiologic and intraoperative findings, and graded pain outcomes in the immediate postoperative period (up to 3 months after MVD) and during long-term follow-up.The mean age of the 73 patients with mixed TN was 53.2 years. In terms of immediate postoperative outcomes, 67 patients (91.8%) experienced pain relief including improvement of atypical pain, whereas 6 patients (8.2%) had no pain relief. Having a preexisting pain syndrome (P = 0.001) or distortion of the trigeminal nerve intraoperatively (P = 0.001) was associated with poor surgical outcome in the patients with mixed TN. The mean duration of follow-up was 20.6 months. Forty-four patients (60.3%) developed recurrence of any TN pain. In comparison, 93% of the patients with classic TN experienced pain relief in the immediate postoperative period, and the recurrence rate was 19.9% in these patients.Patients with mixed TN suffer from both classic and atypical TN symptoms. Following MVD, 91.8% of our patients with mixed TN reported partial or complete pain relief, including improvement of atypical pain, in the immediate postoperative stage, compared with 93% of those with classic TN. Recurrence eventually developed in 60.3% of the patients with mixed TN.

  View details for DOI 10.1016/j.wneu.2018.06.016

  View details for Web of Science ID 000442440400036

  View details for PubMedID 29906578

  View details for PubMedCentralID PMC6489463

• Current state of immunotherapy for glioblastoma NATURE REVIEWS CLINICAL ONCOLOGY Lim, M., Xia, Y., Bettegowda, C., Weller, M. 2018; 15 (7): 422–42

  Abstract

  Glioma is the most common primary cancer of the central nervous system, and around 50% of patients present with the most aggressive form of the disease, glioblastoma. Conventional therapies, including surgery, radiotherapy, and pharmacotherapy (typically chemotherapy with temozolomide), have not resulted in major improvements in the survival outcomes of patients with glioblastoma. Reasons for this lack of progress include invasive tumour growth in an essential organ, which limits the utility of local therapy, as well as the protection of tumour cells by the blood-brain barrier, their intrinsic resistance to the induction of cell death, and lack of dependence on single, targetable oncogenic pathways, all of which impose challenges for systemic therapy. Furthermore, the unique immune environment of the central nervous system needs to be considered when pursuing immune-based therapeutic approaches for glioblastoma. Nevertheless, a range of different immunotherapies are currently being actively investigated in patients with this disease, spurred on by advances in immuno-oncology for other tumour types. Herein, we examine the current state of immunotherapy for gliomas, notably glioblastoma, the implications for combining the current standard-of-care treatment modalities with immunotherapies, potential biomarkers of response, and future directions for glioblastoma immuno-oncology.

  View details for DOI 10.1038/s41571-018-0003-5

  View details for Web of Science ID 000435693800013

  View details for PubMedID 29643471

• Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas CLINICAL CANCER RESEARCH Kim, J. E., Patel, M. A., Mangraviti, A., Kim, E. S., Theodros, D., Velarde, E., Liu, A., Sankey, E. W., Tam, A., Xu, H., Mathios, D., Jackson, C. M., Harris-Bookman, S., Garzon-Muvdi, T., Sheu, M., Martin, A. M., Tyler, B. M., Tran, P. T., Ye, X., Olivi, A., Taube, J. M., Burger, P. C., Drake, C. G., Brem, H., Pardoll, D. M., Lim, M. 2017; 23 (1): 124–36

  Abstract

  Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS.C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed.Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples.This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124-36. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-15-1535

  View details for Web of Science ID 000393876300017

  View details for PubMedID 27358487

  View details for PubMedCentralID PMC5735836

• Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM SCIENCE TRANSLATIONAL MEDICINE Mathios, D., Kim, J. E., Mangraviti, A., Phallen, J., Park, C., Jackson, C. M., Garzon-Muvdi, T., Kim, E., Theodros, D., Polanczyk, M., Martin, A. M., Suk, I., Ye, X., Tyler, B., Bettegowda, C., Brem, H., Pardoll, D. M., Lim, M. 2016; 8 (370): 370ra180

  Abstract

  The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

  View details for DOI 10.1126/scitranslmed.aag2942

  View details for Web of Science ID 000391110700001

  View details for PubMedID 28003545

  View details for PubMedCentralID PMC5724383

• Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination CLINICAL CANCER RESEARCH Jackson, C. M., Kochel, C. M., Nirschl, C. J., Durham, N. M., Ruzevick, J., Alme, A., Francica, B. J., Elias, J., Daniels, A., Dubensky, T. W., Lauer, P., Brockstedt, D. G., Baxi, E. G., Calabresi, P. A., Taube, J. M., Pardo, C. A., Brem, H., Pardoll, D. M., Lim, M., Drake, C. G. 2016; 22 (5): 1161–72

  Abstract

  Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown.The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia.These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials.

  View details for DOI 10.1158/1078-0432.CCR-15-1516

  View details for Web of Science ID 000373355000017

  View details for PubMedID 26490306

  View details for PubMedCentralID PMC4825863

• Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Zeng, J., See, A. P., Phallen, J., Jackson, C. M., Belcaid, Z., Ruzevick, J., Durham, N., Meyer, C., Harris, T. J., Albesiano, E., Pradilla, G., Ford, E., Wong, J., Hammers, H., Mathios, D., Tyler, B., Brem, H., Tran, P. T., Pardoll, D., Drake, C. G., Lim, M. 2013; 86 (2): 343–49

  Abstract

  Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model.We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen.Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms.The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

  View details for DOI 10.1016/j.ijrobp.2012.12.025

  View details for Web of Science ID 000319500200028

  View details for PubMedID 23462419

  View details for PubMedCentralID PMC3963403

• Outcomes of Management of Progressive Radiosurgery-Treated Brain Metastasis With Resection Followed by Pathology-Informed Management: A Retrospective Study NEUROSURGERY PRACTICE Bhatia, R. K., George, J., Siu, C., Lee, E., Redmond, K. J., Baker, B., Jackson, C. M., Bettegowda, C., Mukherjee, D., Hobbs, R. F., Weingart, J., Lim, M., Kleinberg, L. 2024; 5 (4)

  View details for DOI 10.1227/neuprac.0000000000000117

  View details for Web of Science ID 001336036600001

• Radiation immunodynamics in patients with glioblastoma receiving chemoradiation. Frontiers in immunology Sloan, L., Sen, R., Liu, C., Doucet, M., Blosser, L., Katulis, L., Kamson, D. O., Grossman, S., Holdhoff, M., Redmond, K. J., Quon, H., Lim, M., Eberhart, C., Pardoll, D. M., Hu, C., Ganguly, S., Kleinberg, L. R. 2024; 15: 1438044

  Abstract

  This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease.16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics.We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine.These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

  View details for DOI 10.3389/fimmu.2024.1438044

  View details for PubMedID 39346903

  View details for PubMedCentralID PMC11427284

• The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors. Cancer immunology research Pant, A., Jain, A., Chen, Y., Patel, K., Saleh, L., Tzeng, S., Nitta, R. T., Zhao, L., Wu, C. Y., Bederson, M., Wang, W. L., Bergsneider, B. H., Choi, J., Medikonda, R., Verma, R., Cho, K. B., Kim, L. H., Kim, J. E., Yazigi, E., Lee, S. Y., Rajendran, S., Rajappa, P., Mackall, C. L., Li, G., Tyler, B., Brem, H., Pardoll, D. M., Lim, M., Jackson, C. M. 2024

  Abstract

  Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

  View details for DOI 10.1158/2326-6066.CIR-24-0230

  View details for PubMedID 39133127

• Repeat percutaneous rhizotomy for trigeminal neuralgia is not associated with an increased risk of postoperative complications. Clinical neurology and neurosurgery Nair, S. K., Kalluri, A., Ejimogu, N. E., Reddy, S. C., Tantry, D., Wang, X., Carmichael, A., Abdulrahim, M., Xia, Y., Yedavalli, V., Jackson, C. M., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2024; 245: 108466

  Abstract

  Patients undergoing percutaneous rhizotomy for trigeminal neuralgia (TN) may require several procedures to manage their pain. However, it is not fully understood whether repeat procedures influence postoperative complication rates.We retrospectively reviewed patients undergoing rhizotomy at our institution from 2011 to 2022. Patients were included only if they had no history of prior interventions including microvascular decompression (MVD) or radiosurgery. We collected baseline patient information, pain characteristics, and postoperative complications for each patient. Patients were dichotomized into those undergoing primary rhizotomy versus those undergoing a repeat rhizotomy. Potential drivers of postoperative complications were included in a multivariate logistic regression model.Of the 1904 cases reviewed, 965 met our inclusion criteria. 392 patients underwent primary rhizotomy, and 573 patients underwent repeat rhizotomies. The repeat rhizotomy group was significantly older, p<0.001. Patients in the repeat rhizotomy group expressed higher frequencies of bilateral pain, p=0.01. Patients in the repeat rhizotomy group demonstrated a significantly higher rate of preoperative numbness and postoperative numbness, p<0.001. There were no significant differences in any of the considered complications between the single rhizotomy and repeat rhizotomy groups. On multivariate logistic regression, repeat rhizotomy did not predict an increased risk of any postoperative complications, p=0.14.Patients undergoing repeat rhizotomy may be at risk of postoperative numbness but are not at increased risk for postoperative complications. These results are of use to patients who are poor surgical candidates, and thus may require multiple rhizotomies to effectively manage their pain over time.

  View details for DOI 10.1016/j.clineuro.2024.108466

  View details for PubMedID 39116792

• A history of stereotactic radiosurgery may predict failure of procedure following percutaneous glycerol rhizotomy for trigeminal neuralgia. Neurosurgical review Nair, S. K., Oh, H. J., Kalluri, A., Ejimogu, N. E., Al-Khars, H., Abdulrahim, M., Xia, Y., Yedavalli, V., Jackson, C. M., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2024; 47 (1): 289

  Abstract

  Both stereotactic radiosurgery (SRS) and percutaneous glycerol rhizotomy are excellent options to treat TN in patients unable to proceed with microvascular decompression. However, the influence of prior SRS on pain outcomes following rhizotomy is not well understood.We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 2011 to 2022. Only patients undergoing percutaneous glycerol rhizotomy following SRS (SRS-rhizotomy) or those undergoing primary glycerol rhizotomy were considered. We collected basic demographic, clinical, and pain characteristics for each patient. Additionally, we characterized pain presentation and perioperative complications. Immediate failure of procedure was defined as presence of TN pain symptoms within 1-week of surgery, and short-term failure was defined as presence of TN pain symptoms within 3-months of surgery. A multivariate logistic regression model was used to evaluate the relationship of a history SRS and failure of procedure following percutaneous glycerol rhizotomy.Of all patients reviewed, 30 had a history of SRS prior to glycerol rhizotomy whereas 371 underwent primary percutaneous glycerol rhizotomy. Patients with a history of SRS were more likely to endorse V3 pain symptoms, p = 0.01. Additionally, patients with a history of SRS demonstrated higher preoperative BNI pain scores, p = 0.01. Patients with a history of SRS were more likely to endorse preoperative numbness, p < 0.0001. A history of SRS was independently associated with immediate failure [OR = 5.44 (2.06-13.8), p < 0.001] and short-term failure of glycerol rhizotomy [OR = 2.41 (1.07-5.53), p = 0.03]. Additionally, increasing age was found to be associated with lower odds of short-term failure of glycerol rhizotomy [OR = 0.98 (0.97-1.00), p = 0.01] CONCLUSIONS: A history of SRS may increase the risk of immediate and short-term failure following percutaneous glycerol rhizotomy. These results may be of use to patients who are poor surgical candidates and require multiple noninvasive/minimally invasive options to effectively manage their pain.

  View details for DOI 10.1007/s10143-024-02528-4

  View details for PubMedID 38907766

  View details for PubMedCentralID 496031

• TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS Mahdi, J., Dietrich, J., Straathof, K., Roddie, C., Scott, B. J., Davidson, T., Prolo, L., Batchelor, T. T., Campen, C. J., Davis, K. L., Gust, J., Lim, M., Majzner, R. G., Park, J. R., Partap, S., Ramakrishna, S., Richards, R., Schultz, L., Vitanza, N. A., Wang, L. D., Mackall, C. L., Monje, M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae064.384

  View details for Web of Science ID 001252720000574

• Evaluation of VAL-083 in GBM AGILE, a phase 3 registration platform trial for newly diagnosed and recurrent glioblastoma. De Groot, J., Cloughesy, T., Berry, D. A., Buxton, M., Colman, H., Ellingson, B. M., Gordon, G. B., Lassman, A. B., Lim, M., Mellinghoff, I. K., Sulman, E. P., Weller, M., Wen, P. Y., Hyddmark, E., Mikkelsen, T., Owen, S., Mason, W. P., Drappatz, J., Blondin, N., Perry, J. R., Agile Investigators LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400368

• Glioma. Nature reviews. Disease primers Weller, M., Wen, P. Y., Chang, S. M., Dirven, L., Lim, M., Monje, M., Reifenberger, G. 2024; 10 (1): 33

  Abstract

  Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

  View details for DOI 10.1038/s41572-024-00516-y

  View details for PubMedID 38724526

  View details for PubMedCentralID 8408881

• External assessment of preoperative scores for predicting outcome after microvascular decompression for trigeminal neuralgia. Journal of neurosurgery Xie, M. E., Halbert-Elliott, K., Nair, S. K., Jun, J., Dong, B. C., Ran, K. R., Kilgore, C. B., Kalluri, A., Yedavalli, V. S., Jackson, C. M., Lim, M., Huang, J., Bettegowda, C., Xu, R. 2024: 1-7

  Abstract

  Recently, two scoring systems have been developed for predicting pain-free outcomes after microvascular decompression (MVD). Evaluation of these scores on large external datasets has been limited. In this study, the authors aimed to evaluate the performance of published MVD scoring systems in predicting pain-free outcome.A total of 458 patients who underwent MVD for trigeminal neuralgia (TN) between 2007 and 2020 and had at least 6 months of follow-up were included in this study. Hardaway and Panczykowski scores were retrospectively computed for each patient and compared with postoperative pain recurrence and pain-free duration.The mean ± SD area under the receiver operating characteristic curve for predicting any pain recurrence after MVD was 0.567 ± 0.081 using the Hardaway score and 0.546 ± 0.085 using the Panczykowski score. On log-rank tests and Kaplan-Meier analysis, the patients with Hardaway scores of 0-2 had significantly shorter pain-free survival times after MVD than did those with a score of 3. Patients with a Panczykowski score of 1 had a significantly shorter pain-free duration after surgery compared with both patients with scores of 2-3 and patients with scores of 4-5. Patients with Panczykowski scores of 2-3 also had significantly shorter pain-free duration compared with patients with scores of 4-5.Both the Hardaway and Panczykowski scores may be useful for predicting postoperative pain-free duration in TN patients, and their utility may be greatest when scores are clustered. Continued refinement of both scoring systems will help to improve our ability to predict patient outcomes after MVD.

  View details for DOI 10.3171/2024.1.JNS232053

  View details for PubMedID 38669711

• CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy. Oncoimmunology Pant, A., Hwa-Lin Bergsneider, B., Srivastava, S., Kim, T., Jain, A., Bom, S., Shah, P., Kannapadi, N., Patel, K., Choi, J., Cho, K. B., Verma, R., Yu-Ju Wu, C., Brem, H., Tyler, B., Pardoll, D. M., Jackson, C., Lim, M. 2024; 13 (1): 2338965

  Abstract

  Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

  View details for DOI 10.1080/2162402X.2024.2338965

  View details for PubMedID 38590799

  View details for PubMedCentralID PMC11000615

• Intra- and post-pandemic impact of the COVID-19 outbreak on Stanford Health Care. Academic pathology Phongpreecha, T., Berson, E., Xue, L., Shome, S., Saarunya, G., Fralick, J., Ruiz-Tagle, B. G., Foody, A., Chin, A. L., Lim, M., Arthofer, R., Albini, C., Montine, K., Folkins, A. K., Kong, C. S., Aghaeepour, N., Montine, T., Kerr, A. 2024; 11 (2): 100113

  Abstract

  Stanford Health Care, which provides about 7% of overall healthcare to approximately 9 million people in the San Francisco Bay Area, has undergone significant changes due to the opening of a second hospital in late 2019 and, more importantly, the COVID-19 pandemic. We examine the impact of these events on anatomic pathology (AP) cases, aiming to enhance operational efficiency in response to evolving healthcare demands. We extracted historical census, admission, lab tests, operation, and APdata since 2015. An approximately 45% increase in the volume of laboratory tests (P<0.0001) and a 17% increase in AP cases (P<0.0001) occurred post-pandemic. These increases were associated with progressively increasing (P<0.0001) hospital census. Census increase stemmed from higher admission through the emergency department (ED), and longer lengths of stay mostly for transfer patients, likely due to the greater capability of the new ED and changes in regional and local practice patterns post-pandemic. Higher census led to overcapacity, which has an inverted U relationship that peaked at 103% capacity for AP cases and 114% capacity for laboratory tests. Overcapacity led to a lower capability to perform clinical activities, particularly those related to surgical procedures. We conclude by suggesting parameters for optimal operations in the post-pandemic era.

  View details for DOI 10.1016/j.acpath.2024.100113

  View details for PubMedID 38562568

• Preoperative Opioid Use and Postoperative Outcomes in Patients Undergoing Microvascular Decompression for Trigeminal Neuralgia. Neurosurgery Kalluri, A. L., Ejimogu, E., Kilgore, C., Nair, S. K., Ran, K. R., Abdulrahim, M., Xie, M. E., Halbert-Elliott, K., Yedavalli, V., Lim, M., Jackson, C. M., Huang, J., Bettegowda, C., Xu, R. 2024

  Abstract

  BACKGROUND AND OBJECTIVES: The prescription of opioid analgesics for trigeminal neuralgia (TN) is controversial, and their effect on postoperative outcomes for patients with TN undergoing microvascular decompression (MVD) has not been reported. We aimed to describe the relationship between preoperative opioid use and postoperative outcomes in patients with TN undergoing MVD.METHODS: We reviewed the records of 920 patients with TN at our institution who underwent an MVD between 2007 and 2020. Patients were sorted into 2 groups based on preoperative opioid usage. Demographic information, comorbidities, characteristics of TN, preoperative medications, pain and numbness outcomes, and recurrence data were recorded and compared between groups. Multivariate ordinal regression, Kaplan-Meier survival analysis, and Cox proportional hazards were used to assess differences in pain outcomes between groups.RESULTS: One hundred and forty-five (15.8%) patients in this study used opioids preoperatively. Patients who used opioids preoperatively were younger (P = .04), were more likely to have a smoking history (P < .001), experienced greater pain in modified Barrow Neurological Institute pain score at final follow-up (P = .001), and were more likely to experience pain recurrence (P = .01). In addition, patients who used opioids preoperatively were more likely to also have been prescribed TN medications including muscle relaxants and antidepressants preoperatively (P < .001 and P < .001, respectively). On multivariate regression, opioid use was an independent risk factor for greater postoperative pain at final follow-up (P = .006) after controlling for variables including female sex and age. Opioid use was associated with shorter time to pain recurrence on Kaplan-Meier analysis (P = .005) and was associated with increased risk for recurrence on Cox proportional hazards regression (P = .008).CONCLUSION: Preoperative opioid use in the setting of TN is associated with worse pain outcomes and increased risk for pain recurrence after MVD. These results indicate that opioids should be prescribed cautiously for TN and that worse post-MVD outcomes may occur in patients using opioids preoperatively.

  View details for DOI 10.1227/neu.0000000000002904

  View details for PubMedID 38483172

• Adult neuro-oncology trials in the United States over 5 decades: Analysis of trials completion rate to guide the path forward. Neuro-oncology advances Smith, E. J., Naik, A., Goel, M., Wen, P. Y., Lim, M., Chang, S. M., Germano, I. M. 2024; 6 (1): vdad169

  Abstract

  Clinical trials are important to close the gap between therapeutic unmet needs and scientific advances in neuro-oncology. This study analyzes the landscape of neuro-oncology trials to identify completion rates and guide strategies for the path forward.US-registered adult neuro-oncology clinical trials were extracted from www.clinicaltrials.gov (1966-2019), including funding source, trial type, scope, phase, and subjects' demographics. Completed trials defined as those that had completed participants' examinations or intervention administration for the purpose of the final collection of data for the primary outcome were dichotomized against those that failed to reach completion. Univariate and multivariate analyses were used to detect differences across factors comparing the last 2 decades (2000-2009, 2010-2019).Our search yielded 4522 trials, of which 1257 are eligible for this study. In 25 US states, neuro-oncology trial availability is <0.85/100,000 population. Comparing the past 2 decades, trial completion rate decreased from 88% to 64% (P < .001) and National Institutes of Health funding decreased from 47% to 24% (P < .001). Inclusion of subjects >65-year-old and women increased, while inclusion of Hispanic subjects decreased (P < .001). The top 2 reasons for lack of completion included accrual and operational difficulties. A larger proportion of women, non-Hispanic subjects, and older adults were enrolled in completed trials than in those that failed completion.Our study is the first report on the neuro-oncology clinical trial landscape in the United States and supports the development of strategies to further improve access to these trials. Additionally, attention is needed to identify and modify other factors contributing to lack of completion.

  View details for DOI 10.1093/noajnl/vdad169

  View details for PubMedID 38312230

  View details for PubMedCentralID PMC10838133

• Stanford University School of Medicine: Our Neurosurgical Heritage. Neurosurgery Veeravagu, A., Kim, L. H., Rao, V. L., Lim, M., Shuer, L. M., Harris, O. A., Steinberg, G. K. 2023

  Abstract

  The legacy of Stanford University's Department of Neurosurgery began in 1858, with the establishment of a new medical school on the West Coast. Stanford Neurosurgery instilled an atmosphere of dedication to neurosurgical care, scientific research, education, and innovation. We highlight key historical events leading to the formation of the medical school and neurosurgical department, the individuals who shaped the department's vision and expansion, as well as pioneering advances in research and clinical care. The residency program was started in 1961, establishing the basis of the current education model with a strong emphasis on training future leaders, and the Moyamoya Center, founded in 1991, became the largest Moyamoya referral center in the United States. The opening of Stanford Stroke Center (1992) and seminal clinical trials resulted in a significant impact on cerebrovascular disease by expanding the treatment window of IV thrombolysis and intra-arterial thrombectomy. The invention and implementation of CyberKnife® (1994) marks another important event that revolutionized the field of radiosurgery, and the development of Stanford's innovative Brain Computer Interface program is pushing the boundaries of this specialty. The more recent launch of the Neurosurgery Virtual Reality and Simulation Center (2017) exemplifies how Stanford is continuing to evolve in this ever-changing field. The department also became a model for diversity within the school as well as nationwide. The growth of Stanford Neurosurgery from one of the youngest neurosurgery departments in the country to a prominent comprehensive neurosurgery center mirrors the history of neurosurgery itself: young, innovative, and willing to overcome challenges.

  View details for DOI 10.1227/neu.0000000000002799

  View details for PubMedID 38095422

• Neurovascular Compression in Patients With Trigeminal Neuralgia May Be Associated With Worse Outcomes After Primary Percutaneous Rhizotomy. Neurosurgery Nair, S. K., Al-Khars, H., Kalluri, A., Ran, K., Kilgore, C., Budihal, B. R., Abdulrahim, M., Yedavalli, V., Jackson, C. M., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023

  Abstract

  Percutaneous rhizotomy may be an effective primary intervention in patients with trigeminal neuralgia who are poor candidates for microvascular decompression or those who desire a less invasive approach. However, the influence of neurovascular compression on pain-free survival after primary percutaneous rhizotomy is not well understood.We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 1995 to 2022. Patients were included if they had no history of surgical intervention, available preoperative MRI imaging, and postoperative follow-up data. Barrow Neurological Institute pain scores were assigned at various time points. We collected baseline patient information, pain characteristics, and perioperative complications for each patient. In addition, we recorded evidence of pain recurrence. Patients were dichotomized into those with evidence of neurovascular compression on preoperative MRI vs those without. The effect of neurovascular compression on pain-free survival was assessed using Kaplan-Meier Cox proportional hazards analyses.Of the 2726 patients reviewed, 298 met our inclusion criteria. Our study comprised 261 patients with no evidence of neurovascular compression on preoperative MRI vs 37 patients with evidence of neurovascular compression on preoperative MRI. Patients in the compression group had a shorter median duration to recurrence compared with those in the no compression group, P = .01. Kaplan-Meier survival analysis revealed that patients with preoperative evidence of neurovascular compression on MRI imaging demonstrated shorter pain-free survival compared with those without such evidence [hazard ratio = 1.57 (1.03-2.4), P = .037]. Cox proportional hazards analysis demonstrated that evidence of neurovascular compression was associated with poor pain-free survival [hazard ratio = 1.64 (1.06-2.53), P = .03].Patients with neurovascular compression on preoperative MRI may experience reduced time to recurrence compared with those without after percutaneous rhizotomy. These patients should be counseled on potential reduced efficacy of percutaneous rhizotomy as a primary intervention for their pain.

  View details for DOI 10.1227/neu.0000000000002791

  View details for PubMedID 38085926

• Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke. Brain, behavior, and immunity Kim, J. E., Lee, R. P., Yazigi, E., Atta, L., Feghali, J., Pant, A., Jain, A., Levitan, I., Kim, E., Patel, K., Kannapadi, N., Shah, P., Bibic, A., Hou, Z., Caplan, J. M., Gonzalez, L. F., Huang, J., Xu, R., Fan, J., Tyler, B., Brem, H., Boussiotis, V. A., Jantzie, L., Robinson, S., Koehler, R. C., Lim, M., Tamargo, R. J., Jackson, C. M. 2023

  Abstract

  Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1 + monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1 + phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

  View details for DOI 10.1016/j.bbi.2023.12.007

  View details for PubMedID 38070624

• ADULT NEURO-ONCOLOGY TRIAL LANDSCAPE IN THE UNITED STATES OVER FIVE DECADES Smith, E., Naik, A., Goel, M., Wen, P., Lim, M., Chang, S., Germano, I. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401161

• LONG TERM FOLLOW-UP OF A PROSPECTIVE SAFETY AND TOXICITY STUDY OF IMMUNE CHECKPOINT INHIBITOR THERAPY INITIATED 8 DAYS PRIOR TO RADIOSURGERY FOR MELANOMA BRAIN OR SPINE METASTASIS Kleinberg, L., Ye, X., Sharfman, W., Jackson, C., Redmond, K., Bettegowda, C., Szajna, K., Isennock, W., Wollett, J., Lipson, E., Lim, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400244

• GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB Wen, P., Alexander, B., Berry, D., Buxton, M., Cavenee, W., Colman, H., de Groot, J., Ellingson, B., Gordon, G., Hyddmark, E., Khasraw, M., Lim, M., Mellinghoff, I., Mikkelsen, T., Perry, J., Powell, A., Sulman, E., Tanner, K., Weller, M., Yung, W., Blondin, N., Brenner, A., Butt, O., de la Fuente, M., Drappatz, J., Iwamoto, F., Kim, L., Lee, E., Mantica, M., Nabors, B., Newton, H., Schiff, D., Walbert, T., Weathers, S., Cloughesy, T., Lassman, A. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400367

• A RANDOMIZED WINDOW OF OPPORTUNITY TRIAL WITH DOSE ESCALATION TO EVALUATE FLUOXETINE AND TEMOZOLOMIDE IN GLIOMA Singh, K., Railton, C., Hotchkiss, K., Herndon, J., Peters, K., Friedman, H., Desjardins, A., Ashley, D., Johnson, M. O., Patel, A., Friedman, A., Lim, M., Fecci, P., Piccioni, D., McGranahan, T., Nagpal, S., Sulman, E., Mischel, P., Khasraw, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401209

• MITOCHONDRIAL ATP BIOGENESIS REGULATED BY VDAC1 IN TMEM119+TUMOR-ASSOCIATED MICROGLIA AND MACROPHAGES MEDIATES HIGH-GRADE GLIOMA GROWTH Wu, C., Chen, Y., Lin, Y., Wei, K., Chang, K., Feng, L., Wu, A., Chen, K., Ren, A., Nitta, R., Wu, J., Pant, A., Cho, K., Mackall, C., Chuang, J., Huang, C., Li, G., Jackson, C., Chen, P., Lim, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401315

• The influence of prior percutaneous rhizotomy on outcomes following microvascular decompression for trigeminal neuralgia. Journal of neurosurgery Nair, S. K., Xie, M. E., Kalluri, A., Ran, K., Kilgore, C., Halbert-Elliott, K., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023: 1-5

  Abstract

  Microvascular decompression (MVD) is an effective intervention in patients with trigeminal neuralgia (TN). How prior rhizotomy can impact long-term pain outcomes following MVD is not well understood. In this study, the authors sought to compare pain outcomes in patients who had undergone primary MVD versus those who had undergone secondary MVD after a single or multiple rhizotomies.The authors retrospectively reviewed the data on all patients who had undergone MVD at their institution from 2007 to 2020. Patients were included in the study if they had undergone primary MVD or if their surgical history was notable for past rhizotomy. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and final follow-up appointments. Perioperative complications were noted for each patient, and evidence of pain recurrence was recorded as well. A history of rhizotomy as well as other variables that might influence TN pain recurrence were evaluated using a Cox proportional hazards model. The impact of prior rhizotomy on TN pain recurrence following MVD was further assessed using Kaplan-Meier survival analysis.Of 1044 patients reviewed, 947 met the study inclusion criteria. Of these, 796 patients had undergone primary MVD, 84 had a history of a single rhizotomy before MVD, and 67 had a history of ≥ 2 rhizotomies prior to MVD. Patients in the single rhizotomy and multiple rhizotomies cohorts exhibited a greater frequency of preoperative numbness (p < 0.001), higher preoperative BNI pain scores (p < 0.005), and higher rates of postoperative numbness (p = 0.04). However, final follow-up BNI pain scores were not significantly different between the primary MVD and prior rhizotomy groups (p = 0.34). Cox proportional hazards analysis revealed that younger age, multiple sclerosis, and female sex independently predicted an increased risk of pain recurrence following MVD. Neither a history of a single prior rhizotomy nor a history of multiple prior rhizotomies independently increased the risk of pain recurrence. Furthermore, Kaplan-Meier analysis of pain-free survival among the 3 groups revealed no relationship between a history of prior rhizotomy and pain recurrence following MVD (p = 0.57).Percutaneous rhizotomy does not complicate outcomes following subsequent MVD for TN pain. However, patients undergoing rhizotomy before MVD may have an increased risk of postoperative facial numbness compared to that in patients undergoing primary MVD.

  View details for DOI 10.3171/2023.8.JNS231345

  View details for PubMedID 37862713

• Proteomic Analysis to Identify Prospective Biomarkers of Treatment Outcome After Microvascular Decompression for Trigeminal Neuralgia: A Preliminary Study. The journal of pain Doshi, T. L., Dorsey, S. G., Huang, W., Kane, M. A., Lim, M. 2023

  Abstract

  Trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder, often caused by vascular or neuronal compression of the trigeminal nerve. In such cases, microvascular decompression (MVD) surgery can be used to treat TN, but pain relief is not guaranteed. The molecular mechanisms that affect treatment response to MVD are not well understood. In this exploratory study, we performed label-free quantitative proteomic profiling of plasma and cerebrospinal fluid (CSF) samples from patients undergoing MVD for TN, then compared the proteomic profiles of patients graded as responders (n = 7) versus non-responders (n = 9). We quantified 1090 proteins in plasma and 1087 proteins in the CSF, of which 12 were differentially regulated in the same direction in both sample types. Functional analyses of differentially regulated proteins in protein-protein interaction networks suggested pathways of immune system, axon guidance, and cellular stress response to be associated with response to MVD. These findings suggest potential biomarkers of response to MVD, as well as possible mechanisms of variable treatment success in TN patients. PERSPECTIVE: This exploratory study evaluates proteomic profiles in plasma and cerebrospinal fluid of patients undergoing microvascular decompression surgery for trigeminal neuralgia. Differential expression of proteins between surgery responders versus non-responders may serve as biomarkers to predict surgical success and provide insight into surgical mechanisms of pain relief in trigeminal neuralgia.

  View details for DOI 10.1016/j.jpain.2023.10.006

  View details for PubMedID 37838347

• Frailty predicts worse pain outcomes for older TN patients treated with microvascular decompression. World neurosurgery Kilgore, C. B., Kalluri, A. L., Nair, S. K., Halbert-Elliot, K. M., Ejimogu, E., Dong, B., Chakravarti, S., Abdulrahim, M. W., Jackson, C. M., Lim, M., Huang, J., Bettegowda, C., Xu, R. 2023

  Abstract

  Trigeminal neuralgia (TN) is a debilitating orofacial pain disorder. Recent national database data suggests that microvascular decompression (MVD) in frail patients is associated with higher post-operative complications. However, long-term pain outcomes of frail TN patients are not known. We aimed to elucidate the relationship between frailty and long-term pain outcomes following MVD for TN.From 2007 to 2020, 368 TN patients 60 years of age or older were treated via MVD at our institution. Patient demographics, clinical characteristics, post-operative complications and long-term pain outcomes were recorded. Frailty was assessed by modified frailty index-5 (mFI-5) score and patients were dichotomized into non-frail (mFI-5 < 2) and frail (mFI-5 > 1). Differences were assessed via t-test, Chi-squared, multivariate ordinal regression, and Cox proportional hazards analysis.Of the 368 patients analyzed, 9.8% were frail. Frail patients were significantly older (p=0.02) with higher body mass index (p=0.01) and greater incidence of comorbidities (p<0.001). Frail patients presented with significantly higher pain levels at final follow-up (p=0.04). On multivariate analysis, frailty was independently associated with higher pain at follow-up (p=0.01), along with younger age, female sex, and black race. The relationship between frailty and post-operative pain recurrence trended towards significance (p=0.06), while younger age and black race were significantly associated with recurrence.Frail patients undergoing MVD are at risk for worse long-term pain outcomes. Our study provides clinicians with useful information pertaining to the influence of frailty on long-term efficacy of MVD in treating TN.

  View details for DOI 10.1016/j.wneu.2023.10.009

  View details for PubMedID 37821032

• Overcoming EGFR inhibitor resistance in Glioblastoma by targeting co-amplified genes. Proceedings of the National Academy of Sciences of the United States of America Pant, A., Lim, M. 2023; 120 (38): e2312277120

  View details for DOI 10.1073/pnas.2312277120

  View details for PubMedID 37672559

• The role of multiple sclerosis subtype in microvascular decompression outcomes for patients with trigeminal neuralgia. Clinical neurology and neurosurgery Kalluri, A. L., So, R. J., Nair, S. K., Materi, J., Wang, D., Behera, N., Kornberg, M. D., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023; 233: 107967

  Abstract

  OBJECTIVES: While patients with concomitant trigeminal neuralgia (TN) and multiple sclerosis (MS) are understood to experience a more intractable pain phenotype, whether TN pain outcomes differ by the presenting MS subtype is not well characterized. This study's objective is to compare post-operative pain and numbness outcomes following microvascular decompression (MVD) in TN patients with either relapsing-remitting MS (RRMS) or progressive MS.METHODS: We retrospectively reviewed all TN patients who underwent MVDs at our institution from 2007 to 2020. Of the 1044 patients reviewed, 45 (4.3%) patients with MS were identified. Patient demographics, procedural characteristics, and post-operative pain and numbness scores were recorded and compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions.RESULTS: Of the resulting 45 MS patients, 34 (75.6%) patients presented with the RRMS subtype, whereas 11 (24.4%) patients exhibited progressive MS. Using an adjusted multivariate ordinal regression, the subtype of MS was not significantly associated with the Barrow Neurological Institute (BNI) pain score at final follow-up. Using a Kaplan-Meier survival analysis and a multivariate Cox proportional hazards regression, respectively, RRMS was significantly associated with a shorter post-operative pain-free interval (p=0.04) as well as a greater risk for pain recurrence (p=0.02).CONCLUSIONS: Although the degree of pain at final follow-up may not differ, RRMS patients are at increased risk for pain recurrence following MVD for TN. These results align with a growing understanding that neuroinflammation may play a significant role in TN pain.

  View details for DOI 10.1016/j.clineuro.2023.107967

  View details for PubMedID 37703615

• Stereotactic Radiosurgery for Medically Refractory Trigeminal Neuralgia Secondary to Stroke: A Systematic Review and Clinical Case Presentation. World neurosurgery Zamarud, A., Park, D. J., Ung, T. H., McCleary, T. L., Yoo, K. H., Soltys, S. G., Lim, M., Chang, S. D., Meola, A. 2023

  View details for DOI 10.1016/j.wneu.2023.08.092

  View details for PubMedID 37640262

• Optimizing the synergy between stereotactic radiosurgery and immunotherapy for brain metastases. Frontiers in oncology Yoo, K. H., Park, D. J., Choi, J. H., Marianayagam, N. J., Lim, M., Meola, A., Chang, S. D. 2023; 13: 1223599

  Abstract

  Solid tumors metastasizing to the brain are a frequent occurrence with an estimated incidence of approximately 30% of all cases. The longstanding conventional standard of care comprises surgical resection and whole-brain radiotherapy (WBRT); however, this approach is associated with limited long-term survival and local control outcomes. Consequently, stereotactic radiosurgery (SRS) has emerged as a potential alternative approach. The primary aim of SRS has been to improve long-term control rates. Nevertheless, rare observations of abscopal or out-of-field effects have sparked interest in the potential to elicit antitumor immunity via the administration of high-dose radiation. The blood-brain barrier (BBB) has traditionally posed a significant challenge to the efficacy of systemic therapy in managing intracranial metastasis. However, recent insights into the immune-brain interface and the development of immunotherapeutic agents have shown promise in preclinical and early-phase clinical trials. Researchers have investigated combining immunotherapy with SRS to enhance treatment outcomes in patients with brain metastasis. The combination approach aims to optimize long-term control and overall survival (OS) outcomes by leveraging the synergistic effects of both therapies. Initial findings have been encouraging in the management of various intracranial metastases, while further studies are required to determine the optimal order of administration, radiation doses, and fractionation regimens that have the potential for the best tumor response. Currently, several clinical trials are underway to assess the safety and efficacy of administering immunotherapeutic agents concurrently or consecutively with SRS. In this review, we conduct a comprehensive analysis of the advantages and drawbacks of integrating immunotherapy into conventional SRS protocols for the treatment of intracranial metastasis.

  View details for DOI 10.3389/fonc.2023.1223599

  View details for PubMedID 37637032

  View details for PubMedCentralID PMC10456862

• Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid. Cell reports. Medicine Douville, C., Curtis, S., Summers, M., Azad, T. D., Rincon-Torroella, J., Wang, Y., Mattox, A., Avigdor, B., Dudley, J., Materi, J., Raj, D., Nair, S., Bhanja, D., Tuohy, K., Dobbyn, L., Popoli, M., Ptak, J., Nehme, N., Silliman, N., Blair, C., Judge, K., Gallia, G. L., Groves, M., Jackson, C. M., Jackson, E. M., Laterra, J., Lim, M., Mukherjee, D., Weingart, J., Naidoo, J., Koschmann, C., Smith, N., Schreck, K. C., Pardo, C. A., Glantz, M., Holdhoff, M., Kinzler, K. W., Papadopoulos, N., Vogelstein, B., Bettegowda, C. 2023: 101148

  Abstract

  It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.

  View details for DOI 10.1016/j.xcrm.2023.101148

  View details for PubMedID 37552989

• Correcting the drug development paradigm for glioblastoma requires serial tissue sampling. Nature medicine Singh, K., Hotchkiss, K. M., Parney, I. F., De Groot, J., Sahebjam, S., Sanai, N., Platten, M., Galanis, E., Lim, M., Wen, P. Y., Minniti, G., Colman, H., Cloughesy, T. F., Mehta, M. P., Geurts, M., Arrillaga-Romany, I., Desjardins, A., Tanner, K., Short, S., Arons, D., Duke, E., Wick, W., Bagley, S. J., Ashley, D. M., Kumthekar, P., Verhaak, R., Chalmers, A. J., Patel, A. P., Watts, C., Fecci, P. E., Batchelor, T. T., Weller, M., Vogelbaum, M. A., Preusser, M., Berger, M. S., Khasraw, M. 2023

  View details for DOI 10.1038/s41591-023-02464-8

  View details for PubMedID 37488293

  View details for PubMedCentralID 4123637

• Management outcomes of peripontine arteriovenous malformation patients presenting with trigeminal neuralgia. Journal of neurosurgery Yang, W., Sattari, S. A., Feghali, J., Hung, A., Chen, Y., Xu, R., Bettegowda, C., Lim, M., Huang, J. 2023: 1-7

  Abstract

  Trigeminal neuralgia as the presenting symptom of brain arteriovenous malformation (bAVM) has been rarely reported. Treatment of reported cases has been skewed toward surgery for these scarce, deeply located bAVMs. Here, the authors report their management and outcomes of bAVM patients presenting with ipsilateral trigeminal neuralgia (TN) at their institution.This is a retrospective cohort study. The authors' institutional bAVM database was queried for non-hereditary hemorrhagic telangiectasia bAVMs in pontine, cistern, brainstem, trigeminal nerve, or tentorial locations. Patients with complete data were included in a search for trigeminal neuralgia or "facial pain" as the presenting symptom with TN being on the same side as the bAVM. Demographics, TN and bAVM characteristics, management strategies, and outcomes of bAVM and TN management were analyzed.Fifty-seven peripontine bAVMs were identified; 8 (14.0%) of these bAVMs were discovered because of ipsilateral TN, including 4 patients (50%) with facial pain in the V2 distribution. Five patients (62.5%) were treated with carbamazepine as the initial medical therapy, 2 (25%) underwent multiple rhizotomies, and 1 (12.5%) underwent microvascular decompression. None of the patients with TN-associated bAVMs presented with hemorrhage, compared with 25 patients (51%) with bAVMs that were not associated with TN (p < 0.01). TN-associated bAVMs were overall smaller than non-TN-associated bAVMs, but the difference was not statistically significant (1.71 cm vs 2.22 cm, p = 0.117), and the Spetzler-Martin grades were similar. Six patients (75%) underwent radiosurgery to the bAVM (mean dose 1800 cGy, mean target volume 0.563 cm3) and had complete resolution of TN symptoms (100%). The mean time from radiosurgery to TN resolution was 193 (range 21-360) days, and 83.3% of treated TN-associated bAVMs were obliterated via radiosurgery. Two patients (12.5%) were recommended for conservative management, with one undergoing subsequent rhizotomies and another patient died of hemorrhage during follow-up.TN-associated bAVM is a rare condition with limited evidence for management guidance. Radiosurgery can be safe and effective in achieving durable TN control in patients with TN-associated bAVMs. Despite their deep location and unruptured presentation, obliteration can reach 83.3% with radiosurgery.

  View details for DOI 10.3171/2023.5.JNS23771

  View details for PubMedID 37486910

• A Case Series of Stereotactic Radiosurgery First for Trigeminal Neuralgia: A History of Stereotactic Radiosurgery Does Not Complicate Microvascular Decompression. Operative neurosurgery (Hagerstown, Md.) Nair, S. K., Xie, M. E., Ran, K., Kalluri, A., Kilgore, C., Halbert-Elliott, K., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023

  Abstract

  BACKGROUND AND OBJECTIVES: The influence of prior stereotactic radiosurgery (SRS) on outcomes of subsequent microvascular decompression (MVD) for patients with trigeminal neuralgia (TN) is not well understood. To directly compare pain outcomes in patients undergoing primary MVD vs those undergoing MVD with a history of 1 prior SRS procedure.METHODS: We retrospectively reviewed all patients undergoing MVD at our institution from 2007 to 2020. Patients were included if they underwent primary MVD or had a history of SRS alone before MVD. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and immediate postoperative time points and at every follow-up appointment. Evidence of pain recurrence was recorded and compared via Kaplan-Meier analysis. Multivariate Cox proportional hazards regression was used to identify factors associated with worse pain outcomes.RESULTS: Of patients reviewed, 833 met our inclusion criteria. Thirty-seven patients were in the SRS alone before MVD group, and 796 patients were in the primary MVD group. Both groups demonstrated similar preoperative and immediate postoperative BNI pain scores. There were no significant differences between average BNI at final follow-up between the groups. Multiple sclerosis (hazard ratio (HR) = 1.95), age (HR = 0.99), and female sex (HR = 1.43) independently predicted increased likelihood of pain recurrence on Cox proportional hazards analysis. SRS alone before MVD did not predict increased likelihood of pain recurrence. Furthermore, Kaplan-Meier survival analysis demonstrated no relationship between a history of SRS alone and pain recurrence after MVD (P = .58).CONCLUSION: SRS is an effective intervention for TN that may not worsen outcomes for subsequent MVD in patients with TN.

  View details for DOI 10.1227/ons.0000000000000819

  View details for PubMedID 37432012

• Use of tubular retractors to access deep brain lesions: A case series. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Rakovec, M., Camp, S., Day, D., Chakravarti, S., Parker, M., Porras, J. L., Jackson, C. M., Huang, J., Bettegowda, C., Lim, M., Mukherjee, D. 2023; 114: 64-69

  Abstract

  Deep-seated intracranial lesions can be accessed using blade retractors that may disrupt white matter tracts, exert pressure on adjacent tissue, and lead to post-operative venous injury. Tubular retractors may minimize disruption to white matter tracts by radially dispersing pressure onto surrounding tissue. This study characterizes perioperative outcomes in patients undergoing biopsy or resection of intracranial pathologies using tubular retractors.Adult patients (≥18 years) undergoing neurosurgical intervention using tubular retractors at a single health system (January 2016-February 2022) were identified through chart review. Demographics, disease characteristics, management data, and clinical outcomes were collected.A total of 49 patients were included; 23 (47%) had primary brain tumors, 8 (16%) metastases, 6 (12%) intracranial hemorrhage (ICH), 5 (10%) cavernomas, and 7 (14%) other pathologies. Lesions were located subcortically (n = 19, 39%), intraventricularly (n = 15, 31%), and in deep gray matter (n = 11, 22%). Gross total resection (GTR) or near GTR was achieved in 21 of 26 (80.8%) patients with intracranial lesions where GTR was the goal of surgery; 10 of 11 (90.9%) biopsies in patients with masses were diagnostic. Five of six (83.3%) ICHs were totally or near totally evacuated. Seventeen patients (35%) had major complications post-operatively. The most common complications were DVT/PE (n = 7, 14%) and seizures (n = 6, 12%). For patients who experienced post-operative seizures, 3 had seizures preoperatively and 1 had seizures in the context of electrolyte derangements. No patients died of post-operative complications.This operative approach may facilitate safe and efficacious biopsy or resection of deep-seated intracranial pathologies.

  View details for DOI 10.1016/j.jocn.2023.06.002

  View details for PubMedID 37321019

• Translational Models in Glioma Immunotherapy Research. Current oncology (Toronto, Ont.) Ren, A. L., Wu, J. Y., Lee, S. Y., Lim, M. 2023; 30 (6): 5704-5718

  Abstract

  Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.

  View details for DOI 10.3390/curroncol30060428

  View details for PubMedID 37366911

• TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS Mahdi, J., Dietrich, J., Straathof, K., Roddie, C., Scott, B., Davidson, T., Prolo, L., Batchelor, T., Campen, C., Davis, K., Gust, J., Lim, M., Majzner, R., Park, J., Partap, S., Ramakrishna, S., Richards, R., Schultz, L., Vitanza, N., Wang, L., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2023

  View details for DOI 10.1093/neuonc/noad073.192

  View details for Web of Science ID 001023504300193

• Advancing combination therapy for recurrent glioblastoma. Nature medicine Wu, A., Lim, M. 2023

  View details for DOI 10.1038/s41591-023-02350-3

  View details for PubMedID 37188784

  View details for PubMedCentralID 9629431

• Sequential onset of bilateral trigeminal neuralgia: clinical presentation and outcomes. Clinical neurology and neurosurgery Xu, R., So, R. J., Lee, K. K., Kalluri, A. L., Materi, J., Nair, S. K., Huang, J., Lim, M., Bettegowda, C. 2023; 229: 107745

  Abstract

  PURPOSE: Sequential onset of bilateral trigeminal neuralgia (TN) is rare and not well-described in the literature. The objective of this study was to characterize demographic, clinical, and procedural characteristics of patients with sequential onset bilateral TN.METHODS: We retrospectively reviewed patients presenting with sequential onset bilateral TN at our institution from 2007 to 2020. Patient demographics, clinical diagnoses, pain outcomes, and procedural characteristics were recorded and compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions.RESULTS: We identified 34 patients who presented with sequential onset bilateral TN. The average age of onset for the index case was 49.9±15.5 years, and 58.0±16.8 years for the contralateral case. In total for our cohort, 91 surgical procedures were performed for the index case, and 70 for the contralateral case. With each additional surgical intervention, pain-free survival was more likely to decrease, p=0.05. When controlled for order of intervention, glycerin rhizotomy (p=0.01) and glycerin-radiofrequency rhizotomy (p=0.05) were more likely associated with pain recurrence compared to microvascular decompression. While pain outcomes were significantly decreased in our cohort at final follow-up, 82.4% of patients were still dependent on medication for pain management after an average of 5.03±7.74 years.CONCLUSION: Our results represent one of the largest series of sequential onset bilateral TN in North America. Our study demonstrates the high treatment burden and chronicity of pain encountered in this population.

  View details for DOI 10.1016/j.clineuro.2023.107745

  View details for PubMedID 37146369

• Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators. Cancer cell Obradovic, A., Ager, C., Turunen, M., Nirschl, T., Khosravi-Maharlooei, M., Iuga, A., Jackson, C. M., Yegnasubramanian, S., Tomassoni, L., Fernandez, E. C., McCann, P., Rogava, M., DeMarzo, A. M., Kochel, C. M., Allaf, M., Bivalacqua, T., Lim, M., Realubit, R., Karan, C., Drake, C. G., Califano, A. 2023

  Abstract

  Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. Pooled CRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentiality of eight MRs in TI-Treg recruitment and/or retention without affecting other T cell subtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantly reduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activity identified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatment inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased anti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the context of cancer, and a generalizable strategy to systematically elucidate and target MR proteins in immunosuppressive subpopulations.

  View details for DOI 10.1016/j.ccell.2023.04.003

  View details for PubMedID 37116491

• Tumor inflammation-associated neurotoxicity. Nature medicine Mahdi, J., Dietrich, J., Straathof, K., Roddie, C., Scott, B. J., Davidson, T. B., Prolo, L. M., Batchelor, T. T., Campen, C. J., Davis, K. L., Gust, J., Lim, M., Majzner, R. G., Park, J. R., Partap, S., Ramakrishna, S., Richards, R., Schultz, L., Vitanza, N. A., Wang, L. D., Mackall, C. L., Monje, M. 2023

  Abstract

  Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.

  View details for DOI 10.1038/s41591-023-02276-w

  View details for PubMedID 37024595

  View details for PubMedCentralID 7238960

• Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. The lancet. Diabetes & endocrinology Taïeb, D., Wanna, G. B., Ahmad, M., Lussey-Lepoutre, C., Perrier, N. D., Nölting, S., Amar, L., Timmers, H. J., Schwam, Z. G., Estrera, A. L., Lim, M., Pollom, E. L., Vitzthum, L., Bourdeau, I., Casey, R. T., Castinetti, F., Clifton-Bligh, R., Corssmit, E. P., de Krijger, R. R., Del Rivero, J., Eisenhofer, G., Ghayee, H. K., Gimenez-Roqueplo, A. P., Grossman, A., Imperiale, A., Jansen, J. C., Jha, A., Kerstens, M. N., Kunst, H. P., Liu, J. K., Maher, E. R., Marchioni, D., Mercado-Asis, L. B., Mete, O., Naruse, M., Nilubol, N., Pandit-Taskar, N., Sebag, F., Tanabe, A., Widimsky, J., Meuter, L., Lenders, J. W., Pacak, K. 2023

  Abstract

  Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

  View details for DOI 10.1016/S2213-8587(23)00038-4

  View details for PubMedID 37011647

• Outcomes after microvascular decompression for sole arterial versus venous compression in trigeminal neuralgia. World neurosurgery Nair, S. K., Xie, M. E., Ran, K., Kalluri, A., Kilgore, C., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023

  Abstract

  In most cases of trigeminal neuralgia (TN), the trigeminal nerve is compressed by the arterial vasculature. We sought to address the current gap in understanding of pain outcomes in patients with sole arterial versus sole venous compression.We retrospectively reviewed all patients undergoing microvascular decompression at our institution, identifying patients with either sole arterial or venous compression. We dichotomized patients into arterial or venous groups and obtained demographics and postoperative complications for each case. Barrow Neurological Index (BNI) pain scores were collected preoperatively, postoperatively, and at final follow-up, as well as recurrence of pain. Differences were calculated via Chi-squared tests and t-tests. Ordinal regression was used to account for variables known to influence TN pain. Kaplan-Meier analysis was used to determine recurrence-free survival.Of 1044 patients, 642 (61.7%)had either sole arterial or venous compression. 472 of these cases demonstrated arterial compression, and 170 displayed sole venous compression. Patients in the venous compression group were significantly younger (p<0.001). Patients with sole venous compression demonstrated worse preoperative (p=0.04) and final follow-up (p<0.001) pain scores. Patients with sole venous compression had significantly higher rate of pain recurrence (p=0.02) and BNI score at pain recurrence (p=0.04). On ordinal regression, venous compression was found to independently predict worse BNI pain scores (OR= 1.66, p=0.003). Kaplan-Meier analysis demonstrated a significant relationship between sole venous compression and increased risk of pain recurrence (p=0.03).TN patients with sole venous compression demonstrate worse pain outcomes following MVD compared to those with only arterial compression.

  View details for DOI 10.1016/j.wneu.2023.02.090

  View details for PubMedID 36889635

• Sex-specific pain outcomes following microvascular decompression for trigeminal neuralgia. World neurosurgery Kilgore, C. B., So, R. J., Storm, K., Nair, S. K., Ran, K. R., Kalluri, A. L., Lim, M., Huang, J., Bettegowda, C., Xu, R. 2023

  Abstract

  Trigeminal neuralgia (TN) is more prevalent among women. However, while microvascular decompression (MVD) is the most effective long-term surgical treatment for TN, it is unclear whether it is equally efficacious for men and women. We sought to characterize the relationship between sex and pain outcomes following MVD for TN.From 2007 to 2020, 938 unilateral TN patients were treated with MVD at our institution. Patient demographics, clinical characteristics, operative features, and pain outcomes were recorded. Differences between men and women were analyzed via t-test and Chi-squared analyses. A multivariate ordinal regression was used to establish significant predictors of pain outcome. Differences in time to pain recurrence were assessed via Cox proportional hazards and Kaplan-Meier non-parametric survival analysis.A majority (67%) of the 938 patients analyzed were female. Men and women presented with similar pre-operative pain severity (p=0.17). Female sex (p=0.048) and younger age (p=0.03) were independently associated with worsened BNI pain scores at three-month follow-up upon multivariate analysis. Women were also more likely to experience recurrence than men (p=0.01), and time to recurrence was shorter among women (p=0.02). Only female sex was independently associated with increased risk of post-operative pain recurrence upon multivariate Cox proportional hazards regression (p=0.01).Female TN patients undergoing MVD had worse pain outcomes, more frequent pain recurrence, and shorter time to recurrence. Our results indicate a sex-specific dimorphism in response to MVD among TN patients.

  View details for DOI 10.1016/j.wneu.2023.02.074

  View details for PubMedID 36828277

• CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement. Cancers Pant, A., Lim, M. 2023; 15 (4)

  Abstract

  Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the "cold tumor" phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor.

  View details for DOI 10.3390/cancers15041249

  View details for PubMedID 36831591

• PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages. The Journal of clinical investigation Ho, W. S., Mondal, I., Xu, B., Das, O., Sun, R. C., Chiou, P., Cai, X., Tahmasebinia, F., Wu, C. Y., Wu, Z., Matsui, W., Lim, M., Meng, Z., Lu, R. O. 2023

  Abstract

  STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.

  View details for DOI 10.1172/JCI162139

  View details for PubMedID 36757811

• A racial analysis of pain outcomes following microvascular decompression for trigeminal neuralgia. Journal of neurosurgery So, R. J., Kalluri, A. L., Storm, K., Nair, S. K., Budihal, B. R., Huang, J., Lim, M., Bettegowda, C., Xu, R. 2023: 1-7

  Abstract

  OBJECTIVE: Pain outcomes by race in trigeminal neuralgia (TN) are not well investigated. The authors aimed to compare microvascular decompression (MVD) outcomes in TN patients on the basis of self-identified race.METHODS: The authors retrospectively reviewed all patients with TN who underwent MVD at their institution from 2007 to 2020. Each patient's self-reported race was recorded, and Barrow Neurological Institute (BNI) scores for pain and numbness were compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions.RESULTS: Of 1011 patients, 925 reported their racial demographic characteristics, and patients who identified as Native American or American Indian and Native Hawaiian or Pacific Islander were excluded due to small sample sizes. Of the resulting 921 patients, 697 (75.7%) patients identified as White, 108 (11.7%) as Black or African American, 39 (4.2%) as Asian, and 77 (8.4%) as other. Compared with White patients, Black TN patients were more likely to present with type 1 TN (p = 0.02). At final follow-up, the mean BNI pain score of Black patients was significantly higher (p < 0.001) compared with that of White patients, although pain scores did not differ preoperatively. The adjusted multivariate ordinal regression model showed that Black patients were associated with higher BNI pain scores at final follow-up (p = 0.01). Furthermore, compared with White patients, Black patients were at increased risk for postoperative pain recurrence (p = 0.04), which additionally occurred after a shorter median pain-free duration (p = 0.03).CONCLUSIONS: TN patients who identify as Black or African American exhibit worse postoperative pain outcomes after MVD compared with White patients. Future studies investigating the factors driving these racial differences are warranted.

  View details for DOI 10.3171/2022.12.JNS221884

  View details for PubMedID 36738461

• The Tumor Immune Microenvironment in Primary CNS Neoplasms: A Review of Current Knowledge and Therapeutic Approaches. International journal of molecular sciences Kalluri, A. L., Shah, P. P., Lim, M. 2023; 24 (3)

  Abstract

  Primary CNS neoplasms are responsible for considerable mortality and morbidity, and many therapies directed at primary brain tumors have proven unsuccessful despite their success in preclinical studies. Recently, the tumor immune microenvironment has emerged as a critical aspect of primary CNS neoplasms that may affect their malignancy, prognosis, and response to therapy across patients and tumor grades. This review covers the tumor microenvironment of various primary CNS neoplasms, with a focus on glioblastoma and meningioma. Additionally, current therapeutic strategies based on elements of the tumor microenvironment, including checkpoint inhibitor therapy and immunotherapeutic vaccines, are discussed.

  View details for DOI 10.3390/ijms24032020

  View details for PubMedID 36768342

• Immunotherapy as a New Therapeutic Approach for Brain and Spinal Cord Tumors. Advances in experimental medicine and biology Medikonda, R., Pant, A., Lim, M. 2023; 1394: 73-84

  Abstract

  Historically, the central nervous system (CNS) was considered an immune-privileged organ. However, recent studies have shown that the immune system plays a significant role in the CNS. Thus, there is renewed interest in applying cancer immunotherapy to CNS malignancies with the hope of generating a robust anti-tumor immune response and creating long-lasting immunity in patients. There has been some work with non-specific immunotherapy such as IL-2 for brain metastasis. Unfortunately, the results from non-specific immunotherapy studies were lackluster, so the focus has shifted to more specific CNS immunotherapies including cancer vaccines, immune checkpoint inhibitors, oncolytic virus therapy, and chimeric antigen receptor (CAR) T cell therapy. With respect to cancer vaccines, rindopepimut has been well-studied in glioblastoma (GBM) patients with the EGFRvIII mutation, with early results from phase II trials showing possible efficacy in carefully selected GBM patients. Other antigen-specific CNS tumor vaccines are still in the early stages. Immune checkpoint inhibitors are amongst the most promising and widely studied CNS immunotherapy strategies. Anti-PD-1 showed promising results in many non-CNS solid tumors, however, results from early clinical trials show poor efficacy for anti-PD-1 in GBM patients. Anti-PD-1 is also under investigation for CNS metastasis and showed some efficacy in non-small cell lung cancer and renal cell carcinoma patients. Anti-PD-1 is under early stage investigation for other CNS tumors such as chordoma. Oncolytic virus therapy is the strategy of infecting tumor cells with a virus that in turn triggers an innate immune response leading to tumor cell lysis. Oncolytic viruses currently under investigation include several adenovirus-based therapies and a herpes simplex virus-based therapy. Phase I studies have demonstrated the safety of oncolytic virus therapies in GBM patients. Current studies are evaluating the efficacy of these therapies both alone and in combination with other immunotherapy approaches such as checkpoint inhibition in patients with CNS tumors. CAR T cell therapy is a newer immunotherapy approach. CAR T cell therapies, directed against EGFRvIII mutation and HER-2 mutation, demonstrate an acceptable safety profile, although there is no conclusive evidence of the survival benefit of these therapies in early trials. Studies are currently underway to determine optimal tumor-specific antigen selection and modality of administration for CAR T cell therapy. Overall, the prognosis is generally poor for patients with CNS malignancies. The promising results of cancer immunotherapy for non-CNS tumors have created significant interest in applying these therapies for CNS malignancies. Preliminary results have not demonstrated robust efficacy for CNS immunotherapy. However, it is important to keep in mind that the field is still in its infancy and many clinical trials are still early-phase. Several, clinical trials are currently underway to further explore the role of immunotherapy for CNS malignancies.

  View details for DOI 10.1007/978-3-031-14732-6_5

  View details for PubMedID 36587382

• Response JOURNAL OF NEUROSURGERY Xu, R., Nair, S. K., Bettegowda, C., Lim, M. 2023; 138 (1): 295

  View details for DOI 10.3171/2022.7.JNS221421

  View details for Web of Science ID 000927880500039

• The pathophysiology of trigeminal neuralgia: a molecular review. Journal of neurosurgery Dong, B., Xu, R., Lim, M. 2023; 139 (5): 1471-1479

  Abstract

  OBJECTIVE: The goal of this study was to provide a comprehensive overview of the current understanding of molecular and genetic mechanisms underlying the pathophysiology of trigeminal neuralgia (TN).METHODS: The authors searched PubMed systematically for primary research literature investigating specific molecular mechanisms from samples derived from patients with TN. The genes/molecules of interest from the selected literature were then cross-referenced with corresponding studies in animal models of TN.RESULTS: From approximately 345 articles, a total of 12 articles were selected and included in the review, focusing on ionotropic channel expressivity and mutations, reactive oxygen species expressivity, inflammatory marker expressivity, and microRNA expressivity. Of the 12 included articles, only 4 had studies completed in other animal models regarding the corresponding TN mechanism found in humans.CONCLUSIONS: The current literature does not suggest a conclusive disease mechanism for TN in humans. In addition to neurovascular conflict/compression of the trigeminal nerve, recent studies have indicated that TN may be linked to inflammatory and reactive oxygen species signaling as well. Recent genetic studies in patients with TN have yet to be investigated further in animal models.

  View details for DOI 10.3171/2023.2.JNS23274

  View details for PubMedID 37922556

• Multiple Vessel Compression of the Trigeminal Nerve Is Associated With Worse Outcomes in Trigeminal Neuralgia After Microvascular Decompression. Neurosurgery So, R. J., Kalluri, A. L., Zhu, S., Materi, J., Nair, S. K., Lim, M., Huang, J., Bettegowda, C., Xu, R. 2022

  Abstract

  BACKGROUND: Whether the total number of compressive vessels in trigeminal neuralgia (TN) affects outcomes after microvascular decompression (MVD) is unknown.OBJECTIVE: To investigate whether the number of compressive vessels is associated with outcomes after MVD.METHODS: We retrospectively reviewed all patients with TN who underwent MVDs at our institution from 2007 to 2020. The number and identity of compressive vessels on the trigeminal nerve were recorded. Preoperative and postoperative pain and numbness Barrow Neurological Institute scores were compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions.RESULTS: We identified 496 patients with a single vessel and 381 patients with multiple vessels compressing the trigeminal nerve. Compared with patients with a single compressive vessel, patients with multiple sources of compression exhibited increased Barrow Neurological Institute pain scores preoperatively (P = .01). In addition, pain recurrence was more frequent (P < .001) and occurred after a significantly shorter pain-free duration (P < .001) for the multiple compression group. Using multivariate ordinal regression, a greater number of arteries (P = .03) and veins (P = .03) were both significantly associated with higher pain scores at final follow-up. Furthermore, the number of arteries (P = .01) and of veins (P = .01) was significantly associated with a higher risk for pain recurrence.CONCLUSION: TN patients with a single compressive vessel exhibited better pain outcomes after an MVD. Patients with multiple compressive vessels exhibited higher pain scores preoperatively and incurred a higher risk for pain recurrence, which occurred after a shorter pain-free interval compared with the single compression cohort.

  View details for DOI 10.1227/neu.0000000000002323

  View details for PubMedID 36656030

• Advances in co-opting anti-depressant drugs in glioma therapy. Cell reports. Medicine Pant, A., Lim, M. 2022; 3 (12): 100837

  Abstract

  A study by Chryplewicz etal. demonstrated the efficacy of combining tricyclic antidepressant imipramine and anti-VEGF therapy in treating genetically engineered glioma models. Dual therapy synergistically improved vascular integrity, increased autophagy, and modulated the myeloid and lymphoid compartments in glioma.

  View details for DOI 10.1016/j.xcrm.2022.100837

  View details for PubMedID 36543105

• A Case Series of Trigeminal Neuralgia With Pure Venous Compression: Postoperative Outcomes Associated With Intraoperative Venous Transposition Versus Coagulation. Operative neurosurgery (Hagerstown, Md.) So, R. J., Kalluri, A. L., Materi, J., Nair, S. K., Lim, M., Huang, J., Bettegowda, C., Xu, R. 2022

  Abstract

  BACKGROUND: Microvascular decompressions (MVDs) are effective open-surgical procedures for trigeminal neuralgia (TN). Intraoperative management of compressive veins may include either venous transposition or coagulation. Although both are generally considered safe, which technique results in optimal postoperative outcomes remains unclear.OBJECTIVE: To compare postoperative pain and numbness outcomes after an MVD in patients with TN of exclusive venous compression.METHODS: We retrospectively reviewed all patients with TN who underwent MVDs at our institution from 2007 to 2020. Patients with TN of pure venous compression were identified using MRI imaging, which was subsequently confirmed intraoperatively. Patient demographics, procedural characteristics, and postoperative pain and numbness scores were recorded and compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions.RESULTS: We identified 181 patients who presented with TN of pure venous compression. Using a multivariate linear regression, adjusted for age, sex, and presence of multiple sclerosis, use of venous transposition vs coagulation was not significantly associated with the Barrow Neurological Institute pain score at final follow-up, although venous transposition was significantly predictive of a worse postoperative Barrow Neurological Institute numbness score (P = .003). Using a Kaplan-Meier survival analysis and a multivariate Cox proportional hazards regression, respectively, venous transposition was significantly associated with faster (P = .01) as well as higher risk for pain recurrence (P = .01).CONCLUSION: The use of venous coagulation during an MVD is associated with better postoperative pain and numbness outcomes. The results of our study may help inform preoperative patient counseling and surgical management for TN cases that involve pure venous compression.

  View details for DOI 10.1227/ons.0000000000000546

  View details for PubMedID 36661381

• Factors Predicting Cerebrospinal Fluid Leaks in Microvascular Decompressions: A Case Series of 1011 Patients. Operative neurosurgery (Hagerstown, Md.) Xu, R., So, R. J., Materi, J., Nair, S. K., Alomari, S. O., Huang, J., Lim, M., Bettegowda, C. 2022

  Abstract

  BACKGROUND: Microvascular decompression (MVD) using a retrosigmoid approach is a highly effective, open-surgical procedure for neurovascular conflict in the posterior fossa, although there is a risk of postoperative cerebrospinal fluid (CSF) leak.OBJECTIVE: To identify factors associated with postoperative CSF leakage after MVD.METHODS: We retrospectively reviewed all patients who underwent MVDs at our institution from 2007 to 2020. Patient demographics, clinical diagnoses, and procedural characteristics were recorded and compared. Factors leading to CSF leak were analyzed using chi2, univariate, and multivariate regression.RESULTS: Of 1011 patients who underwent MVDs, 37 (3.7%) presented with postoperative CSF leaks. In univariate analysis, the use of Cranios/Norian to obliterate the air cells was protective against CSF leak (P = .01). Craniotomies (P = .002), the use of dural substitutes such as Durepair (P = .04), dural onlays such as DuraGen (P = .04), muscle/fascia (P = .03), and titanium mesh cranioplasty >5 cm (P = .03) were associated with CSF leak. On multivariate analysis, only the presence of craniotomies (P = .04) and nonprimary dural closure (P = .03) were significant risk factors for CSF leak. When excluding the 34 (3.4%) patients who underwent a craniotomy, the lack of primary dural closure still remained significantly associated with postoperative CSF leak (P = .04).CONCLUSION: Our results represent one of the largest series of posterior fossa surgeries for a uniform indication in North America. Our study demonstrates increased risk for postoperative CSF leak when craniotomies are performed and when primary dural closure is not established. Given the small sample of patients who received a craniotomy, however, future studies corroborating this finding should be performed.

  View details for DOI 10.1227/ons.0000000000000503

  View details for PubMedID 36656065

• Updates in intraoperative strategies for enhancing intra-axial brain tumor control. Neuro-oncology Wu, A., Wu, J. Y., Lim, M. 2022; 24 (Supplement_6): S33-S41

  Abstract

  To ensure excellent postoperative clinical outcomes while preserving critical neurologic function, neurosurgeons who manage patients with intra-axial brain tumors can use intraoperative technologies and tools to achieve maximal safe resection. Neurosurgical oncology revolves around safe and optimal extent of resection, which further dictates subsequent treatment regimens and patient outcomes. Various methods can be adapted for treating both primary and secondary intra-axial brain lesions. We present a review of recent advances and published research centered on different innovative tools and techniques, including fluorescence-guided surgery, new methods of drug delivery, and minimally invasive procedural options.

  View details for DOI 10.1093/neuonc/noac170

  View details for PubMedID 36322098

• PROTEASOME REARRANGED PEPTIDES ARE A NOVEL SOURCE OF ANTIGENS FOR THE PEPTIDE VACCINE IMMUNOTHERAPY OF GLIOBLASTOMAS Fidanza, M., Gupta, P., Shanker, V., Wong, N., Skirboll, S., Lim, M., Wong, A. OXFORD UNIV PRESS INC. 2022: 138

  View details for Web of Science ID 000888571000532

• UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA. Buxton, M., Alexander, B., Berry, D., Cavenee, W., Colman, H., de Groot, J., Ellingson, B., Gordon, G., Khasraw, M., Lassman, A., Lee, E., Li, W., Lim, M., Mellinghoff, I., Mikkelsen, T., Nelli, A., Perry, J., Sulman, E., Tanner, K., Weller, M., Wen, P. Y., Yung, W., Cloughesy, T. OXFORD UNIV PRESS INC. 2022: 80

  View details for Web of Science ID 000888571000306

• SINGLE-STAGE RECONSTRUCTION FOLLOWING ONCOLOGIC RESECTION OF BRAIN TUMORS WITH SKULL INVASION Ben-Shalom, N., Anthony, A., Micah, B., Harnof, S., Huang, J., Lim, M., Brem, H., Gordon, C. OXFORD UNIV PRESS INC. 2022: 260

  View details for Web of Science ID 000888571001318

• Can tumor treating fields induce DNA damage and reduce cell motility in medulloblastoma cell lines? Journal of neurosurgery. Pediatrics Nitta, R. T., Luo, E. J., Lim, M., Li, G. 2022: 1-12

  Abstract

  Medulloblastoma (MB) is the most common malignant pediatric brain tumor and accounts for approximately 20% of all pediatric CNS tumors. Current multimodal treatment is associated with a 70%-90% 5-year survival rate; however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. The majority of survivors exhibit long-term neurocognitive complications; thus, more effective and less toxic treatments are critically needed. Tumor treating fields (TTFields) are low-intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. Side effects from TTField therapy are minimal, making it an ideal candidate for MB treatment.To determine if TTFields can be an effective treatment for MB, the authors conducted an in vitro study treating multiple MB cell lines. Three MB molecular subgroups (SHH [sonic hedgehog], group 3, and group 4) were treated for 24, 48, and 72 hours at 100, 200, 300, and 400 kHz. Combinatorial studies were conducted with the small-molecule casein kinase 2 inhibitor CX-4945.TTFields reduced MB cell growth with an optimal frequency of 300 kHz, and the most efficacious treatment time was 72 hours. Treatment with TTFields dysregulated actin polymerization and corresponded with a reduction in cell motility and invasion. TTFields also induced DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. The authors discovered that CX-4945 works synergistically with TTFields to reduce MB growth. In addition, combining CX-4945 and TTFields increased the cellular actin dysregulation, which correlated with a decrease in MB migration.The findings of this study demonstrate that TTFields may be a novel and less toxic method to treat patients with MB.

  View details for DOI 10.3171/2022.8.PEDS22300

  View details for PubMedID 36208441

• The role of preoperative MRI imaging in assessing neurovascular compression prior to microvascular decompression in trigeminal neuralgia. World neurosurgery Xu, R., Nair, S. K., Raj, D., Materi, J., So, R. J., Gujar, S. K., Huang, J., Blitz, A. M., Lim, M., Sair, H. I., Bettegowda, C. 2022

  Abstract

  Preoperative MRI is a standard component of the preoperative clinical workup for patients prior to microvascular decompression (MVD). However, its ability to accurately exclude neurovascular compression of the trigeminal nerve is not well understood.We retrospectively reviewed 1020 patients with available preoperative MRI data prior to microvascular decompression. General patient demographics and clinical characteristics were collected for each case. We recorded both evidence of neurovascular conflict on preoperative MRI radiology notes and intraoperative compression from operative notes. Sensitivity, specificity, positive predictive value, and negative predictive value was determined for general MRI, high-resolution MRI, and non-high resolution.Overall, preoperative MRI prior to MVD demonstrated a sensitivity of 75.8%, specificity of 65.8%, positive predictive value of 92.4%, and negative predictive value of 33.3% in predicting neurovascular compression of the trigeminal nerve. In particular, MRI was unable to identify 21.0% cases of sole arterial compression, 42.5% cases of sole venous compression, and combined arterial and venous compression in 18.5% of cases. 958 (93.9%) patients underwent high-resolution preoperative MRI with skull base sequences. This exhibited a sensitivity of 75.6%, specificity of 66.9%, positive predictive value of 92.5% and a negative predictive value of 33.4% in predicting trigeminal nerve neurovascular compression. Finally, non-high resolution MRI showed a sensitivity of 78.8%, specificity of 50.0%, positive predictive value of 89.1%, and negative predictive value of 31.3%. Importantly, the negative predictive values of general, high resolution, and non-high resolution MRIs were all below 50%.Preoperative MRI may offer a high predictive value for neurovascular conflict and should be part of the standard preoperative care workup for trigeminal neuralgia patients. However, lack of neurovascular conflict on preoperative imaging is not sufficient to exclude patients from undergoing MVD.

  View details for DOI 10.1016/j.wneu.2022.09.092

  View details for PubMedID 36167303

• A potential role for steroids in acute pain management in patients with trigeminal neuralgia. World neurosurgery Xu, R., Nair, S. K., Shah, P. P., Kannapadi, N., Materi, J., Alomari, S., Kim, T., Kalluri, A., Xia, Y., So, R. J., Lim, M., Bettegowda, C. 2022

  Abstract

  OBJECTIVES: Effective therapies for acute pain management in trigeminal neuralgia (TN) are limited. Here, we investigate the role of steroids in TN patients experiencing acute pain flares.METHODS: We retrospectively reviewed patients presenting to the emergency room of a tertiary care institution between 2014-2020 for acute trigeminal neuralgia pain flares. Patients were dichotomized into those who received steroids versus those who did not. Presenting characteristics, admission and surgical intervention rates, Barrow Neurological Institute (BNI) pain scores, pain recurrence rates, and surgical intervention within 6 months of discharge were obtained for each patient.RESULTS: Our cohort consisted of 151 patients, with 40 (26.5%) receiving steroids prior to admission and/or discharge. These patients were less likely to undergo surgical intervention to treat their acute pain, p=0.023. Specifically, patients receiving steroids were less likely to undergo combined glycerin and radiofrequency rhizotomy compared to patients not receiving steroids, p=0.012. Frequency and dosage of opioid administration did not differ between groups. The steroids group demonstrated a lower average BNI pain score on discharge compared to the no steroids group, p=0.013. Patients receiving steroids for acute pain management were less likely to undergo surgical intervention within 6 months of discharge than those who did not receive steroids, p=0.033.CONCLUSIONS: Steroid administration in these cases may reduce the likelihood of surgical intervention both during admission and within 6 months of discharge. Future prospective studies should examine the efficacy of steroids as an adjunctive medication in acute trigeminal neuralgia pain management.

  View details for DOI 10.1016/j.wneu.2022.09.025

  View details for PubMedID 36113711

• Radiomics analysis of amide proton transfer-weighted and structural MR images for treatment response assessment in malignant gliomas. NMR in biomedicine Jiang, S., Guo, P., Heo, H. Y., Zhang, Y., Wu, J., Jin, Y., Laterra, J., Eberhart, C. G., Lim, M., Blakeley, J. O. 2022: e4824

  Abstract

  The purpose of this study was to evaluate the value of amide proton transfer-weighted (APTw) MRI radiomic features for the differentiation of tumor recurrence from treatment effect in malignant gliomas. Eighty-six patients who had suspected tumor recurrence after completion of chemoradiation or radiotherapy, and who had APTw-MRI data acquired at 3T, were retrospectively analyzed. Using a fluid-attenuated inversion recovery (FLAIR) image-based mask, radiomics analysis was applied to the processed APTw and structural MR images. A Chi-square automatic interaction detector (CHAID) decision tree was used for classification analysis. Models with and without APTw features were built using the same strategy. Ten-fold cross-validation was applied to obtain the overall classification performance of each model. Sixty patients were confirmed having as tumor recurrence, and the remaining were confirmed having as treatment effect, at median time points of 190 and 171 days post-therapy, respectively. There were 525 radiomic features extracted from each of the processed APTw and structural MR images. Based on these, the APTw-based model yielded the highest accuracy (86.0%) for the differentiation of tumor recurrence from treatment effect, compared with 74.4%, 76.7%, 83.7%, and 76.7% for T1 w, T2 w, FLAIR, and Gd-T1 w, respectively. Model classification accuracy was 82.6% when using the combined structural MR images (T1 w, T2 w, FLAIR, Gd-T1 w), and increased to 89.5% when using these structural plus APTw images. The corresponding sensitivity and specificity were 85.0% and 76.9% for the combination of structural MR images, and 85.0% and 100% after adding APTw image features. Adding APTw-based radiomic features increased MRI accuracy in the assessment of the treatment response in post-treatment malignant gliomas.

  View details for DOI 10.1002/nbm.4824

  View details for PubMedID 36057449

• Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review. Chinese clinical oncology Wu, J. Y., Ren, A. L., Lim, M. 2022; 11 (4): 26

  Abstract

  Immunotherapy has yielded significant improvements in survival for many cancer types, but its impact on glioblastoma (GBM) has been relatively muted. There is a growing interest in understanding the role of cancer metabolism and its role in tumor growth and therapeutic response. Thus, it is equally important to consider the clinical implications of immune cell metabolism on cancer progression and implications for therapeutic development. Our objective is to present new developments in immunometabolic research that are relevant to immunotherapy development for high-grade gliomas.A literature search and review was conducted, regarding original research articles studying metabolic pathways of immune cells in high-grade gliomas. Searches were conducted in PubMed and Embase databases on May 15 and June 13, 2022. English-language original research articles were selected and prioritized based on their inclusion of findings related to metabolic changes in myeloid and lymphoid cells in the glioma tumor microenvironment.There are many metabolic mechanisms by which immune cells in high-grade gliomas, like GBM, contribute to tumor growth and persistence via immunosuppression and high therapeutic resistance. There are also several ways that metabolic optimization has already been shown to improve immunotherapies already in clinical trials or in use, including dendritic cell vaccines and chimeric antigen receptor T cells.The implications of immunometabolic research presented here should be taken into consideration in future research and immunotherapy development of high-grade gliomas for our best chances at improving patient survival.

  View details for DOI 10.21037/cco-22-58

  View details for PubMedID 36098097

• Learning-based analysis of amide proton transfer-weighted MRI to identify true progression in glioma patients. NeuroImage. Clinical Guo, P., Unberath, M., Heo, H., Eberhart, C. G., Lim, M., Blakeley, J. O., Jiang, S. 2022; 35: 103121

  Abstract

  The purpose of this study was to develop and verify a convolutional neural network (CNN)-based deep-learning algorithm to identify tumor progression versus response by adding amide proton transfer-weighted (APTw) MRI data to structural MR images as the proposed model input. 145 scans with 2175 MR instances from 98 patients with malignant glioma (acquired between April 2010 and February 2018) were re-analyzed. An end-to-end classification framework based on a ResNet backbone was developed. The architecture includes a learnable subtraction layer and a hierarchical classification paradigm, and synthesizes information over multiple MR slices using a long short-term memory. Areas under the receiver-operating-characteristic curves (AUCs) were used to assess the impact of adding APTw MRI to structural MRI (T1w, T2w, FLAIR, and GdT1w) on classification of tumor response vs. progression, both on the slice- and scan-level. With both APTw and structural MRI data, adding a learnable subtraction layer and a hierarchical classification paradigm to the backbone ResNet model improved the slice-level classification performance from an AUC of 0.85 to 0.90. Adding APTw data to structural MR images as input to our proposed CNN classification framework led to an increase in AUCs from 0.88 to 0.90 for the slice-level classification (P<0.001), and from 0.85 to 0.90 for the scan-level classification (P<0.05). Generated saliency maps highlighted the vast majority of lesions. Complementing structural MRI sequences with protein-based APTw MRI enhanced CNN-based classification of recurrent glioma at the slice and scan levels. Addition of APTw MRI to structural MRI sequences enhanced CNN-based classification of recurrent glioma at the slice and scan levels.

  View details for DOI 10.1016/j.nicl.2022.103121

  View details for PubMedID 35905666

• Predictors and Impact of Postoperative 30-Day Readmission in Glioblastoma. Neurosurgery Botros, D., Khalafallah, A. M., Huq, S., Dux, H., Oliveira, L. A., Pellegrino, R., Jackson, C., Gallia, G. L., Bettegowda, C., Lim, M., Weingart, J., Brem, H., Mukherjee, D. 2022

  Abstract

  BACKGROUND: Postoperative 30-day readmissions have been shown to negatively affect survival and other important outcomes in patients with glioblastoma (GBM).OBJECTIVE: To further investigate patient readmission risk factors of primary and recurrent patients with GBM.METHODS: The authors retrospectively reviewed records of 418 adult patients undergoing 575 craniotomies for histologically confirmed GBM at an academic medical center. Patient demographics, comorbidities, and clinical characteristics were collected and compared by patient readmission status using chi-square and Mann-Whitney U testing. Multivariable logistic regression was performed to identify risk factors that predicted 30-day readmissions.RESULTS: The cohort included 69 (12%) 30-day readmissions after 575 operations. Readmitted patients experienced significantly lower median overall survival (11.3 vs 16.4 months, P = .014), had a lower mean Karnofsky Performance Scale score (66.9 vs 74.2, P = .005), and had a longer initial length of stay (6.1 vs 5.3 days, P = .007) relative to their nonreadmitted counterparts. Readmitted patients experienced more postoperative deep vein thromboses or pulmonary embolisms (12% vs 4%, P = .006), new motor deficits (29% vs 14%, P = .002), and nonhome discharges (39% vs 22%, P = .005) relative to their nonreadmitted counterparts. Multivariable analysis demonstrated increased odds of 30-day readmission with each 10-point decrease in Karnofsky Performance Scale score (odds ratio [OR] 1.32, P = .002), each single-point increase in 5-factor modified frailty index (OR 1.51, P = .016), and initial presentation with cognitive deficits (OR 2.11, P = .013).CONCLUSION: Preoperatively available clinical characteristics strongly predicted 30-day readmissions in patients undergoing surgery for GBM. Opportunities may exist to optimize preoperative and postoperative management of at-risk patients with GBM, with downstream improvements in clinical outcomes.

  View details for DOI 10.1227/neu.0000000000002063

  View details for PubMedID 35876679

• Safety and cost savings associated with reduced inpatient hospitalization for microvascular decompression. World neurosurgery Xu, R., Nair, S. K., Materi, J., Raj, D., Park, G., Medikonda, R., Alomari, S., Kim, T., Xia, Y., Huang, J., Lim, M., Bettegowda, C. 2022

  Abstract

  Microvascular decompression (MVD) has grown as a first-line surgical intervention for severe facial pain from trigeminal neuralgia and/or hemifacial spasm. We sought to examine the safety and cost-benefits of discharging MVD patients within one day of admission.We retrospectively reviewed patients undergoing MVD at our institution from 2008-2020. Patients were sorted by 1-day, 2-day, or >2-day days until discharge and by year from 2008-2013, 2014-2018, or 2019-2020. Patient presenting characteristics, intraoperative measures, and complications were documented. Statistical differences were calculated by one-way ANOVA and Chi-squared analyses.Our cohort included 976 patients undergoing MVD with 231 (23.6%) between 2008-2013, 517 (52.9%) between 2014-2018, and 228 (23.3%) between 2019-2020. Over time, postoperative admission rates to the critical care unit, total inpatient hospital admission times, and Barrow Neurological Institute (BNI) scores at first follow-up decreased. Postoperative complications, including CSF leak, decreased significantly. Additionally, patients discharged within one day of admission incurred a total hospital cost of $26,689, which was $3,588 lower than patients discharged within more than one day of admission, p<0.0001. Discharging carefully selected patients who are appropriate for discharge within one day of admission could translate to a potential cost-savings of $255,346 per year in our clinical practice.In our experience, microvascular decompressions are a safe, elective intervention. Our findings suggest that postoperative day one discharge in patients with an uncomplicated postoperative course may be safe while improving hospital resource utilization.

  View details for DOI 10.1016/j.wneu.2022.07.037

  View details for PubMedID 35842175

• Diversity within the Neurosurgical Oncology Workforce in the United States: A Cross-Sectional Study with Proposed Strategies to Pave the Path Forward. Neuro-oncology Asfaw, Z. K., Rodriguez, A., Hodges, T. R., Mazumdar, M., Zhan, S., Lim, M., Germano, I. M. 2022

  Abstract

  BACKGROUND: Improving and fostering diversity within the neurosurgical workforce has become a high priority. This cross-sectional study aims to provide data on the diversity of neurosurgical oncology faculty (NSOF) in the US.METHODS: All 115 neurosurgery (NS) ACGME accredited programs were included in this study. The academic rank, academic and clinical title(s), gender, race, and hiring date of neurosurgical faculty with a primary focus on neurosurgical oncology (NSOF) were recorded. Geographical distribution and "top 10" programs were tabulated according to published data. Underrepresented minorities in medicine (URiM) faculty were identified according to the AAMC definition.RESULTS: The NSOF workforce constitute 21% of the total NS faculty. Of these, 10.1% are women and 9.9% are URiM (p<0.001). Currently, 58% of neurosurgery programs (NSP) do not have URiM and/or women NSOF. The top 10 ranked NSP, according to Blue Ridge Institute for Medical Research, had a significantly less URiM NSOF (p= 0.019) than non-top 10 ranked programs. There was a decreasing trend in the proportion of URiM at higher academic ranks (p= 0.019). All of the URiM department chairs (3/113)- all men- and 1/3 women department chairs nationwide subspecialized in neurosurgical oncology.CONCLUSIONS: Neurosurgical oncology is a sought-after subspecialty attracting a fifth of neurosurgeons practicing in ACGME-accredited training programs. Changing demographics and the benefits of workforce diversity represent a great opportunity for our field to continue leading inclusion efforts and attracting the best and brightest.

  View details for DOI 10.1093/neuonc/noac150

  View details for PubMedID 35705107

• GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma Cloughesy, T., Alexander, B., Berry, D. A., Colman, H., De Groot, J., Ellingson, B. M., Gordon, G. B., Khasraw, M., Lassman, A. B., Lee, E., Lim, M., Mellinghoff, I. K., Nelli, A., Perry, J. R., Sulman, E. P., Tanner, K., Weller, M., Wen, P. Y., Yung, W., Gbm Agile Investigators LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304830

• The future of cancer immunotherapy for brain tumors: a collaborative workshop. Journal of translational medicine Brown, C. E., Bucktrout, S., Butterfield, L. H., Futer, O., Galanis, E., Hormigo, A., Lim, M., Okada, H., Prins, R., Marr, S. S., Tanner, K. 2022; 20 (1): 236

  Abstract

  Harnessing the effector mechanisms of the immune system to combat brain tumors with antigen specificity and memory has been in research and clinical testing for many years. Government grant mechanisms and non-profit organizations have supported many innovative projects and trials while biotech companies have invested in the development of needed tools, assays and novel clinical approaches. The National Brain Tumor Society and the Parker Institute for Cancer Immunotherapy partnered to host a workshop to share recent data, ideas and identify both hurdles and new opportunities for harnessing immunotherapy against pediatric and adult brain tumors. Adoptively transferred cell therapies have recently shown promising early clinical results. Local cell delivery to the brain, new antigen targets and innovative engineering approaches are poised for testing in a new generation of clinical trials. Although several such advances have been made, several obstacles remain for the successful application of immunotherapies for brain tumors, including the need for more representative animal models that can better foreshadow human trial outcomes. Tumor and tumor microenvironment biopsies with multiomic analysis are critical to understand mechanisms of response and patient stratification, yet brain tumors are especially challenging for such biopsy collection. These workshop proceedings and commentary shed light on the status of immunotherapy in pediatric and adult brain tumor patients, including current research as well as opportunities for improving future efforts to bring immunotherapy to the forefront in the management of brain tumors.

  View details for DOI 10.1186/s12967-022-03438-z

  View details for PubMedID 35606815

• Internal neurolysis versus intraoperative glycerin rhizotomy for trigeminal neuralgia. Journal of neurosurgery Xu, R., Materi, J., Raj, D., Alomari, S., Xia, Y., Nair, S. K., Shah, P. P., Kannapadi, N., Kim, T., Huang, J., Bettegowda, C., Lim, M. 2022: 1-6

  Abstract

  OBJECTIVE: Internal neurolysis (IN) and intraoperative glycerin rhizotomy (ioGR) are emerging surgical options for patients with trigeminal neuralgia without neurovascular contact. The objective of this study was to compare the neurological outcomes of patients who underwent IN with those of patients who underwent ioGR.METHODS: The authors retrospectively reviewed all patients who underwent IN or ioGR for trigeminal neuralgia at our institution. Patient demographic characteristics and immediate postoperative outcomes, as well as long-term neurological outcomes, were compared.RESULTS: Of 1044 patients who underwent open surgical treatment for trigeminal neuralgia, 56 patients underwent IN and 91 underwent ioGR. Of these 147 patients, 37 had no evidence of intraoperative neurovascular conflict. All patients who underwent IN and 96.7% of patients who underwent ioGR had immediate postoperative pain relief. At last follow-up, patients who underwent IN had lower Barrow Neurological Institute (BNI) pain intensity scores (p = 0.05), better BNI facial numbness scores (p < 0.01), and a greater degree of pain improvement (p = 0.05) compared with those who underwent ioGR. Patients who underwent IN also had significantly lower rates of symptomatic pain recurrence (p < 0.01) at last follow-up over an average of 9.5 months.CONCLUSIONS: IN appears to provide patients with a greater degree of pain relief, lower rates of facial numbness, and lower rates of pain recurrence compared with ioGR. Future prospective studies will better characterize long-term pain recurrence and outcomes.

  View details for DOI 10.3171/2022.3.JNS212956

  View details for PubMedID 35523261

• Phase 3 Trial of Chemoradiotherapy With Temozolomide Plus Nivolumab or Placebo for Newly Diagnosed Glioblastoma With Methylated MGMT Promoter. Neuro-oncology Lim, M., Weller, M., Idbaih, A., Steinbach, J., Finocchiaro, G., Raval, R. R., Ansstas, G., Baehring, J., Taylor, J. W., Honnorat, J., Petrecca, K., De Vos, F., Wick, A., Sumrall, A., Sahebjam, S., Mellinghoff, I. K., Kinoshita, M., Roberts, M., Slepetis, R., Warad, D., Leung, D., Lee, M., Reardon, D. A., Omuro, A. 2022

  Abstract

  BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase 3 randomized CheckMate 548 study was to evaluate RT+TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).METHODS: Patients (N=716) were randomized 1:1 to NIVO [(240mg every 2 weeks *8, then 480mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75mg/m 2 once daily during RT, then 150-200mg/m 2 once daily days 1-5 of every 28-day cycle *6)] or PBO+RT+TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients.RESULTS: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO+RT+TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO+RT+TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively.CONCLUSIONS: NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.

  View details for DOI 10.1093/neuonc/noac116

  View details for PubMedID 35511454

• Radiotherapy Combined With Nivolumab or Temozolomide for Newly Diagnosed Glioblastoma With Unmethylated MGMT Promoter: An International Randomized Phase 3 Trial. Neuro-oncology Omuro, A., Brandes, A. A., Carpentier, A. F., Idbaih, A., Reardon, D. A., Cloughesy, T., Sumrall, A., Baehring, J., van den Bent, M., Bahr, O., Lombardi, G., Mulholland, P., Tabatabai, G., Lassen, U., Sepulveda, J. M., Khasraw, M., Vauleon, E., Muragaki, Y., Di Giacomo, A. M., Butowski, N., Roth, P., Qian, X., Fu, A. Z., Liu, Y., Potter, V., Chalamandaris, A., Tatsuoka, K., Lim, M., Weller, M. 2022

  Abstract

  BACKGROUND: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in glioblastoma, but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase 3 CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO)+RT compared with TMZ+RT in newly diagnosed glioblastoma with unmethylated MGMT promoter.METHODS: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240mg every 2 weeks for 8 cycles, then 480mg every 4 weeks) or RT+TMZ (75mg/m 2 daily during RT and 150-200mg/m 2/day 5/28 days during maintenance). The primary endpoint was OS.RESULTS: A total of 560 patients were randomized, 280 to each arm. Median OS was 13.4 months (95% CI, 12.6-14.3) with NIVO+RT and 14.9 months (95% CI, 13.3-16.1) with TMZ+RT (hazard ratio [HR], 1.31; 95% CI, 1.09-1.58; P=0.0037). Median progression-free survival was 6.0 months (95% CI, 5.7-6.2) with NIVO+RT and 6.2 months (95% CI, 5.9-6.7) with TMZ+RT (HR, 1.38; 95% CI, 1.15-1.65). Response rates were 7.8% (9/116) with NIVO+RT and 7.2% (8/111) with TMZ+RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively.CONCLUSIONS: The study did not meet the primary endpoint of improved OS; TMZ+RT demonstrated a longer median OS than NIVO+RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ+RT as standard of care for glioblastoma.

  View details for DOI 10.1093/neuonc/noac099

  View details for PubMedID 35419607

• Circulating Immune Cell and Outcome Analysis from the Phase 2 Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Nayak, L., Standifer, N., Dietrich, J., Clarke, J. L., Dunn, G. P., Lim, M., Cloughesy, T., Gan, H. K., Flagg, E., George, E., Gaffey, S., Hayden, J., Holcroft, C., Wen, P. Y., Macri, M., Park, A. J., Ricciardi, T., Ryan, A., Schwarzenberger, P., Venhaus, R., de Los Reyes, M., Durham, N. M., Creasy, T., Huang, R. Y., Kaley, T., Reardon, D. A. 2022

  Abstract

  Programmed death-ligand 1 (PD-L1) is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n=40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n=31), or in combination with standard bevacizumab (cohort B2; n=33), or low-dose bevacizumab (cohort B3; n=33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n=22). Primary endpoints were: OS-12 (A); PFS-6 (B, B2, B3); and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naive cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared to newly diagnosed that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.Recurrent glioblastoma patients have markedly lower baseline levels of multiple circulating immune cell subsets compared to newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among glioblastoma patients undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

  View details for DOI 10.1158/1078-0432.CCR-21-4064

  View details for PubMedID 35395080

• The Molecular Basis and Pathophysiology of Trigeminal Neuralgia. International journal of molecular sciences Chen, Q., Yi, D. I., Perez, J. N., Liu, M., Chang, S. D., Barad, M. J., Lim, M., Qian, X. 2022; 23 (7)

  Abstract

  Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.

  View details for DOI 10.3390/ijms23073604

  View details for PubMedID 35408959

• Case Series in the Utility of Invasive Blood Pressure Monitoring in Microvascular Decompression. Operative neurosurgery (Hagerstown, Md.) Xu, R., Nair, S. K., Materi, J., Raj, D., Medikonda, R., Shah, P. P., Kannapadi, N. V., Wang, A., Mintz, D., Gottschalk, A., Antonik, L. J., Huang, J., Bettegowda, C., Lim, M. 2022

  Abstract

  BACKGROUND: The utility of arterial lines in microvascular decompression (MVD) is not well described.OBJECTIVE: To examine the safety and costs of arterial lines compared with noninvasive blood pressure (NIBP) monitoring in MVDs.METHODS: We retrospectively reviewed patients undergoing MVD from 2012 to 2020. Patients were grouped by procedure date from 2012 to 2014 and 2015 to 2020, reflecting our institution's decreasing trend in arterial line placement around 2014 to 2015. Patient features, intraoperative characteristics, and postoperative complications were collected for all cases. Statistical differences were evaluated using chi-squared analyses and t-tests.RESULTS: Eight hundred fifty-eight patients underwent MVDs, with 204 between 2012 and 2014 and 654 between 2015 and 2020. Over time, the frequency of arterial line placement decreased from 64.2% to 30.1%, P < .001. Arterial lines involved 11 additional minutes of preincision time, P < .001. Patients with arterial lines required both increased doses and costs of vasoactive medications intraoperatively. Patients receiving arterial lines demonstrated no significant differences in complications compared with patients with NIBP monitoring. On average, patients with arterial lines incurred $802 increased costs per case compared with NIBP monitoring.CONCLUSION: NIBP monitoring in MVDs provides neurologically and hemodynamically safe outcomes compared with invasive blood pressure monitoring. For patients without significant cardiopulmonary risk factors, NIBP monitoring may be a cost-effective alternative in MVDs.

  View details for DOI 10.1227/ons.0000000000000130

  View details for PubMedID 35315836

• Cranioplasty With Customized Craniofacial Implants and Intraoperative Resizing for Single-Stage Reconstruction Following Oncologic Resection of Skull Neoplasms. The Journal of craniofacial surgery Ben-Shalom, N., Asemota, A. O., Belzberg, M., Harnof, S., Huang, J., Lim, M., Brem, H., Gordon, C. 2022

  Abstract

  BACKGROUND: Craniectomies requiring skull reconstruction are indicated following oncological resection of masses involving the underlying brain and/or skull. Immediate cranioplasties have previously been performed using suboptimal hand-bending or molding techniques using "off - the - shelf" products. Today with computer - aided design, customized craniofacial implants have become widely available for personalized reconstruction of resected bone and soft tissue. We present here the largest series to date of single stage reconstruction using alloplastic biomaterials in consecutive patient series with oversized customized implants.METHODS: A single-surgeon, retrospective, 8-year study was conducted on all consecutive patients undergoing single stage cranioplasty with prefabricated implants using a myriad of biomaterials. All outcomes were analyzed in detail and compared with previous studies utilizing similar alloplastic implants.RESULTS: In total, 56 patients underwent resection of skull neoplasms and subsequent cranioplasty reconstruction using customized implants. The most common neoplasms were meningiomas (39%). The most common complications seen among patients were dehiscence - (7%), and extrusion of implant - (3.5%). There was no significant difference in the incidence of postoperative complications between patients who had postoperative chemotherapy/radiotherapy versus those that did not (22.2% versus 13.1%, P = 0.39). One-year follow-up revealed acceptable cranial contour and symmetry in all 56 cases.CONCLUSIONS: This is a consecutive case series of prefabricated single-stage cranioplasty, following resection of brain tumors with bone extension or skull bone neoplasm, demonstrating excellent results with regards to safety and patient satisfaction. There are several advantages such as comprehensive resection and reconstruction plan using 3D models, shorter operative time, and better restoration of complex anatomy.

  View details for DOI 10.1097/SCS.0000000000008541

  View details for PubMedID 35288504

• The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors. Journal of neuro-oncology Kim, C., Lim, M., Woodworth, G. F., Arvanitis, C. D. 2022

  Abstract

  BACKGROUND: Focused ultrasound (FUS) is an emerging technology, offering the capability of tuning and prescribing thermal and mechanical treatments within the brain. While early works in utilizing this technology have mainly focused on maximizing the delivery of therapeutics across the blood-brain barrier (BBB), the potential therapeutic impact of FUS-induced controlled thermal and mechanical stress to modulate anti-tumor immunity is becoming increasingly recognized.OBJECTIVE: To better understand the roles of FUS-mediated thermal and mechanical stress in promoting anti-tumor immunity in central nervous system tumors, we performed a comprehensive literature review on focused ultrasound-mediated immunomodulation and immunotherapy in brain tumors.METHODS: First, we summarize the current clinical experience with immunotherapy. Then, we discuss the unique and distinct immunomodulatory effects of the FUS-mediated thermal and mechanical stress in the brain tumor-immune microenvironment. Finally, we highlight recent findings that indicate that its combination with immune adjuvants can promote robust responses in brain tumors.RESULTS: Along with the rapid advancement of FUS technologies into recent clinical trials, this technology through mild-hyperthermia, thermal ablation, mechanical perturbation mediated by microbubbles, and histotripsy each inducing distinct vascular and immunological effects, is offering the unique opportunity to improve immunotherapeutic trafficking and convert immunologically "cold" tumors into immunologically "hot" ones that are prone to generate prolonged anti-tumor immune responses.CONCLUSIONS: While FUS technology is clearly accelerating concepts for new immunotherapeutic combinations, additional parallel efforts to detail rational therapeutic strategies supported by rigorous preclinical studies are still in need to leverage potential synergies of this technology with immune adjuvants. This work will accelerate the discovery and clinical implementation of new effective FUS immunotherapeutic combinations for brain tumor patients.

  View details for DOI 10.1007/s11060-022-03973-1

  View details for PubMedID 35235137

• Advances in Immunotherapies for Gliomas. Current neurology and neuroscience reports Zhang, M., Choi, J., Lim, M. 1800

  Abstract

  PURPOSE OF REVIEW: Immunotherapy-based treatment of glioblastoma has been challenging because of the tumor's limited neoantigen profile and weakly immunogenic composition. This article summarizes the current clinical trials underway by evaluating the leading immunotherapy paradigms, the encountered barriers, and the future directions needed to overcome such tumor evasion.RECENT FINDINGS: A limited number of phase III trials have been completed for checkpoint inhibitor, vaccine, as well as gene therapies, and have been unable to show improvement in survival outcomes. Nevertheless, these trials have also shown these strategies to be safe and promising with further adaptations. Further large-scale studies for chimeric antigen receptors T cell therapies and viral therapies are anticipated. Many current trials are broadening the number of antigens targeted and modulating the microtumor environment to abrogate early mechanisms of resistance. Future GBM treatment will also likely require synergistic effects by combination regimens.

  View details for DOI 10.1007/s11910-022-01176-9

  View details for PubMedID 35107784

• Is There a Role for Immunotherapy in Central Nervous System Cancers? Hematology/oncology clinics of North America Flores, C., Dunn, G., Fecci, P., Lim, M., Mitchell, D., Reardon, D. A. 2022; 36 (1): 237-252

  Abstract

  Glioblastoma has emerged as an immunotherapy-refractory tumor based on negative phase III studies of anti-programmed cell death-1 therapy among newly diagnosed as well as recurrent patients. In addition, although much work on vaccine and cellular approaches is ongoing, therapeutic benefit with these approaches has been underwhelming. Much scientific insight into the multitiered layers of immunosuppression exploited by glioblastoma tumors is emerging that sheds light on the explanation for the disappointing results to date and highlights possible therapeutic avenues that may offer a better likelihood of therapeutic benefit for immune-based therapies.

  View details for DOI 10.1016/j.hoc.2021.09.002

  View details for PubMedID 34801163

• Introduction. Immunology of neurosurgical diseases. Neurosurgical focus Quinones-Hinojosa, A., Rahman, M., Lim, M., Suarez-Meade, P., Marenco-Hillembrand, L. 1800; 52 (2): E1

  View details for DOI 10.3171/2021.12.FOCUS21730

  View details for PubMedID 35104789

• Quantitative Bioluminescence Tomography for In Vivo Volumetric-Guided Radiotherapy. Methods in molecular biology (Clifton, N.J.) Deng, Z., Xu, X., Dehghani, H., Sforza, D. M., Iordachita, I., Lim, M., Wong, J. W., Wang, K. K. 2022; 2393: 701-731

  Abstract

  Several groups, including ours, have initiated efforts to develop small-animal irradiators that mimic radiation therapy (RT) for human treatment. The major image modality used to guide irradiation is cone-beam computed tomography (CBCT). While CBCT provides excellent guidance capability, it is less adept at localizing soft tissue targets growing in a low image contrast environment. In contrast, bioluminescence imaging (BLI) provides strong image contrast and thus is an attractive solution for soft tissue targeting. However, commonly used 2D BLI on an animal surface is inadequate to guide irradiation, because optical transport from an internal bioluminescent tumor is highly susceptible to the effects of optical path length and tissue absorption and scattering. Recognition of these limitations led us to integrate 3D bioluminescence tomography (BLT) with the small animal radiation research platform (SARRP). In this chapter, we introduce quantitative BLT (QBLT) with the advanced capabilities of quantifying tumor volume for irradiation guidance. The detail of system components, calibration protocol, and step-by-step procedure to conduct the QBLT-guided irradiation are described.

  View details for DOI 10.1007/978-1-0716-1803-5_38

  View details for PubMedID 34837208

• The Role of Myeloid Cells in GBM Immunosuppression. Frontiers in immunology Lin, Y., Wu, C. Y., Wu, J. Y., Lim, M. 2022; 13: 887781

  Abstract

  Gliomas are intrinsic brain tumors that originate from glial cells. Glioblastoma (GBM) is the most aggressive glioma type and resistant to immunotherapy, mainly due to its unique immune environment. Dimensional data analysis reveals that the intra-tumoral heterogeneity of immune cell populations in the glioma microenvironment is largely made up of cells of myeloid lineage. Conventional therapies of combined surgery, chemotherapy and radiotherapy have achieved limited improvements in the prognosis of glioma patients, as myeloid cells are prominent mediators of immune and therapeutic responses-like immunotherapy resistance-in glioma. Myeloid cells are frequently seen in the tumor microenvironment (TME), and they are polarized to promote tumorigenesis and immunosuppression. Reprogramming myeloid cells has emerged as revolutionary, new types of immunotherapies for glioma treatment. Here we detail the current advances in classifying epigenetic, metabolic, and phenotypic characteristics and functions of different populations of myeloid cells in glioma TME, including myeloid-derived suppressor cells (MDSCs), glioma-associated microglia/macrophages (GAMs), glioma-associated neutrophils (GANs), and glioma-associated dendritic cells (GADCs), as well as the mechanisms underlying promotion of tumorigenesis. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in glioma patients.

  View details for DOI 10.3389/fimmu.2022.887781

  View details for PubMedID 35711434

• Calcium-Related Gene Signatures May Predict Prognosis and Level of Immunosuppression in Gliomas. Frontiers in oncology Liu, P., Li, Y., Zhang, Y., Choi, J., Zhang, J., Shang, G., Li, B., Lin, Y., Saleh, L., Zhang, L., Yi, L., Yu, S., Lim, M., Yang, X. 2022; 12: 708272

  Abstract

  Gliomas are the most common primary brain cancer. While it has been known that calcium-related genes correlate with gliomagenesis, the relationship between calcium-related genes and glioma prognosis remains unclear. We assessed TCGA datasets of mRNA expressions with differentially expressed genes (DEGs) and enrichment analysis to specifically screen for genes that regulate or are affected by calcium levels. We then correlated the identified calcium-related genes with unsupervised/supervised learning to classify glioma patients into 2 risk groups. We also correlated our identified genes with immune signatures. As a result, we discovered 460 calcium genes and 35 calcium key genes that were associated with OS. There were 13 DEGs between Clusters 1 and 2 with different OS. At the same time, 10 calcium hub genes (CHGs) signature model were constructed using supervised learning, and the prognostic risk scores of the 3 cohorts of samples were calculated. The risk score was confirmed as an independent predictor of prognosis. Immune enrichment analysis revealed an immunosuppressive tumor microenvironment with upregulation of checkpoint markers in the high-risk group. Finally, a nomogram was generated with risk scores and other clinical prognostic independent indicators to quantify prognosis. Our findings suggest that calcium-related gene expression patterns could be applicable to predict prognosis and predict levels of immunosuppression.

  View details for DOI 10.3389/fonc.2022.708272

  View details for PubMedID 35646664

• Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-oncology advances Omuro, A., Reardon, D. A., Sampson, J. H., Baehring, J., Sahebjam, S., Cloughesy, T. F., Chalamandaris, A., Potter, V., Butowski, N., Lim, M. 2022; 4 (1): vdac025

  Abstract

  Background: The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.Methods: In total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS).Results: NIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94-22.08) with NIVO+RT+TMZ and 14.41 months (12.55-17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01-18.6) with NIVO+RT+TMZ and 13.96 months (10.81-18.14) with NIVO+RT in patients with unmethylated MGMT promoter.Conclusions: CheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.

  View details for DOI 10.1093/noajnl/vdac025

  View details for PubMedID 35402913

• CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Frontiers in immunology Lin, Y., Mashouf, L. A., Lim, M. 2022; 13: 817296

  Abstract

  Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Ralpha2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.

  View details for DOI 10.3389/fimmu.2022.817296

  View details for PubMedID 35265074

• Impact of international research fellows in neurosurgery: results from a single academic center JOURNAL OF NEUROSURGERY Yang, W., Rincon-Torroella, J., Feghali, J., Khalafallah, A. M., Ishida, W., Perdomo-Pantoja, A., Quinones-Hinojosa, A., Lim, M., Gallia, G. L., Riggins, G. J., Anderson, W. S., Lo, S., Rigamonti, D., Tamargo, R. J., Witham, T. F., Bydon, A., Cohen, A. R., Jallo, G., Latremoliere, A., Luciano, M. G., Mukherjee, D., Olivi, A., Qu, L., Gokaslan, Z. L., Sciubba, D. M., Tyler, B., Brem, H., Huang, J. 2022; 136 (1): 295-305

  Abstract

  International research fellows have been historically involved in academic neurosurgery in the United States (US). To date, the contribution of international research fellows has been underreported. Herein, the authors aimed to quantify the academic output of international research fellows in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.Research fellows with Doctor of Medicine (MD), Doctor of Philosophy (PhD), or MD/PhD degrees from a non-US institution who worked in the Hopkins Department of Neurosurgery for at least 6 months over the past decade (2010-2020) were included in this study. Publications produced during fellowship, number of citations, and journal impact factors (IFs) were analyzed using ANOVA. A survey was sent to collect information on personal background, demographics, and academic activities.Sixty-four international research fellows were included, with 42 (65.6%) having MD degrees, 17 (26.6%) having PhD degrees, and 5 (7.8%) having MD/PhD degrees. During an average 27.9 months of fellowship, 460 publications were produced in 136 unique journals, with 8628 citations and a cumulative journal IF of 1665.73. There was no significant difference in total number of publications, first-author publications, and total citations per person among the different degree holders. Persons holding MD/PhDs had a higher number of citations per publication per person (p = 0.027), whereas those with MDs had higher total IFs per person (p = 0.048). Among the 43 (67.2%) survey responders, 34 (79.1%) had nonimmigrant visas at the start of the fellowship, 16 (37.2%) were self-paid or funded by their country of origin, and 35 (81.4%) had mentored at least one US medical student, nonmedical graduate student, or undergraduate student.International research fellows at the authors' institution have contributed significantly to academic neurosurgery. Although they have faced major challenges like maintaining nonimmigrant visas, negotiating cultural/language differences, and managing self-sustainability, their scientific productivity has been substantial. Additionally, the majority of fellows have provided reciprocal mentorship to US students.

  View details for DOI 10.3171/2021.1.JNS203824

  View details for Web of Science ID 000751109500004

  View details for PubMedID 34298505

• Quality of Life and Role of Palliative and Supportive Care for Patients With Brain Metastases and Caregivers: A Review Frontiers in Neurology Wu, A., Ruiz Colon, G. D., Lim, M. 2022; 13

  View details for DOI 10.3389/fneur.2022.806344

• Clinical features and surgical outcomes of intracranial and spinal cord subependymomas. Journal of neurosurgery Rincon-Torroella, J., Rakovec, M., Khalafallah, A. M., Liu, A., Bettegowda, A., Kut, C., Rodriguez, F. J., Weingart, J., Luciano, M., Olivi, A., Jallo, G. I., Brem, H., Mukherjee, D., Lim, M., Bettegowda, C. 2022: 1-12

  Abstract

  Subependymomas are low-grade ependymal tumors whose clinical characteristics, radiographic features, and postsurgical outcomes are incompletely characterized due to their rarity. The authors present an institutional case series and a systematic literature review to achieve a better understanding of subependymomas.Adult patients with histologically confirmed subependymoma or mixed subependymoma-ependymoma surgically treated at a tertiary hospital between 1992 and 2020 were identified. A systematic literature review of the PubMed, Embase, Web of Science, and Google Scholar databases from inception until December 4, 2020, was conducted according to PRISMA guidelines. Data extracted from both groups included demographics, radiographic features, tumor characteristics, management, and follow-up variables.Forty-eight unique patients with subependymoma were identified by chart review; of these patients, 8 (16.7%) had mixed subependymoma-ependymoma tumors. The median age at diagnosis was 49 years (IQR 19.8 years), and 26 patients (54.2%) were male. Forty-two patients (87.5%) had intracranial subependymomas, and 6 (12.5%) had spinal tumors. The most common presentation was headache (n = 20, 41.7%), although a significant number of tumors were diagnosed incidentally (n = 16, 33.3%). Among the 42 patients with intracranial tumors, 15 (35.7%) had hydrocephalus, and the most common surgical strategy was a suboccipital approach with or without C1 laminectomy (n = 26, 61.9%). Gross-total resection (GTR) was achieved in 33 cases (68.7%), and 2 patients underwent adjuvant radiotherapy. Most patients had no major postsurgical complications (n = 34, 70.8%), and only 1 (2.1%) had recurrence after GTR. Of 2036 reports initially identified in the systematic review, 39 were eligible for inclusion, comprising 477 patients. Of 462 patients for whom tumor location was reported, 406 (87.9%) were intracranial, with the lateral ventricle as the most common location (n = 214, 46.3%). Spinal subependymomas occurred in 53 patients (11.5%), with 3 cases (0.6%) in multiple locations. Similar to the case series at the authors' institution, headache was the most common presenting symptom (n = 231, 54.0%) among the 428 patients whose presentation was reported. Twenty-seven patients (6.3%) were diagnosed incidentally, and 36 cases (8.4%) were found at autopsy. Extent of resection was reported for 350 patients, and GTR was achieved in 250 (71.4%). Fifteen of 337 patients (4.5%) had recurrence or progression.The authors' case series and literature review demonstrate that patients with subependymoma are well managed with resection and generally have a favorable prognosis.

  View details for DOI 10.3171/2021.12.JNS211643

  View details for PubMedID 35148513

• ATRX loss promotes immunosuppressive mechanisms in IDH1 mutant glioma. Neuro-oncology Hu, C., Wang, K., Damon, C., Fu, Y., Ma, T., Kratz, L., Lal, B., Ying, M., Xia, S., Cahill, D. P., Jackson, C. M., Lim, M., Laterra, J., Li, Y. 1800

  Abstract

  BACKGROUND: ATRX inactivation occurs with IDH1 R132H and p53 mutations in over 80% of Grade II/III astrocytomas. It is believed that ATRX loss contributes to oncogenesis by dysregulating epigenetic and telomere mechanisms but effects on anti-glioma immunity have not been explored. This paper examines how ATRX loss contributes to the malignant and immunosuppressive phenotypes of IDH1 R132H/p53mut glioma cells and xenografts.METHODS: Isogenic astrocytoma cells (+/-IDH1 R132H/+/-ATRXloss) were established in p53mut astrocytoma cell lines using lentivirus encoding doxycycline inducible IDH1 R132H, ATRX shRNA or Lenti-CRISPR/Cas9 ATRX. Effects of IDH1 R132H+/- ATRXloss on cell migration, growth, DNA repair and tumorigenicity were evaluated by clonal growth, transwell and scratch assays, MTT, immunofluorence and immunoblotting assays and xenograft growth. Effects on the expression and function of modulators of the immune microenvironment were quantified by qRT-PCR, immunoblot, T-cell function, macrophage polarization and flow cytometry assays. Pharmacologic inhibitors were used to examine epigenetic drivers of the immunosuppressive transcriptome of IDH1 R132H/p53mut/ATRXloss cells.RESULTS: Adding ATRX loss to the IDH1 R132H/p53mut background promoted astrocytoma cell aggressiveness, induced expression of BET proteins BRD3/4 and an immune suppressive transcriptome consisting of up-regulated immune checkpoints (e.g. PD-L1, PD-L2) and altered cytokine/chemokine profiles (e.g. IL33, CXCL8, CSF2, IL6, CXCL9). ATRX loss enhanced the capacity of IDH1 R132H/p53mut cells to induce T-cell apoptosis, tumorigenic/anti-inflammatory macrophage polarization and Treg infiltration. The transcriptional and biological immune suppressive responses to ATRX loss were enhanced by temozolomide and radiation and abrogated by pharmacologic BET inhibition.CONCLUSIONS: ATRX loss activates a BRD-dependent immune suppressive transcriptome and immune escape mechanism in IDH1 R132H/p53mut astrocytoma cells.

  View details for DOI 10.1093/neuonc/noab292

  View details for PubMedID 34951647

• A RANDOMIZED PHASE 3 STUDY OF NIVOLUMAB OR PLACEBO COMBINED WITH RADIOTHERAPY PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA WITH METHYLATED MGMT PROMOTER: CHECKMATE 548 Weller, M., Lim, M., Idbaih, A., Steinbach, J., Finocchiaro, G., Raval, R., Ashby, L., Ansstas, G., Baehring, J., Taylor, J., Honnorat, J., Petrecca, K., De Vos, F., Wick, A., Sumrall, A., Roberts, M., Slepetis, R., Warad, D., Lee, M., Reardon, D., Omuro, A. OXFORD UNIV PRESS INC. 2021: 55-56

  View details for Web of Science ID 000757356200219

• Checkpoint blockade in recurrent meningiomas: Lessons for future management. Neuro-oncology Pant, A., Lim, M. 2021

  View details for DOI 10.1093/neuonc/noab225

  View details for PubMedID 34626195

• Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Singh, K., Batich, K. A., Wen, P. Y., Tan, A. C., Bagley, S. J., Lim, M., Platten, M., Colman, H., Ashley, D. M., Chang, S. M., Rahman, R., Galanis, E., Mansouri, A., Puduvalli, V. K., Reardon, D. A., Sahebjam, S., Sampson, J. H., Simes, J., Berry, D. A., Zadeh, G., Cloughesy, T. F., Mehta, M. P., Piantadosi, S., Weller, M., Heimberger, A. B., Khasraw, M. 2021

  Abstract

  Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both pre-clinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

  View details for DOI 10.1158/1078-0432.CCR-21-2681

  View details for PubMedID 34561270

• The Challenges and Future of Immunotherapy for Gliomas. Cancer journal (Sudbury, Mass.) Wu, A., Lim, M. 2021; 27 (5): 371-378

  Abstract

  ABSTRACT: Gliomas and glioblastoma comprise the majority of brain malignancies and are difficult to treat despite standard of care and advances in immunotherapy. The challenges of controlling glioma growth and recurrence involve the uniquely immunosuppressive tumor microenvironment and systemic blunting of immune responses. In addition to highlighting key features of glioma and glioblastoma composition and immunogenicity, this review presents several future directions for immunotherapy, such as vaccines and synergistic combination treatment regimens, to better combat these tumors.

  View details for DOI 10.1097/PPO.0000000000000544

  View details for PubMedID 34570451

• Quantitative Bioluminescence Tomography-guided Conformal Irradiation for Pre-clinical Radiation Research. International journal of radiation oncology, biology, physics Xu, X., Deng, Z., Dehghani, H., Iordachita, I., Lim, M., Wong, J. W., Wang, K. K. 2021

  Abstract

  PURPOSE: Widely-used CBCT-guided irradiators in pre-clinical radiation research are limited to localize soft tissue target due to low imaging contrast. Knowledge of target volume is a fundamental need for radiotherapy (RT). Without such information to guide radiation, normal tissue can be over-irradiated, introducing experimental uncertainties. It led us to develop high contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of 3D bioluminescence signal, related to cell viability, for pre-clinical radiation research is one step toward biology-guided RT.METHODS: Our QBLT system enables multi-projection and multi-spectral bioluminescence imaging (BLI) to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labelled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance.RESULTS: The QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5 mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV.CONCLUSION: The QBLT provides a unique opportunity for investigators to use biological information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, expected to increase reproducibility of scientific discovery.

  View details for DOI 10.1016/j.ijrobp.2021.08.010

  View details for PubMedID 34411639

• Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma. Journal of neurosurgery Medikonda, R., Choi, J., Pant, A., Saleh, L., Routkevitch, D., Tong, L., Belcaid, Z., Kim, Y. H., Jackson, C. M., Jackson, C., Mathios, D., Xia, Y., Shah, P. P., Patel, K., Kim, T., Srivastava, S., Huq, S., Ehresman, J., Pennington, Z., Tyler, B., Brem, H., Lim, M. 2021: 1-10

  Abstract

  OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM.METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry.RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05).CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

  View details for DOI 10.3171/2021.1.JNS202482

  View details for PubMedID 34388730

• Emerging Technologies for Non-invasive Monitoring of Treatment Response to Immunotherapy for Brain Tumors. Neuromolecular medicine Mathios, D., Srivastava, S., Kim, T., Bettegowda, C., Lim, M. 2021

  Abstract

  Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, advanced imaging techniques, and immune profiling have emerged to counter premature diagnoses of progressive disease. However, these approaches do not provide a timely diagnosis and are costly and time consuming. Surgery is currently the standard of care for diagnosis of pseudoprogression in cases where MRI is equivocal. However, it is invasive, risky, and disruptive to patient's lives and their oncological treatment. With its increased vascularity, glioblastoma is continually shedding tumor components into the vasculature including tumor cells, genetic material, and extracellular vesicles. These elements can be isolated from routine blood draws and provide a real-time non-invasive indicator of tumor progression. Liquid biopsy therefore presents as an attractive alternative to current methods to guide treatment. While the initial evaluation of liquid biopsy for brain tumors via identification of mutations in the plasma was disappointing, novel technologies and use of alternatives to plasma cell-free DNA analytes provide promise for an effective liquid biopsy approach in brain tumors. This review aims to summarize developments in the use of liquid biopsy to monitor glioblastoma, especially in the context of immunotherapy.

  View details for DOI 10.1007/s12017-021-08677-9

  View details for PubMedID 34297308

• Sustained localized delivery of immunotherapy to lymph nodes reverses immunosuppression and increases long-term survival in murine glioblastoma. Oncoimmunology Choi, J., Pant, A., Medikonda, R., Kim, Y. H., Routkevitch, D., Saleh, L., Tong, L., Chan, H. Y., Nedrow, J., Jackson, C., Jackson, C., Lim, M. 2021; 10 (1): 1940673

  Abstract

  Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure.Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays.Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 (P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment.Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.

  View details for DOI 10.1080/2162402X.2021.1940673

  View details for PubMedID 34290904

  View details for PubMedCentralID PMC8274437

• Systematic review of combinations of targeted or immunotherapy in advanced solid tumors. Journal for immunotherapy of cancer Tan, A. C., Bagley, S. J., Wen, P. Y., Lim, M., Platten, M., Colman, H., Ashley, D. M., Wick, W., Chang, S. M., Galanis, E., Mansouri, A., Khagi, S., Mehta, M. P., Heimberger, A. B., Puduvalli, V. K., Reardon, D. A., Sahebjam, S., Simes, J., Antonia, S. J., Berry, D., Khasraw, M. 2021; 9 (7)

  Abstract

  With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.

  View details for DOI 10.1136/jitc-2021-002459

  View details for PubMedID 34215688

• Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma. Science translational medicine Fidanza, M., Gupta, P., Sayana, A., Shanker, V., Pahlke, S., Vu, B., Krantz, F., Azameera, A., Wong, N., Anne, N., Xia, Y., Rong, J., Anne, A., Skirboll, S., Lim, M., Wong, A. J. 2021; 13 (598)

  Abstract

  Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti-PD-1 therapy cured 45% of the Y6-pepVIII-vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography-tandem mass spectrometry analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant in Y6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.

  View details for DOI 10.1126/scitranslmed.aax4100

  View details for PubMedID 34135109

• Bone Cement Internal Auditory Canal Reconstruction to Reduce CSF Leak After Vestibular Schwannoma Retrosigmoid Approach. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Zhang, L., Galaiya, D., Jackson, C. M., Tamargo, R. J., Lim, M., Carey, J., Creighton, F. X. 2021

  Abstract

  OBJECTIVE: To describe rates of cerebrospinal fluid (CSF) rhinorrhea after reconstruction of the IAC with calcium phosphate bone cement during retrosigmoid resections of vestibular schwannomas.METHODS: A retrospective chart review of 177 patients who underwent retrosigmoid craniotomy and opening of the internal auditory canal for resection of a vestibular schwannoma between January 2016 and September 2019 at a tertiary referral center. Patients with other cerebellopontine angle tumor histology, neurofibromatosis type II, or those undergoing revision surgeries were excluded.RESULTS: Out of 177 patients, six patients (3.4%) developed postoperative rhinorrhea. Four patients (2.3%) were taken back to the OR for mastoidectomy and repair of CSF leak. Three of these patients were noted to have a CSF leak from the peri-labyrinthine air cells, and one was found to have a leak from the craniotomy site communicating with the mastoid air cells. Two patients were conservatively managed with diuretics and had resolution of their CSF leak. Six patients (3.4%) were readmitted for postoperative infection. Two patients were diagnosed with meningitis (1.1%), one aseptic and one H. Influenza, and three patients developed surgical site infections (1.6%). One patient was empirically treated with antibiotics and ultimately had a negative CSF culture.CONCLUSIONS: Our results demonstrate that the use of calcium phosphate bone cement for IAC closure in retrosigmoid resection of vestibular schwannomas is a safe and effective technique with low rates of postoperative CSF rhinorrhea.

  View details for DOI 10.1097/MAO.0000000000003215

  View details for PubMedID 34121078

• GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma. Wen, P. Y., Mellinghoff, I. K., Buxton, M., Cavenee, W. K., Colman, H., De Groot, J., Ellingson, B. M., Gordon, G. B., Khasraw, M., Lassman, A. B., Lim, M., Perry, J. R., Tanner, K., Weller, M., Yung, W., Cloughesy, T., GBM AGILE Investigators LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.TPS2074

  View details for Web of Science ID 000708120306194

• Immunotherapy for Chordoma and Chondrosarcoma: Current Evidence. Cancers Traylor, J. I., Pernik, M. N., Plitt, A. R., Lim, M., Garzon-Muvdi, T. 2021; 13 (10)

  Abstract

  Chordomas and chondrosarcomas are rare but devastating neoplasms that are characterized by chemoradiation resistance. For both tumors, surgical resection is the cornerstone of management. Immunotherapy agents are increasingly improving outcomes in multiple cancer subtypes and are being explored in chordoma and chondrosarcoma alike. In chordoma, brachyury has been identified as a prominent biomarker and potential molecular immunotherapy target as well as PD-1 inhibition. While studies on immunotherapy in chondrosarcoma are sparse, there is emerging evidence and ongoing clinical trials for PD-1 as well as IDH inhibitors. This review highlights potential biomarkers and targets for immunotherapy in chordoma and chondrosarcoma, as well as current clinical evidence and ongoing trials.

  View details for DOI 10.3390/cancers13102408

  View details for PubMedID 34067530

• Combination immunotherapy strategies for glioblastoma. Journal of neuro-oncology Chan, H. Y., Choi, J., Jackson, C., Lim, M. 2021; 151 (3): 375–91

  Abstract

  INTRODUCTION: Despite recent advances in treatment for a number of cancers with immune checkpoint blockade (ICB), immunotherapy has had limited efficacy in glioblastoma (GBM). The recent multi-centered CheckMate 143 trial in first time recurrent GBM and the Checkmate 498 trial in newly diagnosed unmethylated GBM showed that antibodies against programmed cell death protein 1 (PD-1) failed to improve overall survival in patients with GBM. Recent preclinical and clinical studies have explored combining ICB with several other therapies including additional ICB against alternative checkpoint molecules, activation of costimulatory checkpoint molecules such as 4-1BB, radiation-induced tumor cell lysis and immunogenic recruitment, local chemotherapy, neoadjuvant ICB therapy, and myeloid cell reactivation.METHODS: We have reviewed the literature on ICB seminal to the progression of several preclinical studies and clinical trials in order to provide a compendium of the current state of combination immunotherapy for GBM. For ongoing clinical trials without associated publications, we searched clinicaltrials.gov for ongoing studies using the keywords, "GBM" and "glioblastoma", as well as names of checkpoint molecules.RESULTS: Recent trends from clinical trials demonstrate that despite a variety of different combination strategies involving ICB, GBM remains largely elusive to current immunotherapies. There is a discordance of survival outcomes between GBM pre-clinical models and clinical trials, likely due to the heterogeneity of GBM in patients as well as other adaptive immune mechanisms not otherwise represented in murine models. However, in clinical studies, neoadjuvant ICB in GBM was found to diversify the T cell receptor (TCR) repertoire and increase chemokine mRNA transcripts when comparing pre- and post- surgical time points. Moreover, an increase in peripheral and tumor-infiltrating lymphocyte (TIL) clonotypes were also observed when comparing adjuvant and neoadjuvant cohorts.DISCUSSION: Despite the lack of clinical survival benefit, immune modulation was observed in multiple different combination strategies for GBM in both preclinical and clinical studies, indicating that ICB combination therapy results in a significant immunological impact on the tumor microenvironment.

  View details for DOI 10.1007/s11060-020-03481-0

  View details for PubMedID 33611705

• Development of new brain metastases in triple negative breast cancer. Journal of neuro-oncology Medikonda, R., Srivastava, S., Kim, T., Xia, Y., Kim, J., Jackson, C., Weingart, J., Mukherjee, D., Bettegowda, C., Gallia, G., Brem, H., Redmond, K., Stearns, V., Kleinberg, L., Lim, M. 2021

  Abstract

  BACKGROUND: Brain metastases are common in patients with breast cancer, and those with triple negative status have an even higher risk. Triple negative status is currently not considered when managing brain metastases.OBJECTIVE: To determine whether triple negative breast cancer (TNBC) patients with brain metastases have a higher burden of intracranial disease and whether WBRT has a survival benefit in this cohort of patients.METHODS: We conducted a retrospective cohort study with 85 patients meeting the inclusion criteria.RESULTS: 25% of patients had TNBC. 95% of the patients in this study received SRS and 48% received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67±1.1 in the non-TNBC status patients and 2.6±3.7 in the triple negative status patients (p=0.001). A cox proportional hazards model showed that WBRT does not significantly affect overall survival in patients with TNBC (HR1.48; 95% CI 0.47-4.67; p=0.50).CONCLUSION: Our findings highlight the highly aggressive intracranial nature of TNBC. The rate of new brain metastasis formation is higher in TNBC patients compared to non-TNBC patients. Furthermore, there is no survival benefit for WBRT in TNBC patients. These findings are relevant for clinicians planning brain radiation for TNBC patients as they may find more brain metastases at the time of brain radiation than they anticipated based on initial brain imaging.

  View details for DOI 10.1007/s11060-021-03702-0

  View details for PubMedID 33512631

• In Reply: Absence of Ischemic Injury After Sacrificing the Superior Petrosal Vein During Microvascular Decompression. Operative neurosurgery (Hagerstown, Md.) Xia, Y., Lim, M. 2021

  View details for DOI 10.1093/ons/opaa437

  View details for PubMedID 33442747

• Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases. Journal of neuro-oncology Zhang, M. n., Rodrigues, A. J., Pollom, E. L., Gibbs, I. C., Soltys, S. G., Hancock, S. L., Neal, J. W., Padda, S. K., Ramchandran, K. J., Wakelee, H. A., Chang, S. D., Lim, M. n., Hayden Gephart, M. n., Li, G. n. 2021

  Abstract

  Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described.We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed.A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF.In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

  View details for DOI 10.1007/s11060-020-03686-3

  View details for PubMedID 33415659

• In Vivo Evaluation of Near-Infrared Fluorescent Probe for TIM3 Targeting in Mouse Glioma. Molecular imaging and biology Zhang, M., Zhou, Q., Huang, C., Chan, C. T., Wu, W., Li, G., Lim, M., Gambhir, S. S., Daldrup-Link, H. E. 2021

  Abstract

  Current checkpoint inhibitor immunotherapy strategies in glioblastoma are challenged by mechanisms of resistance including an immunosuppressive tumor microenvironment. T cell immunoglobulin domain and mucin domain 3 (TIM3) is a late-phase checkpoint receptor traditionally associated with T cell exhaustion. We apply fluorescent imaging techniques to explore feasibility of in vivo visualization of the immune state in a glioblastoma mouse model.TIM3 monoclonal antibody was conjugated to a near-infrared fluorescent dye, IRDye-800CW (800CW). The TIM3 experimental conjugate and isotype control were assessed for specificity with immunofluorescent staining and flow cytometry in murine cell lines (GL261 glioma and RAW264.7 macrophages). C57BL/6 mice with orthotopically implanted GL261 cells were imaged in vivo over 4 days after intravenous TIM3-800CW injection to assess tumor-specific uptake. Cell-specific uptake was then assessed on histologic sections.The experimental TIM3-800CW, but not its isotype control, bound to RAW264.7 macrophages in vitro. Specificity to RAW264.7 macrophages and not GL261 tumor cells was quantitatively confirmed with the corresponding clone of TIM3 on flow cytometry. In vivo fluorescence imaging of the 800CW signal was localized to the intracranial tumor and significantly higher for the TIM3-800CW cohort, relative to non-targeting isotype control, immediately after tail vein injection and for up to 48 h after injection. Resected organs of tumor bearing mice showed significantly higher uptake in the liver and spleen. TIM3-800CW was seen to co-stain with CD3 (13%), CD11b (29%), and CD206 (26%).We propose fluorescent imaging of immune cell imaging as a potential strategy for monitoring and localizing immunologically relevant foci in the setting of brain tumors. Alternative markers and target validation will further clarify the temporal relationship of immunosuppressive effector cells throughout glioma resistance.

  View details for DOI 10.1007/s11307-021-01667-0

  View details for PubMedID 34846678

• The safety and efficacy of dexamethasone in the perioperative management of glioma patients. Journal of neurosurgery Medikonda, R., Patel, K., Jackson, C., Saleh, L., Srivastava, S., Feghali, J., Mohan, A., Pant, A., Jackson, C. M., Weingart, J., Mukherjee, D., Bettegowda, C., Gallia, G. L., Brem, H., Lim, M. 2021: 1-8

  Abstract

  In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection.A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019.The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062).Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone use.

  View details for DOI 10.3171/2021.4.JNS204127

  View details for PubMedID 34560653

• Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma ONCOIMMUNOLOGY Choi, J., Medikonda, R., Saleh, L., Kim, T., Pant, A., Srivastava, S., Kim, Y., Jackson, C., Tong, L., Routkevitch, D., Jackson, C., Mathios, D., Zhao, T., Cho, H., Brem, H., Lim, M. 2021; 10 (1): 1956142

  Abstract

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

  View details for DOI 10.1080/2162402X.2021.1956142

  View details for Web of Science ID 000690760100001

  View details for PubMedID 34484870

  View details for PubMedCentralID PMC8409779

• Roles of Neutrophils in Glioma and Brain Metastases. Frontiers in immunology Lin, Y., Wei, K., Chen, P., Lim, M., Hwang, T. 2021; 12: 701383

  Abstract

  Neutrophils, which are the most abundant circulating leukocytes in humans, are the first line of defense against bacterial and fungal infections. Recent studies have reported the role and importance of neutrophils in cancers. Glioma and brain metastases are the most common malignant tumors of the brain. The tumor microenvironment (TME) in the brain is complex and unique owing to the brain-blood barrier or brain-tumor barrier, which may prevent drug penetration and decrease the efficacy of immunotherapy. However, there are limited studies on the correlation between brain cancer and neutrophils. This review discusses the origin and functions of neutrophils. Additionally, the current knowledge on the correlation between neutrophil-to-lymphocyte ratio and prognosis of glioma and brain metastases has been summarized. Furthermore, the implications of tumor-associated neutrophil (TAN) phenotypes and the functions of TANs have been discussed. Finally, the potential effects of various treatments on TANs and the ability of neutrophils to function as a nanocarrier of drugs to the brain TME have been summarized. However, further studies are needed to elucidate the complex interactions between neutrophils, other immune cells, and brain tumor cells.

  View details for DOI 10.3389/fimmu.2021.701383

  View details for PubMedID 34484197

• A Crowdsourced Consensus on Supratotal Resection Versus Gross Total Resection for Anatomically Distinct Primary Glioblastoma. Neurosurgery Khalafallah, A. M., Rakovec, M., Bettegowda, C., Jackson, C. M., Gallia, G. L., Weingart, J. D., Lim, M., Esquenazi, Y., Zacharia, B. E., Goldschmidt, E., Ziu, M., Ivan, M. E., Venteicher, A. S., Nduom, E. K., Mamelak, A. N., Chu, R. M., Yu, J. S., Sheehan, J. P., Nahed, B. V., Carter, B. S., Berger, M. S., Sawaya, R., Mukherjee, D. 2021

  Abstract

  Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma.To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR.A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans.Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P < .005). Cases were divided into 3 anatomically distinct groups based upon perceived eloquence. Anterior temporal and right frontal glioblastomas were considered the best randomization candidates.We established a consensus definition for SpTR of glioblastoma and identified anatomically distinct locations deemed most amenable to SpTR. These results may be used to plan prospective trials investigating the potential clinical utility of SpTR for glioblastoma.

  View details for DOI 10.1093/neuros/nyab257

  View details for PubMedID 34320218

• Sustained localized delivery of immunotherapy to lymph nodes reverses immunosuppression and increases long-term survival in murine glioblastoma ONCOIMMUNOLOGY Choi, J., Pant, A., Medikonda, R., Kim, Y., Routkevitch, D., Saleh, L., Tong, L., Chan, H., Nedrow, J., Jackson, C., Jackson, C., Lim, M. 2021; 10 (1)

  View details for DOI 10.1080/2162402X.2021.1940673

  View details for Web of Science ID 000670783300001

• Mutation status and postresection survival of patients with non-small cell lung cancer brain metastasis: implications of biomarker-driven therapy. Journal of neurosurgery Shah, P. P., Franke, J. L., Medikonda, R., Jackson, C. M., Srivastava, S., Choi, J., Forde, P. M., Brahmer, J. R., Ettinger, D. S., Feliciano, J. L., Levy, B. P., Marrone, K. A., Naidoo, J., Redmond, K. J., Kleinberg, L. R., Lim, M. 2021: 1-11

  Abstract

  Non-small cell lung cancer (NSCLC) is the most common primary tumor to develop brain metastasis. Prognostic markers are needed to better determine survival after neurosurgical resection of intracranial disease. Given the importance of mutation subtyping in determining systemic therapy and overall prognosis of NSCLC, the authors examined the prognostic value of mutation status for postresection survival of patients with NSCLC brain metastasis.The authors retrospectively analyzed all cases of NSCLC brain metastasis with available molecular testing data that were resected by a single surgeon at a single academic center from January 2009 to February 2019. Mutation status, demographic characteristics, clinical factors, and treatments were analyzed. Association between predictive variables and overall survival after neurosurgery was determined with Cox regression.Of the included patients (n = 84), 40% were male, 76% were smokers, the mean ± SD Karnofsky Performance Status was 85 ± 14, and the mean ± SD age at surgery was 63 ± 11 years. In total, 23%, 26%, and 4% of patients had EGFR, KRAS, and ALK/ROS1 alterations, respectively. On multivariate analysis, survival of patients with EGFR (HR 0.495, p = 0.0672) and KRAS (HR 1.380, p = 0.3617) mutations were not significantly different from survival of patients with wild-type (WT) tumor. However, the subgroup of patients with EGFR mutation who also received tyrosine kinase inhibitor (TKI) therapy had significantly prolonged survival (HR 0.421, p = 0.0471). In addition, postoperative stereotactic radiosurgery (HR 0.409, p = 0.0177) and resected tumor diameter < 3 cm (HR 0.431, p = 0.0146) were also significantly associated with prolonged survival, but Graded Prognostic Assessment score ≤ 1.0 (HR 2.269, p = 0.0364) was significantly associated with shortened survival.Patients with EGFR mutation who receive TKI therapy may have better survival after resection of brain metastasis than patients with WT tumor. These results may inform counseling and decision-making regarding the appropriateness of resection of NSCLC brain metastasis.

  View details for DOI 10.3171/2020.10.JNS201787

  View details for PubMedID 34087798

• The state of neuro-oncology during the COVID-19 pandemic: a worldwide assessment. Neuro-oncology advances Mrugala, M. M., Ostrom, Q. T., Pressley, S. M., Taylor, J. W., Thomas, A. A., Wefel, J. S., Coven, S. L., Acquaye, A. A., Haynes, C., Agnihotri, S., Lim, M., Peters, K. B., Sulman, E. P., Salcido, J. T., Butowski, N. A., Hervey-Jumper, S., Mansouri, A., Oliver, K. R., Porter, A. B., Nassiri, F., Schiff, D., Dunbar, E. M., Hegi, M. E., Armstrong, T. S., van den Bent, M. J., Chang, S. M., Zadeh, G., Chheda, M. G. 2021; 3 (1): vdab035

  Abstract

  Background: It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.Methods: We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.Results: Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.Conclusions: The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.

  View details for DOI 10.1093/noajnl/vdab035

  View details for PubMedID 34007966

• Reprogramming transcription factors Oct4 and Sox2 induces a BRD-dependent immunosuppressive transcriptome in GBM-propagating cells. Cancer research Laterra, J. n., Ma, T. n., Hu, C. n., Lal, B. n., Zhou, W. n., Ma, Y. n., Ying, M. n., Prinos, P. n., Quiñones-Hinojosa, A. n., Lim, M. n., Li, Y. n. 2021

  Abstract

  A subset of stem-like tumor-propagating cells in GBM (GSC) underlies tumor propagation, therapeutic resistance and tumor recurrence. Immune evasion is critical for GSCs to carry out these functions. However, the molecular mechanisms employed by GSCs to escape anti-tumor immunity remain largely unknown. The reprogramming transcription factors Oct4 and Sox2 function as core multipotency factors and play an essential role in the formation and maintenance of GSCs, but the roles of these transcription factors in GSC immune escape have not been well explored. Here we examine how Oct4/Sox2 co-expression contributes to the immunosuppressive phenotype of GSCs. Combined transcription profiling and functional studies of Oct4/Sox2 co-expressing GSCs and differentiated GBM cells demonstrated that Oct4 and Sox2 cooperatively induce an immunosuppressive transcriptome consisting of multiple immunosuppressive checkpoints (i.e., PD-L1, CD70, A2aR, TDO) and dysregulation of cytokines and chemokines that are associated with an immunosuppressive tumor microenvironment. Mechanistically, induction and function of BRD/H3k27Ac-dependent immunosuppressive genes played a role in the immunosuppressive phenotype of GSCs. Pan-BET bromodomain inhibitors (e.g., JQ1) and shBRD4 constructs significantly inhibited the immunosuppressive transcriptome and immunosuppressive biological responses induced by Oct4/Sox2. Our findings identify targetable mechanisms by which tumor-propagating GSCs contribute to the immunosuppressive microenvironment in GBM.

  View details for DOI 10.1158/0008-5472.CAN-20-2489

  View details for PubMedID 33574085

• Role of surgery for glioblastoma: response to letters from Dr. Gerritsen and his colleagues and Dr. Vargas Lopez. Neuro-oncology Wen, P. Y., Weller, M. n., Chiocca, E. A., Lim, M. n., Tonn, J. C., Zadeh, G. n., Aldape, K. n., van den Bent, M. n. 2021

  View details for DOI 10.1093/neuonc/noaa305

  View details for PubMedID 33471080

• Unique challenges for glioblastoma immunotherapy - Discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Neuro-oncology Chuntova, P., Chow, F., Watchmaker, P., Galvez, M., Heimberger, A. B., Newell, E. W., Diaz, A., DePinho, R. A., Li, M. O., Wherry, E. J., Mitchell, D., Terabe, M., Wainwright, D. A., Berzofsky, J. A., Herold-Mende, C., Heath, J. R., Lim, M., Margolin, K. A., Chiocca, E. A., Kasahara, N., Ellingson, B. M., Brown, C., Chen, Y., Fecci, P., Reardon, D. A., Dunn, G. P., Liau, L. M., Costello, J. F., Wick, W., Cloughesy, T., Timmer, W. C., Wen, P. Y., Prins, R. M., Platten, M., Okada, H. 2020

  Abstract

  Cancer immunotherapy has made remarkable advances with over fifty separate Food and Drug Administration (FDA) approvals as first or second line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T-cells and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights in the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells and T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.

  View details for DOI 10.1093/neuonc/noaa277

  View details for PubMedID 33367885

• Alternative Checkpoints as Targets for Immunotherapy. Current oncology reports Pant, A., Medikonda, R., Lim, M. 2020; 22 (12): 126

  Abstract

  PURPOSE OF REVIEW: Immunotherapy has shown an unprecedented response in treatment of tumors. However, challenges such as lack of cytotoxic lymphocytes to mount an immune response or development of resistance to therapy can limit efficacy. Here, we discuss alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system.RECENT FINDINGS: Blockade of alternative checkpoints has improved anti-tumor immunity in mouse models and is being tested clinically with encouraging findings. In addition to modulating T cell function directly, alternative checkpoints can also regulate activity of myeloid cells and regulatory T cells to affect anti-tumor response. Combination of immune checkpoint inhibitors can improve treatment of tumors by activating multiple arms of the immune system.

  View details for DOI 10.1007/s11912-020-00983-y

  View details for PubMedID 33141349

• Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee. Journal for immunotherapy of cancer Gastman, B., Agarwal, P. K., Berger, A., Boland, G., Broderick, S., Butterfield, L. H., Byrd, D., Fecci, P. E., Ferris, R. L., Fong, Y., Goff, S. L., Grabowski, M. M., Ito, F., Lim, M., Lotze, M. T., Mahdi, H., Malafa, M., Morris, C. D., Murthy, P., Neves, R. I., Odunsi, A., Pai, S. I., Prabhakaran, S., Rosenberg, S. A., Saoud, R., Sethuraman, J., Skitzki, J., Slingluff, C. L., Sondak, V. K., Sunwoo, J. B., Turcotte, S., Yeung, C. C., Kaufman, H. L. 2020; 8 (2)

  Abstract

  Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.

  View details for DOI 10.1136/jitc-2020-001583

  View details for PubMedID 33199512

• THE SAFETY AND EFFICACY OF DEXAMETHASONE IN THE MANAGEMENT OF GLIOMA PATIENTS Medikonda, R., Patel, K., Saleh, L., Srivastava, S., Jackson, C., Mohan, A., Weingart, J., Bettegowda, C., Gallia, G., Brem, H., Lim, M. OXFORD UNIV PRESS INC. 2020: 136

  View details for Web of Science ID 000590061300571

• EFFICACY OF ANTICONVULSANT THERAPY IN GLIOMA PATIENTS Medikonda, R., Patel, K., Saleh, L., Srivastava, S., Jackson, C., Mohan, A., Shah, P., Weingart, J., Bettegowda, C., Gallia, G., Brem, H., Lim, M. OXFORD UNIV PRESS INC. 2020: 134

  View details for Web of Science ID 000590061300564

• MANAGEMENT OF BRAIN METASTASIS IN TRIPLE NEGATIVE BREAST CANCER Medikonda, R., Srivastava, S., Kim, T., Xia, Y., Patel, M., Jackson, C., Theodros, D., Kim, J., Kleinberg, L., Redmond, K., Weingart, J., Mukherjee, D., Bettegowda, C., Gallia, G., Brem, H., Lim, M. OXFORD UNIV PRESS INC. 2020: 130

  View details for Web of Science ID 000590061300545

• GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA Buxton, M., Alexander, B., Berry, D., Cavenee, W., Colman, H., de Groot, J., Ellingson, B., Gordon, G., Khasraw, M., Lassman, A., Lee, W., Lim, M., Mellinghoff, I., Perry, J., Sulman, E., Tanner, K., Weller, M., Wen, P., Yung, W., Cloughesy, T., GBM AGILE Investigators OXFORD UNIV PRESS INC. 2020: 195–96

  View details for Web of Science ID 000590061300817

• A CROWDSOURCED CONSENSUS ON SUPRATOTAL RESECTION VERSUS GROSS TOTAL RESECTION FOR ANATOMICALLY DISTINCT PRIMARY GLIOBLASTOMA Mukherjee, D., Rakovec, M., Bettegowda, C., Jackson, C., Gallia, G., Lim, M., Weingart, J., Esquenazi, Y., Zacharia, B., Goldschmidt, E., Ziu, M., Ivan, M., Venteicher, A., Nduom, E., Mamelak, A., Chu, R., Yu, J., Sheehan, J., Nahed, B., Carter, B., Berger, M., Sawaya, R., Khalafallah, A. OXFORD UNIV PRESS INC. 2020: 208

  View details for Web of Science ID 000590061300869

• SINGLE CELL RNA-SEQUENCING IDENTIFIES NOVEL BONE MARROW DERIVED MYELOID CELLS IN GLIOBLASTOMA ASSOCIATED WITH TUMOR AGGRESSION Jackson, C., Cherry, C., Bom, S., Zhang, H., Choi, J., Yegnasubramanian, V., Lim, M., Elisseeff, J., Pardoll, D. OXFORD UNIV PRESS INC. 2020: 110

  View details for Web of Science ID 000590061300458

• EFFICACY OF CXCR6 BLOCKADE AS A POTENTIATOR OF ANTI-PD-1 THERAPY FOR THE TREATMENT OF GLIOBLASTOMA Pant, A., Saleh, L., Patel, K., Medikonda, R., Lim, M. OXFORD UNIV PRESS INC. 2020: 107

  View details for Web of Science ID 000590061300444

• THE STATE OF NEURO-ONCOLOGY DURING THE COVID-19 PANDEMIC: A WORLDWIDE ASSESSMENT Mrugala, M., Ostrom, Q., Pressley, S., Thomas, A., Wefel, J. S., Coven, S., Acquaye, A., Haynes, C., Agnihotri, S., Lim, M., Peters, K., Butowski, N., Hervey-Jumper, S., Porter, A., Oliver, K., Dunbar, E., Taylor, J., Schiff, D., Nassiri, F., Hegi, M., Armstrong, T., van den Bent, M., Chang, S., Zadeh, G., Chheda, M. OXFORD UNIV PRESS INC. 2020: 27

  View details for Web of Science ID 000590061300113

• Scalp Invasion by Atypical or Anaplastic Meningioma Is a Risk Factor for Development of Systemic Metastasis WORLD NEUROSURGERY Garzon-Muvdi, T., Maxwell, R., Luksik, A., Kessler, R., Weingart, J., Olivi, A., Bettegowda, C., Tamargo, R., Brem, H., Lim, M. 2020; 142: E133–E139

  Abstract

  Atypical and anaplastic meningiomas (AAMs) are rare and comprise approximately 5% of all meningiomas. Extracranial metastases in meningioma patients occur in 0.1% of all cases, but these lesions are difficult to treat and may be a poor prognostic factor.We conducted a retrospective chart review between 1990 and 2016 of patients who had surgical resection of AAM. In a cohort of 149 patients, 6 had metastatic lesions that were histologically confirmed to be meningioma. We compared baseline characteristics between patients with and without metastasis and performed a multivariate Cox regression analysis to assess risk factors for the development of systemic metastasis.Six patients had histologically confirmed meningioma metastasis. We hypothesized that the presence of scalp invasion in patients could be a potential risk factor for the development of systemic meningioma metastasis. Nine out of the 149 patients without metastasis had scalp invasion, whereas 4 out of the 6 patients with metastasis had scalp invasion. Patients with metastasis had a median age of 62 ± 20. Patients without metastasis had a median age of 59 ± 15 years. Gender distribution was similar; approximately 50% of patients in each group were female. Eighty-five percent of patients with metastatic disease were white, and 65% of patients without metastatic disease were white. Among patients without metastatic disease, 77% had World Health Organization II tumors, whereas 50% of patients with metastatic disease had World Health Organization II tumors. In multivariate analysis including age, tumor grade, size, location, extent of resection, sex, and scalp invasion, the only significant predictor of systemic metastasis was scalp invasion (odds ratio = 39.67; 95% confidence interval = 3.74-421.12; P = 0.0023). Median overall survival (OS) with metastasis was 126 months, and median OS without metastasis was 158 months. Having metastatic disease was not significantly associated with worse OS (P = 0.33).Metastasis development from AAM is a rare but serious event. Because scalp invasion is a strongly associated predictive factor for development of systemic metastasis in patients with AAM, it is necessary to consider strategies to prevent and to be vigilant of the development of scalp invasion.

  View details for DOI 10.1016/j.wneu.2020.06.148

  View details for Web of Science ID 000576459300016

  View details for PubMedID 32599198

• Cottonoid Sliders: A Simple and Cost-Effective Tool for Retractorless Intracranial Surgery. Operative neurosurgery (Hagerstown, Md.) Shao, J., Borghei-Razavi, H., Kshettry, V. R., Lim, M., Recinos, P. F. 2020; 19 (4): E428–E431

  Abstract

  BACKGROUND AND IMPORTANCE: Retraction injury can result in significant complications during intracranial operations. Alternative surgical techniques to minimize retraction pressure and duration of retraction can minimize the risk of retraction injury. We describe the use of a cottonoid "slider," which is a simple, cost-effective modification of a commonly used cottonoid, in multiple applications.CLINICAL PRESENTATION: The cottonoid sliders are constructed preoperatively by overlaying an adhesive plastic incision drape on one side of a dry cottonoid patty and trimming the edges to fit the form of the cottonoid. Intraoperatively, the sliders can slide across the parenchymal surface atraumatically and are used for gentle retraction to expose desired areas. In addition, suction may be placed on the slider to clear fluid from the operative view. The plastic side of the slider prevents adherence to the parenchymal surface. Retractorless surgical techniques have been developed to minimize risk of retractor associated injury in intracranial surgery by reducing retraction pressure and duration. Given that the cottonoid sliders glide along the parenchyma, do not stick, and are used for dynamic retraction, the main objectives to minimize retraction injury can be met while not compromising operative efficiency.CONCLUSION: Cottonoid sliders are a simple and cost-effective method of providing gentle exposure during intracranial surgery. This technique represents a valuable and cost-effective addition to the neurosurgical armamentarium.

  View details for DOI 10.1093/ons/opaa099

  View details for PubMedID 32357243

• A Dose-Response Model of Local Tumor Control Probability After Stereotactic Radiosurgery for Brain Metastases Resection Cavities. Advances in radiation oncology Gui, C., Grimm, J., Kleinberg, L. R., Zaki, P., Spoleti, N., Mukherjee, D., Bettegowda, C., Lim, M., Redmond, K. J. 2020; 5 (5): 840–49

  Abstract

  Purpose: Recent randomized controlled trials evaluating stereotactic surgery (SRS) for resected brain metastases question the high rates of local control previously reported in retrospective studies. Tumor control probability (TCP) models were developed to quantify the relationship between radiation dose and local control after SRS for resected brain metastases.Methods and Materials: Patients with resected brain metastases treated with SRS were evaluated retrospectively. Melanoma, sarcoma, and renal cell carcinoma were considered radio-resistant histologies. The planning target volume (PTV) was the region of enhancement on T1 post-gadolinium magnetic resonance imaging plus a 2-mm uniform margin. The primary outcome was local recurrence, defined as tumor progression within the resection cavity. Cox regression evaluated predictors of local recurrence. Dose-volume histograms for the PTV were obtained from treatment plans and converted to 3-fraction equivalent doses (alpha/beta = 12 Gy). TCP models evaluated local control at 1-year follow-up as a logistic function of dose-volume histogram data.Results: Among 150 cavities, 41 (27.3%) were radio-resistant. The median PTV volume was 14.6 mL (range, 1.3-65.3). The median prescription was 21 Gy (range, 15-25) in 3 fractions (range, 1-5). Local control rates at 12 and 24 months were 86% and 82%. On Cox regression, larger cavities (PTV > 12 cm3) predicted increased risk of local recurrence (P = .03). TCP modeling demonstrated relationships between improved 1-year local control and higher radiation doses delivered to radio-resistant cavities. Maximum PTV doses of 30, 35, and 40 Gy predicted 78%, 89%, and 94% local control among all radio-resistant cavities, versus 69%, 79%, and 86% among larger radio-resistant cavities.Conclusions: After SRS for resected brain metastases, larger cavities are at greater risk of local recurrence. TCP models suggests that higher radiation doses may improve local control among cavities of radio-resistant histology. Given maximum tolerated doses established for single-fraction SRS, fractionated regimens may be required to optimize local control in large radio-resistant cavities.

  View details for DOI 10.1016/j.adro.2020.06.007

  View details for PubMedID 33083646

• CLEC5A expressed on myeloid cells as a M2 biomarker relates to immunosuppression and decreased survival in patients with glioma CANCER GENE THERAPY Tong, L., Li, J., Choi, J., Pant, A., Xia, Y., Jackson, C., Liu, P., Yi, L., Boussouf, E., Lim, M., Yang, X. 2020; 27 (9): 669–79

  Abstract

  Glioma is the most common tumor in the central nervous system that portends a poor prognosis. Key genes negatively related to survival may provide targets for therapy to improve the outcome of glioma. Here, we report a protein-coding gene CLEC5A, which is the top 1 gene by univariate Cox regression analysis of 524 primary GBM samples. Expression of CLEC5A is significantly correlated with decreased overall survival in patients with glioma via large-scale analysis. An analysis of 2589 patient samples showed that CLEC5A expression is higher in (1) glioblastoma than in lower-grade glioma and nontumor tissue, (2) in the mesenchymal subtype than in other subtypes, and (3) in IDH1-wild type glioblastoma than in IDH1-mutated glioblastoma. Notably, this tumor-associated biomarker is expressed preferentially on myeloid cells over glioma cells. And it shows a strong co-expression with M2 macrophage biomarker. Furthermore, CLEC5A-associated genes are enriched in immunosuppressive biological processes. The silico flow cytometry also showed CLEC5A expression related to less tumor purity and more tumor-promoting leukocytes infiltration. In conclusion, we proposed a new M2 biomarker expressed on myeloid cells that may decrease survival in patients with glioma through immunosuppressive mechanisms.

  View details for DOI 10.1038/s41417-019-0140-8

  View details for Web of Science ID 000569884000004

  View details for PubMedID 31591460

• Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma GENOME BIOLOGY Sa, J. K., Chang, N., Lee, H., Cho, H., Ceccarelli, M., Cerulo, L., Yin, J., Kim, S., Caruso, F. P., Lee, M., Kim, D., Oh, Y., Lee, Y., Her, N., Min, B., Kim, H., Jeong, D., Kim, H., Kim, H., Chung, S., Woo, H., Lee, J., Kong, D., Seol, H., Lee, J., Kim, J., Park, W., Wang, Q., Sulman, E. P., Heimberger, A. B., Lim, M., Park, J., Iavarone, A., Verhaak, R. W., Nam, D. 2020; 21 (1): 216

  Abstract

  Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

  View details for DOI 10.1186/s13059-020-02140-x

  View details for Web of Science ID 000566942700002

  View details for PubMedID 32847614

  View details for PubMedCentralID PMC7448990

• Characterizing long non-coding RNA expression of tumor-infiltrating lymphocytes across solid cancers Dinalankara, W., Imada, E., Jackson, C. M., Nirschl, T. R., Lim, M., Drake, C. G., Marchionni, L. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-4491

  View details for Web of Science ID 000590059306017

• The Effects of Postoperative Neurological Deficits on Survival in Patients With Single Brain Metastasis. Operative neurosurgery (Hagerstown, Md.) Medikonda, R., Jackson, C. M., Feghali, J., Lim, M. 2020

  Abstract

  BACKGROUND: The prognosis for brain metastasis is poor, and surgical resection is part of the standard of care for these patients as it has been shown to improve median overall survival. Development of neurological deficits after surgical resection has been associated with worsened outcomes in patients with glioblastoma. The effect of postoperative neurological deficits on survival in patients with single brain metastasis has not been studied to date.OBJECTIVE: To evaluate the association between postoperative neurological deficits and median overall survival.METHODS: A single-institution retrospective cohort study was performed on all patients with single brain metastasis undergoing surgical resection by a single neurosurgeon.RESULTS: A total of 121 patients met the inclusion criteria for this study. Among them 61% of patients presented with a preoperative deficit, and 26% of patients had a new postoperative deficit. However, most postoperative deficits resolved and only 3.3% of patients developed a new permanent postoperative deficit. Median overall survival in patients with a new postoperative deficit was 2.4 mo, whereas mOS in patients without a postoperative deficit was 12.6 mo (P<.0001).CONCLUSION: This study suggests that a new neurological deficit is associated with worsened outcomes after surgical resection of a single brain metastasis. This finding has potential implications for patient selection and counseling as the patients most likely to benefit from surgical resection are the patients who are most likely to have resolution of a preoperative deficit.

  View details for DOI 10.1093/ons/opaa224

  View details for PubMedID 32717025

• A systematic review and meta-analysis of supratotal versus gross total resection for glioblastoma JOURNAL OF NEURO-ONCOLOGY Jackson, C., Choi, J., Khalafallah, A. M., Price, C., Bettegowda, C., Lim, M., Gallia, G., Weingart, J., Brem, H., Mukherjee, D. 2020; 148 (3): 419–31

  Abstract

  Due to the infiltrative nature of glioblastoma (GBM) outside of the contrast-enhancing region on MRI, there is interest in exploring supratotal resections (SpTR) that extend beyond the contrast-enhancing portion of the tumor. However, there is currently no consensus on the potential survival benefit of SpTR in GBM compared to gross total resection (GTR). In this study, we compare the impact of SpTR versus GTR on overall survival (OS) of GBM patients.We performed a systematic review and meta-analysis of literature published on PubMed, Embase, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov, from inception to August 16, 2018, to identify articles comparing OS after SpTR versus GTR.We identified 8902 unique citations, of which 11 articles met study inclusion criteria. 810 patients underwent SpTR out of a total of 2056 patients. 9 of 11 studies demonstrated improved outcomes with SpTR compared to GTR (median improvement in OS of 10.5 months), with no significant difference in postoperative complication rate. Overall study quality was variable, with ten studies presenting level IV evidence and one study presenting level IIIb evidence. Subgroup meta-analysis based on SpTR definition demonstrated a statistically significant 35% lower risk of mortality in patients who underwent anatomical SpTR compared to patients who underwent GTR (Hazard ratio = 0.65, 95% CI 0.47- 0.91, p = 0.003).Our systematic review indicates SpTR may be associated with improved OS compared to GTR for GBM, especially with anatomical SpTR. However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies. There is need for prospective clinical data to further guide parameters regarding the use of SpTR in GBM.

  View details for DOI 10.1007/s11060-020-03556-y

  View details for Web of Science ID 000542816500001

  View details for PubMedID 32562247

• Updated safety phase I trial of anti-LAG-3 alone and in combination with anti-PD-1 in patients with recurrent GBM. Lim, M., Ye, X., Piotrowski, A. F., Desai, A., Ahluwalia, M., Walbert, T., Fisher, J. D., Desideri, S., Nabors, L. B., Wen, P. Y., Grossman, S. A. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301207

• GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma. Buxton, M., Alexander, B., Berry, D. A., Cavenee, W. K., Colman, H., De Groot, J., Ellingson, B. M., Gordon, G. B., Khasraw, M., Lassman, A. B., Li, W., Lim, M., Mellinghoff, I. K., Perry, J. R., Sulman, E. P., Tanner, K., Weller, M., Wen, P. Y., Yung, W., Cloughesy, T., GBM AGILE Investigators LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368309059

• A review of glioblastoma immunotherapy JOURNAL OF NEURO-ONCOLOGY Medikonda, R., Dunn, G., Rahman, M., Fecci, P., Lim, M. 2020

  Abstract

  Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy.Literature search was performed on PubMed between 1961 and 2020.Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma's highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction.Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.

  View details for DOI 10.1007/s11060-020-03448-1

  View details for Web of Science ID 000524415500001

  View details for PubMedID 32253714

• Understanding innate immune response in glioblastoma in search of a way forward NEURO-ONCOLOGY Pant, A., Lim, M. 2020; 22 (4): 444–45

  View details for DOI 10.1093/neuonc/noaa038

  View details for Web of Science ID 000537427200005

  View details for PubMedID 32090256

  View details for PubMedCentralID PMC7158638

• New Prospects for Molecular Targets for Chordomas NEUROSURGERY CLINICS OF NORTH AMERICA Ozair, M., Shah, P., Mathios, D., Lim, M., Moss, N. S. 2020; 31 (2): 289-+

  Abstract

  Chordomas are malignant, highly recurrent tumors of the midline skeleton that arise from the remnants of the notochord. The development of systemic therapy is critically important to ultimately managing this tumor. Several ongoing trials are attempting to use molecular targeted therapies for mutated pathways in recurrent and advanced chordomas and have shown promise. In addition, immunotherapies, including brachyury-directed vaccination and checkpoint inhibition, have also been attempted with encouraging results. This article discusses the major pathways that have been implicated in the pathogenesis of chordoma with an emphasis on molecular vulnerabilities that future therapies are attempting to exploit.

  View details for DOI 10.1016/j.nec.2019.11.004

  View details for Web of Science ID 000527837300012

  View details for PubMedID 32147018

  View details for PubMedCentralID PMC7374924

• Characterizing patterns of cytokine coexpression with immune checkpoint markers in CD4 and CD8 tumor-infiltrating lymphocytes. Jackson, C. M., Dinalankara, W., Choi, J., Nirschl, T. R., Kochel, C. M., Pant, A., Routkevitch, D., Saleh, L., Jackson, C., Skaist, A. M., Gupta, A., Snyder, L. A., Schaeffer, E. M., Ross, A. E., Carter, B., Allaf, M. E., Bivalacqua, T. J., DeMarzo, A. M., Weingart, J. D., Bettegowda, C., Brem, H., Pardoll, D. M., Marchionni, L., Drake, C. G., Lim, M. AMER ASSOC CANCER RESEARCH. 2020: 47–48

  View details for Web of Science ID 000518188200066

• Absence of Ischemic Injury after Sacrificing the Superior Petrosal Vein during Microvascular Decompression. Operative neurosurgery (Hagerstown, Md.) Xia, Y., Kim, T. Y., Mashouf, L. A., Patel, K. K., Xu, R., Casaos, J., Choi, J., Kim, E. S., Hung, A. L., Wu, A., Garzon-Muvdi, T., Bender, M. T., Jackson, C. M., Bettegowda, C., Lim, M. 2020; 18 (3): 316–20

  Abstract

  BACKGROUND: Sacrificing the superior petrosal vein (SPV) is controversial during a microvascular decompression (MVD). There have been multiple reports of complications including life-threatening brainstem infarction and cerebellar edema.OBJECTIVE: To analyze the potential for vascular complications when the SPV is sacrificed during an MVD.METHODS: Retrospective chart review was performed to identify all MVDs for trigeminal neuralgia and hemifacial spasm from 2007 to 2018 at 1 institution. Cases with≥1 mo of follow-up were included and SPV sacrifice was noted. The primary outcome was complications related to SPV sacrifice including sinus thrombosis, cerebellar edema, and midbrain or pontine infarction. Imaging was used to confirm all potential vascular complications noted in medical records. Fisher's exact test and unpaired t-tests were used to compare between groups.RESULTS: A total of 732 MVD cases were identified and 592 met inclusion criteria with an average follow-up of 11.8±16.4 mo and a male-to-female ratio of 1:2.2. The SPV was sacrificed in 217 cases and retained in 375 cases. No SPV-related vascular complications were found in this study. Two unrelated cases of vascular complications were identified and both were in the nonsacrificed group. One case involved cerebellar bleeding while the other was an ipsilateral transverse sinus thrombosis that was present preoperatively.CONCLUSION: In MVDs, there is no difference in the rate of vascular complications when the SPV is sacrificed compared to preserved. To best visualize a cranial nerve and optimize safe decompression, surgeons should feel free to sacrifice the SPV.

  View details for DOI 10.1093/ons/opz163

  View details for PubMedID 31214696

• In Vivo Bioluminescence Tomography Center of Mass-Guided Conformal Irradiation INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Deng, Z., Xu, X., Garzon-Muvdi, T., Xia, Y., Kim, E., Belcaid, Z., Luksik, A., Maxwell, R., Choi, J., Wang, H., Yu, J., Iordachita, I., Lim, M., Wong, J. W., Wang, K. 2020; 106 (3): 612–20

  Abstract

  The cone-beam computed tomography (CBCT)-guided small animal radiation research platform (SARRP) has provided unique opportunities to test radiobiologic hypotheses. However, CBCT is less adept to localize soft tissue targets growing in a low imaging contrast environment. Three-dimensional bioluminescence tomography (BLT) provides strong image contrast and thus offers an attractive solution. We introduced a novel and efficient BLT-guided conformal radiation therapy and demonstrated it in an orthotopic glioblastoma (GBM) model.A multispectral BLT system was integrated with SARRP for radiation therapy (RT) guidance. GBM growth curve was first established by contrast CBCT/magnetic resonance imaging (MRI) to derive equivalent sphere as approximated gross target volume (aGTV). For BLT, mice were subject to multispectral bioluminescence imaging, followed by SARRP CBCT imaging and optical reconstruction. The CBCT image was acquired to generate anatomic mesh for the reconstruction and RT planning. To ensure high accuracy of the BLT-reconstructed center of mass (CoM) for target localization, we optimized the optical absorption coefficients μa by minimizing the distance between the CoMs of BLT reconstruction and contrast CBCT/MRI-delineated GBM volume. The aGTV combined with the uncertainties of BLT CoM localization and target volume determination was used to generate estimated target volume (ETV). For conformal irradiation procedure, the GBM was first localized by the predetermined ETV centered at BLT-reconstructed CoM, followed by SARRP radiation. The irradiation accuracy was qualitatively confirmed by pathologic staining.Deviation between CoMs of BLT reconstruction and contrast CBCT/MRI-imaged GBM is approximately 1 mm. Our derived ETV centered at BLT-reconstructed CoM covers >95% of the tumor volume. Using the second-week GBM as an example, the ETV-based BLT-guided irradiation can cover 95.4% ± 4.7% tumor volume at prescribed dose. The pathologic staining demonstrated the BLT-guided irradiated area overlapped well with the GBM location.The BLT-guided RT enables 3-dimensional conformal radiation for important orthotopic tumor models, which provides investigators a new preclinical research capability.

  View details for DOI 10.1016/j.ijrobp.2019.11.003

  View details for Web of Science ID 000510861900027

  View details for PubMedID 31738948

  View details for PubMedCentralID PMC7007925

• Integrin alpha 6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells ONCOGENE Herrmann, A., Lahtz, C., Song, J., Aftabizadeh, M., Cherryholmes, G. A., Xin, H., Adamus, T., Lee, H., Grunert, D., Armstrong, B., Chu, P., Brown, C., Lim, M., Forman, S., Yu, H. 2020; 39 (10): 2156–69

  Abstract

  Both the extracellular matrix (ECM) and DNA epigenetic regulation are critical for maintaining stem cell phenotype and cancer progression. Whether and how ECM regulates epigenetic alterations to influence cancer stem cells (CSCs) remain to be explored. Here we report that ECM through laminin-integrin α6 upregulates ten-eleven translocation enzyme 3 (TET3) dioxygenase. TET3 in turn mediates DNA cytosine 5'-hydroxymethylation (5hmC) and upregulates genes critical for maintenance of glioma stem cells (GSCs). Activating integrin α6-FAK pathway increases STAT3 activity, TET3 expression and 5hmC levels in GSCs. Moreover, targeting STAT3 disrupts integrin α6-FAK signaling and inhibits TET3+ GSC maturation in vivo. STAT3 directly regulates TET3 expression and the two proteins are co-localized with 5hmC in GSC clusters. 5hmC is upregulated by STAT3 at the promoters of several tumorigenic genes, including c-Myc, known to be critical for GSCs. In vivo silencing of TET3 in GSC-enriched tumors reduces 5hmC accumulation and expression of the GSC critical genes, leading to tumor growth inhibition. TET3 expression and 5hmC accumulation also co-segregate with integrin α6 in patient malignant glioma. Thus, ECM- integrin α6-STAT3-TET3 axis regulates hydroxymethylation of genes important for GSCs, thereby increasing GSC tumorigenicity and resistance to therapies.

  View details for DOI 10.1038/s41388-019-1134-6

  View details for Web of Science ID 000518584000010

  View details for PubMedID 31819166

  View details for PubMedCentralID PMC7060098

• Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy. Neuro-oncology advances Belcaid, Z., Berrevoets, C., Choi, J., van Beelen, E., Stavrakaki, E., Pierson, T., Kloezeman, J., Routkevitch, D., van der Kaaij, M., van der Ploeg, A., Mathios, D., Sleijfer, S., Dirven, C., Lim, M., Debets, R., Lamfers, M. L. 2020; 2 (1): vdaa011

  Abstract

  Background: The tumor-selective human adenovirus Delta24-RGD is currently under investigation in phase II clinical trials for patients with recurrent glioblastoma (GBM). To improve treatments for patients with GBM, we explored the potential of combining Delta24-RGD with antibodies targeting immune checkpoints.Methods: C57BL/6 mice were intracranially injected with GL261 cells and treated with a low dose of Delta24-RGD virus. The expression dynamics of 10 co-signaling molecules known to affect immune activity was assessed in tumor-infiltrating immune cells by flow cytometry after viral injection. The antitumor activity was measured by tumor cell killing and IFNgamma production in co-cultures. Efficacy of the combination viro-immunotherapy was tested in vitro and in the GL261 and CT2A orthotopic mouse GBM models. Patient-derived GBM cell cultures were treated with Delta24-RGD to assess changes in PD-L1 expression induced by virus infection.Results: Delta24-RGD therapy increased intratumoral CD8+ T cells expressing Inducible T-cell co-stimulator (ICOS) and PD-1. Functionality assays confirmed a significant positive correlation between tumor cell lysis and IFNgamma production in ex vivo cultures (Spearman r = 0.9524; P < .01). Co-cultures significantly increased IFNgamma production upon treatment with PD-1 blocking antibodies. In vivo, combination therapy with low-dose Delta24-RGD and anti-PD-1 antibodies significantly improved outcome compared to single-agent therapy in both syngeneic mouse glioma models and increased PD-1+ tumor-infiltrating CD8+ T cells. Delta24-RGD infection induced tumor-specific changes in PD-L1 expression in primary GBM cell cultures.Conclusions: This study demonstrates the potential of using low-dose Delta24-RGD therapy to sensitize glioma for combination with anti-PD-1 antibody therapy.

  View details for DOI 10.1093/noajnl/vdaa011

  View details for PubMedID 32642679

• PD-1+ Monocytes Mediate Cerebral Vasospasm Following Subarachnoid Hemorrhage. Neurosurgery Jackson, C. M., Choi, J. n., Routkevitch, D. n., Pant, A. n., Saleh, L. n., Ye, X. n., Caplan, J. M., Huang, J. n., McDougall, C. G., Pardoll, D. M., Brem, H. n., Tamargo, R. J., Lim, M. n. 2020

  Abstract

  Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options.To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm.Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm.We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm.Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy.

  View details for DOI 10.1093/neuros/nyaa495

  View details for PubMedID 33370819

• PD-L1 Expression in Pediatric Low-Grade Gliomas Is Independent of BRAF V600E Mutational Status JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Martin, A. M., Bell, W., Yuan, M., Harris, L., Poore, B., Arnold, A., Engle, E. L., Asnaghi, L., Lim, M., Raabe, E. H., Eberhart, C. G. 2020; 79 (1): 74–85

  Abstract

  To evaluate a potential relationship between BRAF V600E mutation and PD-L1 expression, we examined the expression of PD-L1 in pediatric high- and low-grade glioma cell lines as well as a cohort of pediatric low-grade glioma patient samples. Half of the tumors in our patient cohort were V600-wildtype and half were V600E mutant. All tumors expressed PD-L1. In most tumors, PD-L1 expression was low (<5%), but in some cases over 50% of cells were positive. Extent of PD-L1 expression and immune cell infiltration was independent of BRAF V600E mutational status. All cell lines evaluated, including a BRAF V600E mutant xenograft, expressed PD-L1. Transient transfection of cell lines with a plasmid expressing mutant BRAF V600E had minimal effect on PD-L1 expression. These findings suggest that the PD-1 pathway is active in subsets of pediatric low-grade glioma as a mechanism of immune evasion independent of BRAF V600E mutational status. Low-grade gliomas that are unresectable and refractory to traditional therapy are associated with significant morbidity and continue to pose a treatment challenge. PD-1 pathway inhibitors may offer an alternative treatment approach. Clinical trials will be critical in determining whether PD-L1 expression indicates likely therapeutic benefit with immune checkpoint inhibitors.

  View details for DOI 10.1093/jnen/nlz119

  View details for Web of Science ID 000521584000007

  View details for PubMedID 31819973

• Tumor-Treating Field Arrays Do Not Reduce Target Volume Coverage for Glioblastoma Radiation Therapy ADVANCES IN RADIATION ONCOLOGY Stachelek, G. C., Grimm, J., Moore, J., Huang, E., Spoleti, N., Redmond, K. J., Lim, M., Bettegowda, C., Kleinberg, L. 2020; 5 (1): 62–69

  Abstract

  To inform development of procedures for using tumor-treating field arrays (TTFields) during glioblastoma radiation therapy by determining whether the placement and repositioning of arrays affects target volume coverage and cranial skin dose.Radiation plans from 10 consecutive patients treated for glioblastoma were copied to a cranial phantom and reoptimized for phantom anatomy. Dose distributions were then recalculated on 3 additional computed tomographic scans of the phantom with the TTFields electrode arrays placed over distinct locations on the phantom scalp to compare planning target volume (PTV) coverage and skin dose with and without TTFields in place in varying positions. Percent depth dose curves were also measured for radiation beams passing through the electrodes and compared with commonly used bolus material.The presence of TTFields arrays decreased PTV V97% and D97% by as much as 1.7% and 2.7%, respectively, for a single array position, but this decrease was mitigated by array repositioning. On averaging the 3 array positions, there was no statistically significant difference in any dosimetric parameter of PTV coverage (V95-97%, D95-97%) across all cases compared with no array. Mean increases in skin D1cc and D20cc of 3.1% were calculated for the cohort. Surface dose for TTFields electrodes was less than that with a 5-mm superflab bolus.Our work demonstrates that placement of TTFields arrays does not significantly affect target volume coverage. We show that repositioning of TTFields arrays, as is required in clinical use, further minimizes any dosimetric changes and eliminates the need for replanning when arrays are moved. A slight, expected bolus effect is observed, but the calculated increases in skin dose are not clinically significant. These data support the development of clinical trials to assess the safety and efficacy of combining concurrent chemoradiotherapy with TTFields therapy for glioblastoma.

  View details for DOI 10.1016/j.adro.2019.08.005

  View details for Web of Science ID 000516862400007

  View details for PubMedID 32051891

  View details for PubMedCentralID PMC7004938

• Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-oncology Wen, P. Y., Weller, M., Lee, E. Q., Alexander, B. M., Barnholtz-Sloan, J. S., Barthel, F. P., Batchelor, T. T., Bindra, R. S., Chang, S. M., Chiocca, E. A., Cloughesy, T. F., DeGroot, J. F., Galanis, E., Gilbert, M. R., Hegi, M. E., Horbinski, C., Huang, R. Y., Lassman, A. B., Le Rhun, E., Lim, M., Mehta, M. P., Mellinghoff, I. K., Minniti, G., Nathanson, D., Platten, M., Preusser, M., Roth, P., Sanson, M., Schiff, D., Short, S. C., Taphoorn, M. J., Tonn, J., Tsang, J., Verhaak, R. G., von Deimling, A., Wick, W., Zadeh, G., Reardon, D. A., Aldape, K. D., van den Bent, M. J. 2020; 22 (8): 1073–1113

  Abstract

  Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

  View details for DOI 10.1093/neuonc/noaa106

  View details for PubMedID 32328653

• Adult immuno-oncology: using past failures to inform the future. Neuro-oncology Rahman, M., Sawyer, W. G., Lindhorst, S., Deleyrolle, L. P., Harrison, J. K., Karachi, A., Dastmalchi, F., Flores-Toro, J., Mitchell, D. A., Lim, M., Gilbert, M. R., Reardon, D. A. 2020; 22 (9): 1249–61

  Abstract

  In oncology, "immunotherapy" is a broad term encompassing multiple means of utilizing the patient's immune system to combat malignancy. Prominent among these are immune checkpoint inhibitors, cellular therapies including chimeric antigen receptor T-cell therapy, vaccines, and oncolytic viruses. Immunotherapy for glioblastoma (GBM) has had mixed results in early trials. In this context, the past, present, and future of immune oncology for the treatment of GBM was discussed by clinical, research, and thought leaders as well as patient advocates at the first annual Remission Summit in 2019. The goal was to use current knowledge (published and unpublished) to identify possible causes of treatment failures and the best strategies to advance immunotherapy as a treatment modality for patients with GBM. The discussion focuses on past failures, current limitations, failure analyses, and proposed best practices moving forward.

  View details for DOI 10.1093/neuonc/noaa116

  View details for PubMedID 32391559

• ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma THERANOSTICS Tong, L., Li, J., Li, Q., Wang, X., Medikonda, R., Zhao, T., Li, T., Ma, H., Yi, L., Liu, P., Xie, Y., Choi, J., Yu, S., Lin, Y., Dong, J., Huang, Q., Jin, X., Lim, M., Yang, X. 2020; 10 (13): 5943–56

  Abstract

  ACT001, which is derived from an ancient anti-inflammatory drug, has been shown to cross the blood-brain barrier in preclinical studies and has demonstrated anti-glioblastoma (GBM) activity in clinical trials. However, its pharmacological potential for anti-GBM immune response modulation remains unclear. The chemical structure of ACT001 indicates that it may bind to STAT3 and thus modulate antitumor immune response. Methods: Bioinformatics and immunohistochemistry (IHC) were used to assess STAT3 and PD-L1 expression in gliomas. Western blotting, RT-PCR and immunofluorescence were used to detect PD-L1 and p-STAT3 expression in glioma cells exposed to ACT001. Chromatin immunoprecipitation, an ACT001-Biotin probe, and a dual-luciferase reporter assay were used to detect direct modulation. The in vivo efficacy of ACT001 was evaluated in GL261 murine glioma model. Survival analyses were conducted using the log-rank (Mantel-Cox) test. Results: Bioinformatic analysis of 1,837 samples from 4 public glioma datasets showed that STAT3 mRNA expression was correlated with the degree of malignancy and therapeutic resistance and that STAT3 mRNA expression was related to immunosuppression, leukocyte infiltration, and PD-L1 expression. IHC staining of 53 tissue samples confirmed that relatively high phosphorylated STAT3 and PD-L1 protein expression was associated with a relatively advanced World Health Organization (WHO) glioma grade. Next, we confirmed that ACT001 treatment reduced PD-L1 expression and STAT3 phosphorylation. An ACT001-biotin probe was used to verify that ACT001 bound to STAT3. We also demonstrated that STAT3 bound to the PD-L1 promoter. The inhibition of PD-L1 expression and STAT3 phosphorylation by ACT001 could be rescued by STAT3 overexpression. Additionally, ACT001 inhibited GBM growth and decreased PD-L1 expression in vivo. The expression of the M2 markers CD206 and CD163 was decreased, while that of the antitumor immune markers iNOS and IFNγ was increased by ACT001 in vivo. Conclusion: Our results demonstrate that STAT3 plays a key role in immunosuppression of glioma and is inhibited by ACT001. ACT001 inhibits PD-L1 transcription and modulates anti-tumor immune response in glioma bearing mice. These findings will help us to understand the mechanism of ACT001 in GBM therapy.

  View details for DOI 10.7150/thno.41498

  View details for Web of Science ID 000530611900020

  View details for PubMedID 32483429

  View details for PubMedCentralID PMC7254983

• Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma CASE REPORTS IN ONCOLOGY Thummalapalli, R., Heumann, T., Stein, J., Khan, S., Priemer, D. S., Duffield, A. S., Laterra, J., Couzi, R., Lim, M., Holdhoff, M. 2020; 13 (2): 508–14

  Abstract

  Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.

  View details for DOI 10.1159/000507281

  View details for Web of Science ID 000572519300005

  View details for PubMedID 32518546

  View details for PubMedCentralID PMC7265705

• Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types INTERNATIONAL JOURNAL OF CANCER Mathios, D., Hwang, T., Xia, Y., Phallen, J., Rui, Y., See, A. P., Maxwell, R., Belcaid, Z., Casaos, J., Burger, P. C., McDonald, K. L., Gallia, G. L., Cope, L., Kai, M., Brem, H., Pardoll, D. M., Ha, P., Green, J. J., Velculescu, V. E., Bettegowda, C., Park, C., Lim, M. 2019; 145 (12): 3425–35

  Abstract

  DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

  View details for DOI 10.1002/ijc.32587

  View details for Web of Science ID 000491231500023

  View details for PubMedID 31373686

• PD-L1, PD-1, LAG-3, and TIM-3 in Melanoma: Expression in Brain Metastases Compared to Corresponding Extracranial Tumors CUREUS Wang, J., Burger, P., Taube, J., Soni, A., Chaichana, K., Sheu, M., Belcaid, Z., Jackson, C., Lim, M. 2019; 11 (12): e6352

  Abstract

  Background Metastatic melanoma to the brain carries a particularly poor prognosis that may be associated with an attenuated antitumor response in the presence of central nervous system malignancies. Thus, the development of brain metastases could theoretically accelerate cancer progression both locally and systemically. Although dysregulation of checkpoint markers, such as programmed death-ligand 1 (PD-L1), programmed cell death receptor 1 (PD-1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), have been implicated in immune dysfunction, the exact relationship between these markers and brain tumor-mediated immune suppression remains unclear. Thus, the objective of this study was to explore whether there exists a differential expression of the above checkpoint markers in the intracranial milieu as compared to tumors in the periphery, which may shed light on the mechanism behind the diminished antitumor response. Methods We identified nine patients with extracranial melanomas and matched intracranial metastases. Formalin-fixed, paraffin-embedded slides were stained for PD-L1, PD-1, LAG-3, and TIM-3 via immunohistochemistry. Qualitative analysis was performed to assess the staining of the markers in the neoplastic and lymphocytic cells, which were the two cell lineages in each biopsy.  Results Expression of PD-1 and TIM-3 between extracranial and intracranial tumoral sites was conserved. Specifically, in lymphocytes, PD-1 expression was observed in 100% of extracranial and 100% of intracranial slides, whereas TIM-3 expression was seen in 33.33% of extracranial and 33.33% of intracranial slides. Neither marker stained tumor cells, as expected. PD-L1 showed a slight variation in staining between sites, with lymphocyte staining in 100% of extracranial and 88.89% of intracranial slides, and the same percentages per site for tumor cells. The greatest variability was observed in LAG-3 lymphocyte staining, with staining in 77.78% of extracranial and 33.33% of intracranial slides. No LAG-3 staining of tumor cells was noted, as expected. Conclusion Preliminary analysis revealed the conservation of PD-L1, PD-1, LAG-3, and TIM-3 expression intra- and extracranially. This could suggest that these markers are important in maintaining an immunosuppressive phenotype at both sites. Another possibility is that this pattern of expression is associated with patients who develop brain metastasis, as this was the only subset of patients included in this study. Interestingly, LAG-3 staining of lymphocytes appeared more prominent in extracranial over intracranial tumors. Future studies should include more samples to draw out potential patterns masked by the small sample size, as well as to compare checkpoint expression in other patient groups, such as those with non-brain metastasis or those with no metastasis at all.

  View details for DOI 10.7759/cureus.6352

  View details for Web of Science ID 000504823500010

  View details for PubMedID 31938638

  View details for PubMedCentralID PMC6952042

• PD-L1 EXPRESSION IS NEGATIVELY CORRELATED TO OUTCOMES IN PATIENTS WITH MGMT METHYLATED PROMOTERS IN GBM Srivastava, S., Choi, J., Lim, M. OXFORD UNIV PRESS INC. 2019: 250

  View details for Web of Science ID 000509478706060

• IMMUNOGENOMIC RESPONDER PHENOTYPE FROM A PHASE I TRIAL OF ANTI-LAG3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM Jackson, C., Choi, J., Zhang, J., Piotrowski, A., Walbert, T., Desai, A., Ahluwalia, M., Nabors, B., Ye, X., Desideri, S., Fisher, J., Wen, P., Grossman, S., Smith, K., Pardoll, D., Lim, M. OXFORD UNIV PRESS INC. 2019: 122

  View details for Web of Science ID 000509478702175

• SUPRATOTAL VERSUS GROSS TOTAL RESECTION OF GLIOBLASTOMA: A SYSTEMATIC REVIEW Jackson, C., Choi, J., Price, C., Bettegowda, C., Lim, M., Gallia, G., Weingart, J., Brem, H., Mukherjee, D. OXFORD UNIV PRESS INC. 2019: 243

  View details for Web of Science ID 000509478706029

• NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE Weller, M., Reardon, D., Brandes, A., Sampson, J., Mulholland, P., Wick, A., Baehring, J., Ahluwalia, M., Roth, P., Baehr, O., Phuphanich, S., Sepulveda, J., De Souza, P., Sahebjam, S., Potter, V., Tatsuoka, K., Taitt, C., Zwirtes, R., Omuro, A., Lim, M. OXFORD UNIV PRESS INC. 2019: 12

  View details for Web of Science ID 000509478700046

• MULTI-TIME POINT EVALUATION OF PERIPHERAL BLOOD MYELOID-DERIVED SUPPRESSOR CELL AND LYMPHOCYTE POPULATIONS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA RECEIVING ADJUVANT THERAPY Sloan, L., Sen, R., Doucet, M., Blosser, L., Shpitser, I., Sherman, E., San, N., Cheng, Z., Katulis, L., Wemmer, J., Kamson, D., Jackson, C., Hu, C., McNutt, T., Grossman, S., Holdhoff, M., Lim, M., Redmond, K. J., Eberhart, C., Quon, H., Pardoll, D., Ganguly, S., Kleinberg, L. OXFORD UNIV PRESS INC. 2019: 283

  View details for Web of Science ID 000509478706201

• Radiotherapy, Lymphopenia, and Host Immune Capacity in Glioblastoma: A Potentially Actionable Toxicity Associated With Reduced Efficacy of Radiotherapy NEUROSURGERY Kleinberg, L., Sloan, L., Grossman, S., Lim, M. 2019; 85 (4): 441–53

  Abstract

  Radiotherapy is cytotoxic to tumor cells and is therefore a critical component of therapy for many malignancies, including glioblastoma (GBM). We now appreciate the value of the immunomodulatory effects of radiation that may be important to overall therapeutic success in some patients with this primary brain tumor. Although potentially beneficial immune-stimulating properties of radiotherapy treatment have been the focus of recent study, this modality is actually at the same time associated with the depletion of lymphocytes, which are crucial to the defense against neoplastic development and progression. In this review, we describe the association of systemic lymphopenia with poor tumor outcome, present evidence that radiotherapy is an important contributing cause of lymphodepletion, describe the systemic immune context of tumor and brain injury that contributes to immunosuppression, describe other contributing factors to lymphopenia including concomitant medications and treatments, and speculate about the role of the normal physiologic response to brain injury in the immunosuppressive dynamics of GBM. Radiotherapy is one significant and potentially actionable iatrogenic suppressor of immune response that may be limiting the success of therapy in GBM and other tumor types. Altered strategies for radiotherapy more permissive of a vigorous antineoplastic immune response may improve outcome for malignancy.

  View details for DOI 10.1093/neuros/nyz198

  View details for Web of Science ID 000491255600002

  View details for PubMedID 31232425

• Assessing the Effectiveness of Systemic Therapy after Stereotactic Radiosurgery on Cancer Recurrence and All-Cause Mortality WORLD NEUROSURGERY Al-Khindi, T., Shen, C. J., Peng, L., Redmond, K. J., Lim, M., Kleinberg, L. R., Bettegowda, C. 2019; 129: E572–E581

  Abstract

  Patients with cancer often present with brain metastases in the setting of controlled extracranial disease, for which they receive stereotactic radiosurgery (SRS) and surgical resection. The role of systemic therapy after SRS is unclear. Brain metastasis indicates active cancer dissemination, and microscopic systemic disease may be present despite absence of gross disease as assessed by conventional imaging modalities.The aim was to determine if post-SRS systemic therapy reduces the risk of brain relapse, systemic relapse, and death in patients with brain metastases and controlled extracranial disease.We retrospectively reviewed the medical records of 67 patients with controlled extracranial disease who received SRS for brain metastases. Kaplan-Meier analysis and Cox proportional hazards regression were used to assess how post-SRS systemic therapy affected the risk of brain relapse, systemic relapse, and all-cause mortality.In our sample, 31% of patients received systemic therapy after SRS. Post-SRS systemic therapy did not affect median time to brain relapse (P = 0.43), systemic relapse (P = 0.16), or death (P = 0.33) by univariate analysis. After accounting for confounding factors such as cancer histology and age, post-SRS systemic therapy significantly reduced the risk of brain relapse (hazard ratio [HR], 0.22; P = 0.002) but not systemic relapse (HR, 0.38; P = 0.09) or all-cause mortality (HR, 2.16; P = 0.09).Only a minority of patients with brain metastases and controlled extracranial disease receive adjuvant systemic therapy after SRS, but those that do have a reduced risk of brain relapse. Post-SRS systemic therapy may act prophylactically to reduce the risk of intracranial cancer recurrence.

  View details for DOI 10.1016/j.wneu.2019.05.218

  View details for Web of Science ID 000481607900073

  View details for PubMedID 31158536

• Association Between Radiofrequency Rhizotomy Parameters and Duration of Pain Relief in Trigeminal Neuralgia Patients with Recurrent Pain WORLD NEUROSURGERY Xie, E., Garzon-Muvdi, T., Bender, M., Doshi, T., Carson, B., Lim, M., Bettegowda, C. 2019; 129: E128–E133

  Abstract

  Radiofrequency rhizotomy (RFR) is a commonly used, effective procedure for trigeminal neuralgia (TN), but a subset of patients experiences pain recurrence and requires subsequent surgeries. Currently, the rhizotomy temperature and duration of application are empirically determined, and there is no consensus on what settings are most beneficial. In this study, we analyzed patients who underwent trigeminal RFR and had subsequent surgeries to identify whether rhizotomy parameters were associated with the duration of pain relief.Single-center, retrospective analysis of patients undergoing RFR for TN from 1995 to 2016. The primary endpoint was subsequent procedure. Associations with rhizotomy parameters and covariates were assessed using Cox regression analysis.The study included 338 patients, average age 65 years; 61% were women. Temperature was significantly associated with both the degree of immediate postoperative pain relief and the duration of pain relief, and in subgroup analyses by multiple sclerosis status and RFR procedural count. Ablation duration was also independently significant, though not when analyzed alongside age, sex, and race. Duration of pain relief was generally shorter in patients with multiple sclerosis and in repeated RFR.Higher temperatures may be necessary to achieve pain relief in some patients, given the progressive nature of the facial pain, but they are not associated with longer duration of pain relief in patients who have recurrent pain. Modulation of the ablation duration does not seem to affect the short-term or long-term outcomes.

  View details for DOI 10.1016/j.wneu.2019.05.059

  View details for Web of Science ID 000481607900017

  View details for PubMedID 31102773

• Targeting Myeloid Cells in Combination Treatments for Glioma and Other Tumors FRONTIERS IN IMMUNOLOGY Ding, A. S., Routkevitch, D., Jackson, C., Lim, M. 2019; 10: 1715

  Abstract

  Myeloid cells constitute a significant part of the immune system in the context of cancer, exhibiting both immunostimulatory effects, through their role as antigen presenting cells, and immunosuppressive effects, through their polarization to myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. While they are rarely sufficient to generate potent anti-tumor effects on their own, myeloid cells have the ability to interact with a variety of immune populations to aid in mounting an appropriate anti-tumor immune response. Therefore, myeloid therapies have gained momentum as a potential adjunct to current therapies such as immune checkpoint inhibitors (ICIs), dendritic cell vaccines, oncolytic viruses, and traditional chemoradiation to enhance therapeutic response. In this review, we outline critical pathways involved in the recruitment of the myeloid population to the tumor microenvironment and in their polarization to immunostimulatory or immunosuppressive phenotypes. We also emphasize existing strategies of modulating myeloid recruitment and polarization to improve anti-tumor immune responses. We then summarize current preclinical and clinical studies that highlight treatment outcomes of combining myeloid targeted therapies with other immune-based and traditional therapies. Despite promising results from reports of limited clinical trials thus far, there remain challenges in optimally harnessing the myeloid compartment as an adjunct to enhancing anti-tumor immune responses. Further large Phase II and ultimately Phase III clinical trials are needed to elucidate the treatment benefit of combination therapies in the fight against cancer.

  View details for DOI 10.3389/fimmu.2019.01715

  View details for Web of Science ID 000476752300001

  View details for PubMedID 31396227

  View details for PubMedCentralID PMC6664066

• Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced somatic mutation rates in survival outliers of glioblastoma ACTA NEUROPATHOLOGICA COMMUNICATIONS Hwang, T., Mathios, D., McDonald, K. L., Daris, I., Park, S., Burger, P. C., Kim, S., Dho, Y., Carolyn, H., Bettegowda, C., Shin, J., Lim, M., Park, C. 2019; 7: 88

  Abstract

  The study of survival outliers of glioblastoma can provide important clues on gliomagenesis as well as on the ways to alter clinical course of this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of glioblastoma. Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the glioblastoma patients who lived longer than 3 years (n = 17) and the patients who lived less than 1 year (n = 12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of DNA methylation patterns specific to long-term survivors of glioblastoma were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of long-term survivors of glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the long-term survival glioblastoma-specific sites distant from CGI, somatic mutations of glioblastoma are enriched with higher DNA methylation, suggesting that the hypomethylation in long-term survival glioblastoma can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type glioblastoma, we also showed that these two patterns of DNA methylation can be used as molecular markers of long-term survival glioblastoma. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of glioblastoma.

  View details for DOI 10.1186/s40478-019-0744-0

  View details for Web of Science ID 000473749100001

  View details for PubMedID 31159876

  View details for PubMedCentralID PMC6545689

• Surgical Resection for Primary Central Nervous System Lymphoma: A Systematic Review WORLD NEUROSURGERY Labak, C. M., Holdhoff, M., Bettegowda, C., Gallia, G. L., Lim, M., Weingart, J. D., Mukherjee, D. 2019; 126: E1436–E1448

  Abstract

  Primary central nervous system lymphomas (PCNSLs) account for 1%-2% of primary central nervous system tumors. Until recently, treatment has centered on biopsy, radiotherapy, and high-dose methotrexate, without a clear role for cytoreductive surgery. The objective of this article is to compare the impact of biopsy versus cytoreductive surgery in outcomes of patients with PCNSL, including postoperative complications and survival.We performed a systematic review of literature published from January 1, 1968 to May 2, 2018 related to PCNSL treatment in patients undergoing biopsy or resection. Data on morbidity, progression-free survival, and overall survival were extracted and analyzed.A total of 1291 nonduplicate citations were identified, with 244 articles selected for full-text review. Twenty-four articles were included for data abstraction including 2 level IIb studies, 4 level IIIb studies, and the remaining 18 articles representing level IVb studies. Of these articles, 15 failed to show benefit with cytoreductive surgery; most of these articles included relatively small sample sizes and predated standardization of high-dose systemic methotrexate treatment. Larger, more recent series included 9 articles providing evidence in support of cytoreductive surgery. Patient age, functional status, and treatment with chemotherapy and/or radiation were associated with improved survival across studies.The treatment of PCNSL is challenging and ever-evolving. Earlier, smaller studies failed to show the benefit of cytoreductive surgery over biopsy in patients with PCNSL. Larger, more recent series seem to show the possible benefit of cytoreductive surgery in PCNSL. Future well-designed prospective studies may help further elucidate the role of resection in the modern treatment of PCNSL.

  View details for DOI 10.1016/j.wneu.2019.02.252

  View details for Web of Science ID 000469222400181

  View details for PubMedID 30904794

• Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM. Lim, M., Ye, X., Piotrowski, A. F., Desai, A., Ahluwalia, M., Walbert, T., Fisher, J. D., Desideri, S., Belcaid, Z., Jackson, C., Nabors, L. B., Wen, P. Y., Grossman, S. A. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2017

  View details for Web of Science ID 000487345804399

• Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) plus radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM). Reardon, D. A., Kaley, T., Dietrich, J., Clarke, J., Dunn, G., Lim, M., Cloughesy, T., Gan, H., Park, A. J., Schwarzenberger, P., Ricciardi, T., Macri, M. J., Ryan, A., Venhaus, R. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2032

  View details for Web of Science ID 000487345804414

• Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment. Journal of neuro-oncology Wu, A., Maxwell, R., Xia, Y., Cardarelli, P., Oyasu, M., Belcaid, Z., Kim, E., Hung, A., Luksik, A. S., Garzon-Muvdi, T., Jackson, C. M., Mathios, D., Theodros, D., Cogswell, J., Brem, H., Pardoll, D. M., Lim, M. 2019

  Abstract

  BACKGROUND: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model.METHODS: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry.RESULTS: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines.CONCLUSIONS: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

  View details for DOI 10.1007/s11060-019-03172-5

  View details for PubMedID 31025274

• Utilization of the Nasoseptal Flap for Repair of Cerebrospinal Fluid Leak after Endoscopic Endonasal Approach for Resection of Pituitary Tumors. Brain tumor research and treatment Kessler, R. A., Garzon-Muvdi, T., Kim, E., Ramanathan, M., Lim, M. 2019; 7 (1): 10–15

  Abstract

  BACKGROUND: One of the most frequent complications after endoscopic endonasal approach (EEA) for resection of pituitary tumors is cerebrospinal fluid (CSF) leaks. With the introduction of the pedicled nasoseptal flap, the reconstruction of the skull base has improved significantly resulting in a decrease in the occurrence of persistent CSF leaks. We present our experience utilizing the pedicled nasoseptal flap technique after EEA for reconstruction of the skull base in cases where CSF leak was detected.METHODS: Data for patients undergoing EEA for pituitary tumors was retrospectively reviewed. These included demographic, clinical, operative, radiographic, and pathological information. Incidence of post-operative complications and CSF leaks were recorded. Descriptive statistical analysis was performed.RESULTS: Between 2008 and 2015, 67 patients and 69 hospital admissions with pituitary tumors underwent a nasoseptal flap to reconstruct a skull base defect at Johns Hopkins Hospital. The mean age at surgery was 54.5±14.2 years. Fifty-two percent of patients were male. Forty-six percent of patients were white, 33% African-American, and 12% belonged to other racial groups. There was an intraoperative CSF leak in 39% of patients. Seventy percent of patients with an intraoperative CSF leak had a nasoseptal flap reconstruction of the skull base. There were zero postoperative CSF leaks.CONCLUSION: With the introduction of the pedicled nasoseptal flap for reconstruction of the skull base after EEA for resection of pituitary adenomas, the incidence of postoperative CSF leaks has decreased significantly. In this retrospective analysis, we demonstrate the effectiveness of the use of nasoseptal flap in repairing CSF leak after EEA.

  View details for DOI 10.14791/btrt.2019.7.e19

  View details for PubMedID 31062526

• A Characterization of Dendritic Cells and Their Role in Immunotherapy in Glioblastoma: From Preclinical Studies to Clinical Trials CANCERS Srivastava, S., Jackson, C., Kim, T., Choi, J., Lim, M. 2019; 11 (4)

  Abstract

  Glioblastoma (GBM) is the most common and fatal primary central nervous system malignancy in adults with a median survival of less than 15 months. Surgery, radiation, and chemotherapy are the standard of care and provide modest benefits in survival, but tumor recurrence is inevitable. The poor prognosis of GBM has made the development of novel therapies targeting GBM of paramount importance. Immunotherapy via dendritic cells (DCs) has garnered attention and research as a potential strategy to boost anti-tumor immunity in recent years. As the "professional" antigen processing and presenting cells, DCs play a key role in the initiation of anti-tumor immune responses. Pre-clinical studies in GBM have shown long-term tumor survival and immunological memory in murine models with stimulation of DC activity with various antigens and costimulatory molecules. Phase I and II clinical trials of DC vaccines in GBM have demonstrated some efficacy in improving the median overall survival with minimal to no toxicity with promising initial results from the first Phase III trial. However, there remains no standardization of vaccines in terms of which antigens are used to pulse DCs ex vivo, sites of DC injection, and optimal adjuvant therapies. Future work with DC vaccines aims to elucidate the efficacy of DC-based therapy alone or in combination with other immunotherapy adjuvants in additional Phase III trials.

  View details for DOI 10.3390/cancers11040537

  View details for Web of Science ID 000467773400105

  View details for PubMedID 30991681

  View details for PubMedCentralID PMC6521200

• Extracranial Abscopal Responses after Radiation Therapy for Intracranial Metastases: A Review of the Clinical Literature and Commentary on Mechanism CUREUS Gui, C., Kleinberg, L. R., Lim, M., Redmond, K. J. 2019; 11 (3): e4207

  Abstract

  The current literature contains a small number of case series and individual case reports that describe radiographic regression of extracranial tumors after treatment of one or more brain metastases with radiation therapy. These observations suggest an abscopal effect that traverses the blood-brain barrier. The purpose of this review is to describe the clinical evidence for this phenomenon and potential mechanistic relationships between radiation, the blood-brain barrier, and the abscopal effect. Among reported cases, the majority of patients received systemic immunotherapy, which is consistent with an immunologic mechanism underlying abscopal responses. Preclinical data suggest that radiation may play multiple roles in this process, including the release of tumor-associated antigens and disruption of the blood-brain barrier. Future studies investigating the abscopal effect would benefit from more rigorous methods to control for patient and treatment factors that may affect distant tumor response.

  View details for DOI 10.7759/cureus.4207

  View details for Web of Science ID 000462072400002

  View details for PubMedID 31114726

  View details for PubMedCentralID PMC6505720

• Bespoke immunotherapy: how close are we? NEURO-ONCOLOGY Jackson, C., Lim, M. 2019; 21 (3): 289–90

  View details for DOI 10.1093/neuonc/noz017

  View details for Web of Science ID 000462164400001

  View details for PubMedID 31222359

  View details for PubMedCentralID PMC6380408

• Commentary: Does Stereotactic Radiosurgery Have a Role in the Management of Patients Presenting With 4 or More Brain Metastases? NEUROSURGERY Kleinberg, L., Lim, M. 2019; 84 (3): 567–68

  View details for DOI 10.1093/neuros/nyy255

  View details for Web of Science ID 000460636600050

  View details for PubMedID 30010955

• Why is immunotherapy for glioblastoma "Lag"-ging. Oncotarget Mathios, D., Lim, M. 2019; 10 (12): 1228–29

  View details for DOI 10.18632/oncotarget.26648

  View details for PubMedID 30815223

• Investigating in vivo synergistic effect of checkpoint blockade and radiation therapy against chordomas in a humanized mouse model Ishida, W., McCormick, K. L., Mahajan, A., Feldstein, E., Lim, M., Bruce, J. N., Canoll, P. D., Lo, S. L. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/2326-6074.CRICIMTEATIAACR18-B165

  View details for Web of Science ID 000557035600359

• Risk of Developing Postoperative Deficits Based on Tumor Location after Surgical Resection of an Intracranial Meningioma JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Ehresman, J. S., Garzon-Muvdi, T., Rogers, D., Lim, M., Gallia, G. L., Weingart, J., Brem, H., Bettegowda, C., Chaichana, K. L. 2019; 80 (1): 59–66

  Abstract

  Object  Meningiomas occur in various intracranial locations. Each location is associated with a unique set of surgical nuances and risk profiles. The incidence and risk factors that predispose patients to certain deficits based on tumor locations are unclear. This study aimed to determine which preoperative factors increase the risk of patients having new deficits after surgery based on tumor location for patients undergoing intracranial meningioma surgery. Methods  Adult patients who underwent primary, nonbiopsy resection of a meningioma at a tertiary care institution between 2007 and 2015 were retrospectively reviewed. Stepwise multivariate logistic regression analyses were used to identify associations with postoperative deficits based on tumor location. Results  Postoperatively, from the 761 included patients, there were 39 motor deficits (5.1%), 23 vision deficits (3.0%), 19 language deficits (2.5%), 27 seizures (3.5%), and 26 cognitive deficits (3.4%). The factors independently associated with any postoperative deficits were preoperative radiation (hazard ratio [HR] [95% confidence interval, CI] 3.000 [1.346-6.338], p  = 0.008), cerebellopontine angle tumors (HR [95% CI] 2.126 [1.094-3.947], p  = 0.03), Simpson grade 4 resections (HR [95% CI] 2.000 [1.271-3.127], p  = 0.003), preoperative motor deficits (HR [95% CI] 1.738 [1.005-2.923], p  = 0.048), preoperative cognitive deficits (HR [95% CI] 2.033 [1.144-3.504], p  = 0.02), and perioperative pulmonary embolisms (HR [95% CI] 11.741 [2.803-59.314], p  = 0.0009). Conclusion  Consideration of the factors associated with postoperative deficits in this study may help guide treatment strategies for patients with meningiomas.

  View details for DOI 10.1055/s-0038-1667066

  View details for Web of Science ID 000458922400009

  View details for PubMedID 30733902

  View details for PubMedCentralID PMC6365240

• Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy CLINICAL CANCER RESEARCH Jiang, S., Eberhart, C. G., Lim, M., Heo, H., Zhang, Y., Blair, L., Wen, Z., Holdhoff, M., Lin, D., Huang, P., Qin, H., Quinones-Hinojosa, A., Weingart, J. D., Barker, P. B., Pomper, M. G., Laterra, J., van Zijl, P. M., Blakeley, J. O., Zhou, J. 2019; 25 (2): 552–61

  Abstract

  To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation.Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis.Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff.APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity.

  View details for DOI 10.1158/1078-0432.CCR-18-1233

  View details for Web of Science ID 000456143100015

  View details for PubMedID 30366937

  View details for PubMedCentralID PMC6335169

• Deferred Radiotherapy After Debulking of Non-functioning Pituitary Macroadenomas: Clinical Outcomes FRONTIERS IN ONCOLOGY Nicholas, S. E., Salvatori, R., Quinones-Hinojosa, A., Redmond, K., Gallia, G., Lim, M., Rigamonti, D., Brem, H., Kleinberg, L. 2019; 8: 660

  Abstract

  Background: To describe the outcome for a cohort of patients with non-functioning pituitary macroadenomas (NFPMA), managed by debulking surgery with radiation therapy delayed until progression. Methods: Two hundred and sixty-seven patients were treated surgically for pituitary tumors at our institution between 1997 and 2005. One hundred and twenty-six patients met the inclusion criteria of NFPMA. They were followed for at least 2 years. Results: At presentation, 58% of patients had objectively decreased visual function, 66% had endocrine abnormalities, and 46% had headaches. Of the entire cohort, 75% of tumors abutted the optic chiasm and 87% had suprasellar extension. Over a median follow up of 112 months from surgery, 52% of patients had evidence of radiographic tumor progression, and 39% required additional treatment. There was a significant difference freedom from progression and in the number of patients receiving additional treatment with preoperative adenoma size of < 2 vs. ≥2 cm (p < 0.05). Conclusion: Close observation with radiation therapy delayed until the time of progression is an appropriate option for patients presenting with initial adenoma size < 2 cm, and can be considered for those with initial sizes up to 4 cm, as the majority of patients do not require further intervention for 10 or more years, thereby meaningfully postponing the risks of radiotherapy.

  View details for DOI 10.3389/fonc.2018.00660

  View details for Web of Science ID 000455378500001

  View details for PubMedID 30687636

  View details for PubMedCentralID PMC6335347

• Updated risk models demonstrate low risk of symptomatic radionecrosis following stereotactic radiosurgery for brain metastases. Surgical neurology international Peng, L., Grimm, J., Gui, C., Shen, C. J., Redmond, K. J., Sloan, L., Hazell, S., Moore, J., Huang, E., Spoleti, N., Laub, W., Quon, H., Bettegowda, C., Lim, M., Kleinberg, L. R. 2019; 10: 32

  Abstract

  Background: Improvements in systemic therapy continue to increase survival for patients with brain metastases. Updated dosimetric models are required to optimize long-term safety of stereotactic radiosurgery (SRS) for this indication.Methods: Patients at a single institution receiving SRS from December 2011 to December 2014 were retrospectively reviewed. Patients with radiographic progression of at least one lesion, and with at least 6 months of follow-up from the start of SRS were included. Grade 3 necrosis was defined as requiring surgical intervention. This data were combined with two additional published datasets to construct logistic models describing necrosis risk as a function of dose and volume.Results: From our institution, 294 brain metastases across 57 patients in 139 treatment plans met inclusion criteria. Primary histologies included non-small cell lung cancer (n = 19), melanoma (n = 13), breast carcinoma (n = 9), renal cell carcinoma (n = 7), and other (n = 9). Median follow-up from SRS of first cranial metastasis was 21.7 months (range: 6.3-56.6) and median overall survival was 25.6 months (range: 6.5-56.6). There were eight cases of Grade 1-2 and two cases of Grade 3 necrosis. As a useful clinical reference point, 20 cc of total brain receiving a single-fraction equivalent dose ≥14 Gy corresponded to 12.1% risk for Grade 1-3 (P < 0.003) and 3.4% risk for Grade 3 necrosis (P < 0.001).Conclusions: These results compare favorably with the QUANTEC brain tolerance estimates for radiosurgery, providing optimism for lower toxicity in the modern era. Additional studies are needed to determine dose tolerance parameters across a broad spectrum of patients.

  View details for DOI 10.4103/sni.sni_303_18

  View details for PubMedID 31528370

• Thalamic gliomas: Advances in the surgical management NEW TECHNIQUES FOR MANAGEMENT OF INOPERABLE GLIOMAS Hung, A., Wu, A., Jackson, C., Lim, M., Sughrue, M. E., Yang 2019: 117-135

  View details for DOI 10.1016/B978-0-12-813633-1.00011-6

  View details for Web of Science ID 000582656500012

• Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33 TRANSLATIONAL ONCOLOGY Tantravedi, S., Vesuna, F., Winnard, P. T., Martin, A., Lim, M., Eberhart, C. G., Berlinicke, C., Raabe, E., van Diest, P. J., Raman, V. 2019; 12 (1): 96–105

  Abstract

  Medulloblastoma is the most common malignant tumor that arises from the cerebellum of the central nervous system. Clinically, medulloblastomas are treated by surgery, radiation, and chemotherapy, all of which result in toxicity and morbidity. Recent reports have identified that DDX3, a member of the RNA helicase family, is mutated in medulloblastoma. In this study, we demonstrate the role of DDX3 in driving medulloblastoma. With the use of a small molecule inhibitor of DDX3, RK-33, we could inhibit growth and promote cell death in two medulloblastoma cell lines, DAOY and UW228, with IC50 values of 2.5 μM and 3.5 μM, respectively. Treatment of DAOY and UW228 cells with RK-33 caused a G1 arrest, resulted in reduced TCF reporter activity, and reduced mRNA expression levels of downstream target genes of the WNT pathway, such as Axin2, CCND1, MYC, and Survivin. In addition, treatment of DAOY and UW228 cells with a combination of RK-33 and radiation exhibited a synergistic effect. Importantly, the combination of RK-33 and 5 Gy radiation caused tumor regression in a mouse xenograft model of medulloblastoma. Using immunohistochemistry, we observed DDX3 expression in both pediatric (55%) and adult (66%) medulloblastoma patients. Based on these results, we conclude that RK-33 is a promising radiosensitizing agent that inhibits DDX3 activity and down-regulates WNT/β-catenin signaling and could be used as a frontline therapeutic strategy for DDX3-expressing medulloblastomas in combination with radiation.

  View details for DOI 10.1016/j.tranon.2018.09.002

  View details for Web of Science ID 000452892800012

  View details for PubMedID 30292066

  View details for PubMedCentralID PMC6171097

• Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma INTERNATIONAL JOURNAL OF CANCER Harris-Bookman, S., Mathios, D., Martin, A. M., Xia, Y., Kim, E., Xu, H., Belcaid, Z., Polanczyk, M., Barberi, T., Theodros, D., Kim, J., Taube, J. M., Burger, P. C., Selby, M., Taitt, C., Korman, A., Ye, X., Drake, C. G., Brem, H., Pardoll, D. M., Lim, M. 2018; 143 (12): 3201–8

  Abstract

  Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.

  View details for DOI 10.1002/ijc.31661

  View details for Web of Science ID 000451115900014

  View details for PubMedID 30248181

  View details for PubMedCentralID PMC7105259

• Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system ONCOIMMUNOLOGY Maxwell, R., Luksik, A. S., Garzon-Muvdi, T., Hung, A. L., Kim, E. S., Wu, A., Xia, Y., Belcaid, Z., Gorelick, N., Choi, J., Theodros, D., Jackson, C. M., Mathios, D., Ye, X., Tran, P. T., Redmond, K. J., Brem, H., Pardoll, D. M., Kleinberg, L. R., Lim, M. 2018; 7 (12): e1500108

  Abstract

  Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

  View details for DOI 10.1080/2162402X.2018.1500108

  View details for Web of Science ID 000450462000018

  View details for PubMedID 30524891

  View details for PubMedCentralID PMC6279341

• Distinguishing True Progression From Radionecrosis After Stereotactic Radiation Therapy for Brain Metastases With Machine Learning and Radiomics INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Peng, L., Parekh, V., Huang, P., Lin, D. D., Sheikh, K., Baker, B., Kirschbaum, T., Silvestri, F., Son, J., Robinson, A., Huang, E., Ames, H., Grimm, J., Chen, L., Shen, C., Soike, M., McTyre, E., Redmond, K., Lim, M., Lee, J., Jacobs, M. A., Kleinberg, L. 2018; 102 (4): 1236–43

  Abstract

  Treatment effect or radiation necrosis after stereotactic radiosurgery (SRS) for brain metastases is a common phenomenon often indistinguishable from true progression. Radiomics is an emerging field that promises to improve on conventional imaging. In this study, we sought to apply a radiomics-based prediction model to the problem of diagnosing treatment effect after SRS.We included patients in the Johns Hopkins Health System who were treated with SRS for brain metastases who subsequently underwent resection for symptomatic growth. We also included cases of likely treatment effect in which lesions grew but subsequently regressed spontaneously. Lesions were segmented semiautomatically on preoperative T1 postcontrast and T2 fluid-attenuated inversion recovery magnetic resonance imaging, and radiomic features were extracted with software developed in-house. Top-performing features on univariate logistic regression were entered into a hybrid feature selection/classification model, IsoSVM, with parameter optimization and further feature selection performed using leave-one-out cross-validation. Final model performance was assessed by 10-fold cross-validation with 100 repeats. All cases were independently reviewed by a board-certified neuroradiologist for comparison.We identified 82 treated lesions across 66 patients, with 77 lesions having pathologic confirmation. There were 51 radiomic features extracted per segmented lesion on each magnetic resonance imaging sequence. An optimized IsoSVM classifier based on top-ranked radiomic features had sensitivity and specificity of 65.38% and 86.67%, respectively, with an area under the curve of 0.81 on leave-one-out cross-validation. Only 73% of cases were classifiable by the neuroradiologist, with a sensitivity of 97% and specificity of 19%.Radiomics holds promise for differentiating between treatment effect and true progression in brain metastases treated with SRS. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions.

  View details for DOI 10.1016/j.ijrobp.2018.05.041

  View details for Web of Science ID 000447789700068

  View details for PubMedID 30353872

  View details for PubMedCentralID PMC6746307

• TUMOR-TREATING FIELDS THERAPY IS COMPATIBLE WITH STANDARD CHEMORADIOTHERAPY FOR GLIOBLASTOMA Stachelek, G., Grimm, J., Lim, M., Bettegowda, C., Redmond, K., Kleinberg, L. OXFORD UNIV PRESS INC. 2018: 228

  View details for Web of Science ID 000460646301298

• Local recurrence patterns after postoperative stereotactic radiation surgery to resected brain metastases: A quantitative analysis to guide target delineation PRACTICAL RADIATION ONCOLOGY Gui, C., Moore, J., Grimm, J., Kleinberg, L., McNutt, T., Shen, C., Chen, L., Bettegowda, C., Lim, M., Redmond, K. J. 2018; 8 (6): 388–96

  Abstract

  In the treatment of resected metastatic brain disease, a recent phase 3 trial by the North Central Cancer Treatment Group (N107C/CEC.3) surprisingly found that the local control rate for whole-brain radiation therapy was better than that of stereotactic radiation surgery (SRS). To optimize target delineation, we performed a quantitative analysis of local failure patterns after postoperative SRS.Patients with brain metastases who were treated with surgery and SRS to the cavity were evaluated. Local failure was defined by pathologic confirmation or magnetic resonance imaging evidence of progression leading to further overlapping radiation therapy. T1 postgadolinium magnetic resonance imaging scans that were taken preoperatively and at recurrence were co-registered to the simulation computed tomography. Three volumes were compared: (1) Preoperative tumors, (2) resection cavities that were originally contoured as clinical target volumes for SRS, and (3) recurrent tumors. Overlap volume histograms quantified the proximity of the three volumes to the meninges.In the cohort of 173 patients, 18 patients experienced local failure in 19 resection cavities. The original SRS target volume overlapped with a median of 69.6% of the recurrent tumor. When the entire preoperative tumor was included, the overlap with the recurrent tumor increased to a median of 76.8%. Recurrent tumors were closer to the meninges than corresponding preoperative tumors (P = .03) but a median 8.2 mm expansion of the target volume from the meninges was needed to increase overlap with the recurrent tumor to 90%. Increases in overlap with the recurrent tumor were achieved most efficiently by uniformly expanding the contoured cavity and a median 2.8 mm expansion covered 90% of the recurrent tumor.Our quantitative analysis of recurrence patterns suggests that a larger 3 mm uniform expansion of the SRS target volume substantially increases coverage of the volume that is later occupied by the recurrent tumor and may provide improved local control. The extent of the preoperative tumor in the target volume or expanding the target volume from the meninges provides little benefit.

  View details for DOI 10.1016/j.prro.2018.04.010

  View details for Web of Science ID 000448881600012

  View details for PubMedID 30029965

• IN VIVO SYNERGISTIC EFFECT OF CHECKPOINT BLOCKADE AND RADIATION THERAPY AGAINST CHORDOMAS IN A HUMANIZED MOUSE MODEL Ishida, W., McCormick, K., Mahajan, A., Feldstein, E., Lim, M., Bruce, J., Canoll, P., Lo, S. OXFORD UNIV PRESS INC. 2018: 276

  View details for Web of Science ID 000460646301502

• LOCAL ONCOLYTIC ADENOVIRUS TREATMENT AFFECTS BOTH THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM AND PROVIDES AN AVENUE FOR ENHANCING IMMUNOTHERAPIES FOR GBM Lamfers, M., Belcaid, Z., van den Bossche, W., Kleijn, A., Berrevoets, C., Lamers, C., Teunissen, C., Noske, D., Lim, M., Sleijfer, S., Debets, R., van Dongen, J., Dirven, C. OXFORD UNIV PRESS INC. 2018: 85

  View details for Web of Science ID 000460646300354

• PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB, DURVA) plus BEVACIZUMAB (BEV) IN BEV-NAIVE PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM) Reardon, D., Kaley, T., Dietrich, J., Clarke, J., Dunn, G., Lim, M., Cloughesy, T., Gan, H., Park, A., Schwarzenberger, P., Ricciardi, T., Macri, M., Ryan, A., Venhaus, R. OXFORD UNIV PRESS INC. 2018: 10

  View details for Web of Science ID 000460646300035

• UPDATED RESULTS OF A PHASE I TRIAL OF ANTI-LAG-3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM Lim, M., Ye, X., Nabors, L., Piotrowski, A., Ahluwalia, M., Desai, A., Walbert, T., Fisher, J., Desideri, S., Sims, M., Wen, P., Grossman, S. OXFORD UNIV PRESS INC. 2018: 5

  View details for Web of Science ID 000460646300018

• Absence of host NF-kappa B p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization CANCER IMMUNOLOGY IMMUNOTHERAPY Barberi, T., Martin, A., Suresh, R., Barakat, D. J., Harris-Bookman, S., Drake, C. G., Lim, M., Friedman, A. D. 2018; 67 (10): 1491–1503

  Abstract

  High-grade gliomas harbor abundant myeloid cells that suppress anti-tumor immunity and support tumor growth. Targeting transcription factors, such as NF-κB p50, that mediate suppressive myeloid M2 polarization may prove therapeutic. GL261-Luc glioblastoma cells were inoculated into wild-type and p50-/- mice, followed by analysis of tumor growth, survival, tumor myeloid cells, and T cells. The absence of host p50 slows tumor growth and enables regression in 30% of recipients, leading to prolonged survival. Tumors developing in p50-/- mice possess a greater concentration of tumor-infiltrating myeloid cells (TIMs) than those in wild-type mice. TIMs are predominantly F4/80hi macrophages which, along with tumor-associated microglia, express increased pro-inflammatory M1 and reduced immune-suppressive M2 markers. In p50-/- mice, total tumor CD4 T cells are threefold more abundant, whereas CD8 T-cell numbers are unchanged, and both produce increased IFNγ and Granzyme B. Naïve splenic p50-/- CD8 T cells manifest increased activation, whereas naïve p50-/- and WT CD4 T cells show similar Th1, Th2, and Th17 polarization. Antibody targeting CD4, but not CD8, fully obviates the p50-/- survival advantage. Combined CD4 and CD8 T-cell depletion reverses myeloid M2 polarization in wild-type hosts, without affecting myeloid M1 polarization in p50-/- hosts. Finally, gliomas grow similarly in p50(f/f) and p50(f/f);Lysozyme-Cre mice, the latter having reduced p50 specifically in myeloid cells and tumor microglia. Thus, high-grade glioma T cells play a key role in directing M2 polarization of tumor myeloid cells, and reducing NF-κB p50 in both tumor myeloid cells and T cells may contribute to glioma therapy.

  View details for DOI 10.1007/s00262-018-2184-2

  View details for Web of Science ID 000446577600002

  View details for PubMedID 30030559

  View details for PubMedCentralID PMC6168375

• REPLY TO HAFFNER ET AL.: DNA hypomethylation renders tumors more immunogenic PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Stone, M. L., Chiappinelli, K. B., Li, H., Murphy, L. M., Travers, M. E., Topper, M. J., Mathios, D., Lim, M., Shih, L., Wang, T., Hung, C., Bhargava, V., Wiehagen, K. R., Cowley, G. S., Bachman, K. E., Strick, R., Strissel, P. L., Baylin, S. B., Zahnow, C. A. 2018; 115 (37): E8583–E8584

  View details for DOI 10.1073/pnas.1811015115

  View details for Web of Science ID 000444257200002

  View details for PubMedID 30181297

  View details for PubMedCentralID PMC6140504

• Immunotherapy for Glioblastoma: Playing Chess, Not Checkers CLINICAL CANCER RESEARCH Jackson, C. M., Lim, M. 2018; 24 (17): 4059–61

  Abstract

  Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immunosuppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM. Clin Cancer Res; 24(17); 4059-61. ©2018 AACRSee related articles by Woroniecka et al., p. 4175 and Mohme et al., p. 4187.

  View details for DOI 10.1158/1078-0432.CCR-18-0491

  View details for Web of Science ID 000444040400001

  View details for PubMedID 29691293

• Concurrent Immune Checkpoint Inhibitors and Radiation Therapy Reply INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, L., Redmond, K., Lim, M. 2018; 101 (4): 998–99

  View details for DOI 10.1016/j.ijrobp.2018.04.050

  View details for Web of Science ID 000436809700037

  View details for PubMedID 29976512

• Targeting DDX3 in medulloblastoma by RK-33 Tantravedi, S., Vesuna, F., Martin, A., Lim, M., Eberhart, C. G., van Diest, P. J., Raman, V. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-5874

  View details for Web of Science ID 000468819505288

• Outcomes of Metastatic Brain Lesions Treated with Radioactive Cs-131 Seeds after Surgery: Experience from One Institution CUREUS Xia, Y., Mashouf, L. A., Baker, B. R., Maxwell, R., Bettegowda, C., Redmond, K. J., Kleinberg, L. R., Lim, M. 2018; 10 (7): e3075

  Abstract

  Introduction Brain metastases are common in patients with advanced systemic cancer and often recur despite treatment with surgical resection and radiotherapy. Whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) have significantly improved local control rates but are limited by complications including neurocognitive deficits and radiation necrosis. These risks can be higher in the re-irradiation setting. Brachytherapy may be an alternative method of additional targeted adjuvant radiotherapy with acceptable rates of toxicity. Methods A retrospective chart review of all patients undergoing resection for metastatic brain lesions and permanent low-dose rate Cs-131 brachytherapy was performed for one institution over a 10-year period. All patients had previous radiation therapy already and, after surgery, were followed with imaging every three months. Patient demographics, disease characteristics, intracranial disease, peri- and post-operative complications, and outcomes were recorded. The primary outcome of interest was local tumor recurrence at the site of brachytherapy while secondary outcomes included distant disease progression (within the brain) and complications such as radiation necrosis. Results During the study period, nine cases of individual patients met inclusion criteria. The median preoperative lesion diameter was 3 cm (0.8-4.1). The median overall survival after surgery and brachytherapy was 10.3 months, after excluding two patients who were lost to follow-up. Six of nine patients had no local recurrence, while three patients had development or progression of distant lesions. No patients experienced acute or delayed complications. Conclusion Cs-131 brachytherapy is a promising alternative method for controlling brain metastases after previous radiation interventions and surgical resection. In this case series, there were no incidences of local tumor recurrence or complications such as radiation necrosis.

  View details for DOI 10.7759/cureus.3075

  View details for Web of Science ID 000450942900172

  View details for PubMedID 30280070

  View details for PubMedCentralID PMC6166914

• The combination of CXCR4 and checkpoint receptor inhibition improves survival in an orthotopic murine glioma model Wu, A., Cardarelli, P., Oyasu, M., Menezes, D., Ponath, P., Cogswell, J., Maxwell, R., Luksik, A., Hung, A., Kim, E., Belcaid, Z., Brem, H., Pardoll, D., Lim, M. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-1736

  View details for Web of Science ID 000468818904126

• Prior ablative procedure: a prognostic factor for poor outcome of microvascular decompression? Response JOURNAL OF NEUROSURGERY Theodros, D., Lim, M. 2018; 128 (6): 1905

  View details for Web of Science ID 000440653000048

• Adult Cranioplasty Reconstruction With Customized Cranial Implants: Preferred Technique, Timing, and Biomaterials JOURNAL OF CRANIOFACIAL SURGERY Wolff, A., Santiago, G. F., Belzberg, M., Huggins, C., Lim, M., Weingart, J., Anderson, W., Coon, A., Huang, J., Brem, H., Gordon, C. 2018; 29 (4): 887–94

  Abstract

  Complex cranial defects requiring delayed reconstruction present numerous challenges. Delayed cranioplasties accompany frequent complications approaching an incidence of 35 to 40%. Therefore, the authors sought to collate their experience in hopes of sharing their perspective on several topics including technique, timing, and preferred biomaterials.The authors' 5-year consecutive experience over 430 customized cranial implants is described herein. Since its inception in 2012, the authors' team has employed the pericranial-onlay cranioplasty technique instead of the standard epidural approach. Optimal timing for cranioplasty is determined using objective criteria such as scalp healing and parenchymal edema, close collaboration with neuroplastic surgery, conversion from autologous bone to sterile implant in instances of questionable viability/storage, and the first-line use of solid poly(methylmethacrylate) implants for uncomplicated, delayed cases, first-line porous polyethylene (MEDPOR) implants for single-stage cranioplasty, and first-line polyether-ether-ketone implants for cases with short notice. Furthermore, the use of the pterional design algorithm with temporal bulking for all customized implants has helped to correct and/or prevent temporal hollowing deformities.The authors' team has observed a three-fold reduction in reported complications as compared with the existing literature, with a major complication rate of 11%. The multidisciplinary center has provided an optimal stage for synergy and improved outcomes versus standard cranioplasty techniques.Secondary cranial reconstruction, or cranioplasty, can be challenging due to numerous reasons. These best practices, developed in collaboration with neuroplastic surgery and neurosurgery, appear to encompass the largest published experience to date. The authors find this approach to be both safe and reliable.

  View details for DOI 10.1097/SCS.0000000000004385

  View details for Web of Science ID 000434304300055

  View details for PubMedID 29489570

• Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143 NEURO-ONCOLOGY Omuro, A., Vlahovic, G., Lim, M., Sahebjam, S., Baehring, J., Cloughesy, T., Voloschin, A., Ramkissoon, S. H., Ligon, K. L., Latek, R., Zwirtes, R., Strauss, L., Paliwal, P., Harbison, C. T., Reardon, D. A., Sampson, J. H. 2018; 20 (5): 674–86

  Abstract

  Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported.Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm.Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients.Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

  View details for DOI 10.1093/neuonc/nox208

  View details for Web of Science ID 000430161300012

  View details for PubMedID 29106665

  View details for PubMedCentralID PMC5892140

• Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. Oncotarget Garzon-Muvdi, T., Theodros, D., Luksik, A. S., Maxwell, R., Kim, E., Jackson, C. M., Belcaid, Z., Ganguly, S., Tyler, B., Brem, H., Pardoll, D. M., Lim, M. 2018; 9 (29): 20681–97

  Abstract

  Introduction: The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade.Results: We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response.Conclusions: This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB.Methods: Using a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

  View details for DOI 10.18632/oncotarget.25061

  View details for PubMedID 29755681

• PD-L1 expression in medulloblastoma: an evaluation by subgroup. Oncotarget Martin, A. M., Nirschl, C. J., Polanczyk, M. J., Bell, W. R., Nirschl, T. R., Harris-Bookman, S., Phallen, J., Hicks, J., Martinez, D., Ogurtsova, A., Xu, H., Sullivan, L. M., Meeker, A. K., Raabe, E. H., Cohen, K. J., Eberhart, C. G., Burger, P. C., Santi, M., Taube, J. M., Pardoll, D. M., Drake, C. G., Lim, M. 2018; 9 (27): 19177–91

  Abstract

  Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor.Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-gamma robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1.Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-gamma), radiation, and MYC overexpression.Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

  View details for DOI 10.18632/oncotarget.24951

  View details for PubMedID 29721192

• Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, L., Douglass, J., Kleinberg, L., Ye, X., Marciscano, A. E., Forde, P. M., Brahmer, J., Lipson, E., Sharfman, W., Hammers, H., Naidoo, J., Bettegowda, C., Lim, M., Redmond, K. J. 2018; 100 (4): 916–25

  Abstract

  To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs).We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64).Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

  View details for DOI 10.1016/j.ijrobp.2017.11.041

  View details for Web of Science ID 000425720600020

  View details for PubMedID 29485071

• TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM ONCOIMMUNOLOGY Hung, A. L., Maxwell, R., Theodros, D., Belcaid, Z., Mathios, D., Luksik, A. S., Kim, E., Wu, A., Xia, Y., Garzon-Muvdi, T., Jackson, C., Ye, X., Tyler, B., Selby, M., Korman, A., Barnhart, B., Park, S., Youn, J., Chowdhury, T., Park, C., Brem, H., Pardoll, D. M., Lim, M. 2018; 7 (8): e1466769

  Abstract

  The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

  View details for DOI 10.1080/2162402X.2018.1466769

  View details for Web of Science ID 000443907300034

  View details for PubMedID 30221069

  View details for PubMedCentralID PMC6136875

• The Relevance of Simpson Grade Resections in Modern Neurosurgical Treatment of World Health Organization Grade I, II, and III Meningiomas WORLD NEUROSURGERY Ehresman, J. S., Garzon-Muvdi, T., Rogers, D., Lim, M., Gallia, G. L., Weingart, J., Brem, H., Bettegowda, C., Chaichana, K. L. 2018; 109: E588–E593

  Abstract

  The Simpson grading system has played an important role in surgical resections of meningiomas. The aim of this study was to determine if this grading system predicts meningioma recurrence in a modern cohort of patients with tumors of all World Health Organization grades.Adult patients who underwent primary, nonbiopsy resection of a meningioma at a tertiary care institution between 2007 and 2015 were retrospectively reviewed. Stepwise multivariate proportional hazard analyses were used to identify associations with recurrence after resection. Log-rank analyses were used to compare Kaplan-Meier plots for time to recurrence between each Simpson grade.Of 572 patients who met inclusion criteria, 72 (12.6%) presented with recurrence. Factors associated with recurrence after gross total resection (Simpson grades I-III) were non-World Health Organization grade I (hazard ratio [HR] [95% confidence interval (CI)] 6.215 [2.864-12.419], P < 0.0001) and preoperative neurologic deficits (HR [95% CI] 2.862 [1.512-5.499], P = 0.001). Factors associated with recurrence after subtotal resections (Simpson IV) were African American race (HR [95% CI] 2.776 [1.232-5.890], P = 0.02) and parafalcine location (HR [95% CI] 3.956 [1.624-8.775], P = 0.004). Simpson grade was not an independent risk factor for recurrence.Identification and consideration of factors associated with recurrence after gross total or subtotal resections may help guide treatment strategies for patients with meningiomas.

  View details for DOI 10.1016/j.wneu.2017.10.028

  View details for Web of Science ID 000419015000072

  View details for PubMedID 29042332

• Adjuvant radiotherapy and outcomes of presumed hemorrhagic melanoma brain metastases without malignant cells. Surgical neurology international Xia, Y., Mashouf, L. A., Maxwell, R., Peng, L. C., Lipson, E. J., Sharfman, W. H., Bettegowda, C., Redmond, K. J., Kleinberg, L. R., Lim, M. 2018; 9: 146

  Abstract

  Background: Patients with melanoma can present with a hemorrhagic intracranial lesion. Upon resection, pathology reports may not detect any malignant cells. However, the hemorrhage may obscure their presence and so physicians may still decide whether adjuvant radiotherapy should be applied. Here, we report on the outcomes of a series of patients with melanoma with hemorrhagic brain lesions that returned with no tumor cells.Methods: All melanoma patients who had craniotomies from 2008 to 2017 at a single institution for hemorrhagic brain lesions were identified through retrospective chart review. Those who had pathology reports with no malignant cells were analyzed. Recurrence at the former site of hemorrhage and resection was the primary outcome.Results: Ten patients met inclusion criteria, and the median follow-up time was 8.5 (1.8-27.3) months. At the time of craniotomy, the median number of brain lesions was 3 (1-25). Two patients had prior craniotomies, eight had prior radiation, and six had prior immunotherapy to the lesion of interest. After surgery, one patient received stereotactic radiosurgery (SRS) to the resection bed. Only one patient developed subsequent melanoma at the resection site; this patient developed the lesion recurrence once and had not received postoperative SRS.Conclusion: Although small foci of metastatic disease as a source of bleeding for some patients cannot be excluded, melanoma patients with a suspected hemorrhagic brain metastasis that shows no tumor cells on pathology may benefit from close observation. The local recurrence risk in such cases appears to be low, even without adjuvant radiation.

  View details for DOI 10.4103/sni.sni_140_18

  View details for PubMedID 30105140

• Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Stone, M. L., Chiappinelli, K. B., Li, H., Murphy, L. M., Travers, M. E., Topper, M. J., Mathios, D., Lim, M., Shih, I., Wang, T., Hung, C., Bhargava, V., Wiehagen, K. R., Cowley, G. S., Bachman, K. E., Strick, R., Strissel, P. L., Baylin, S. B., Zahnow, C. A. 2017; 114 (51): E10981–E10990

  Abstract

  Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

  View details for DOI 10.1073/pnas.1712514114

  View details for Web of Science ID 000418321600018

  View details for PubMedID 29203668

  View details for PubMedCentralID PMC5754782

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited - Authors' reply. The Lancet. Oncology Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): e709-e710

  View details for DOI 10.1016/S1470-2045(17)30856-2

  View details for PubMedID 29208433

• Postoperative sinonasal morbidity in sellar reconstruction: mucosal autograft versus acellular dermal allograft Roxbury, C. R., Magruder, J., Ramanathan, M., Lim, M., Gallia, G. L., Ishii, M., Reh, D. D. WILEY. 2017: 1178–85

  Abstract

  Sellar pathology is increasingly addressed using the expanded endonasal approach (EEA). Although avascular graft reconstruction is an acceptable means to prevent cerebrospinal fluid leak, there are few data regarding sinonasal morbidity in these patients. In this study we compare rates of persistent postoperative crusting (PPC) and rhinosinusitis in patients undergoing sellar reconstruction with mucosal autografting and acellular dermal allografting (ADA).Patients undergoing the EEA between 2008 and 2014 were categorized into 2 subgroups: mucosal reconstruction and ADA reconstruction. Univariate analyses were performed to compare differences in PPC and rhinosinusitis in these groups and to identify risk factors for sinonasal morbidity. Multivariate propensity matching analysis was performed to match ADA and mucosa reconstruction groups with respect to age, race, gender, smoking status, diabetes status, tumor type, tumor size, and revision vs primary surgery.A total of 149 patients were identified. There were 105 patients reconstructed with autologous mucosa (70.5%) and 44 reconstructed with ADA (29.5%). Overall, PPC was seen in 20 patients (13.4%) and rhinosinusitis in 10 patients (6.7%). Propensity matching generated 39 patients reconstructed with ADA and 39 reconstructed with mucosa. There was a significant increase in PPC in patients reconstructed with ADA compared to those reconstructed with mucosa (8 of 39 [20.5%] vs 2 of 39 [5.1%], p = 0.04). There was no association between reconstruction with ADA and increased rhinosinusitis (3 of 39 [7.7%] vs 4 of 39 [10.3%], p = 0.64).Sinonasal morbidity is not uncommon after sellar reconstruction. Patients undergoing sellar reconstruction with ADA may be at increased risk of postoperative crusting compared with those undergoing reconstruction with mucosa.

  View details for DOI 10.1002/alr.22019

  View details for Web of Science ID 000417284900011

  View details for PubMedID 28985037

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited Reply LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): E709–E710

  View details for Web of Science ID 000417001900003

• PHASE I TRIAL OF ANTI-LAG-3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM Lim, M., Ye, X., Nabors, B., Piotrowski, A. F., Fisher, J., Desideri, S., Sims, M., Wen, P., Grossman, S. A. OXFORD UNIV PRESS INC. 2017: 31

  View details for Web of Science ID 000415152500119

• POPULATION PHARMACOKINETIC (PPK) ANALYSIS OF NIVOLUMAB FLAT AND WEIGHT-BASED DOSING REGIMENS AND ASSOCIATIONS WITH SAFETY IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM) TREATED IN CHECKMATE 143 Shen, J., Hruska, M., Zwirtes, R., Potter, V., Paliwal, P., Roy, A., Bello, A., Suryawanshi, S., Lim, M. OXFORD UNIV PRESS INC. 2017: 30

  View details for Web of Science ID 000415152500115

• PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB [DUR]) IN PATIENTS WITH BEVACIZUMAB (BEV)-REFRACTORY RECURRENT GLIOBLASTOMA (GBM) Reardon, D., Kaley, T., Dietrich, J., Clarke, J. L., Dunn, G. P., Lim, M., Cloughesy, T., Gan, H. K., Park, A., Schwarzenberger, P., Ricciardi, T., Macri, M., Ryan, A., Venhaus, R. OXFORD UNIV PRESS INC. 2017: 28

  View details for Web of Science ID 000415152500109

• A PILOT STUDY OF STEREOTACTIC RADIOSURGERY (SRS) COMBINED WITH IPILIMUMAB PROLONGED SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED MELANOMA BRAIN METASTASES Lim, M., Kleinberg, L., Ye, X., Nicholas, S., Lin, D., Redmond, K., Bettegowda, C., Sharfman, W., Lipson, E. OXFORD UNIV PRESS INC. 2017: 27

  View details for Web of Science ID 000415152500103

• Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H., ACT IV Trial Investigators 2017; 18 (10): 1373–85

  Abstract

  Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.Celldex Therapeutics, Inc.

  View details for PubMedID 28844499

• The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors NEUROTHERAPEUTICS Luksik, A. S., Maxwell, R., Garzon-Muvdi, T., Lim, M. 2017; 14 (4): 1049–65

  Abstract

  The standard of care for malignant gliomas of the brain has changed very little over the last few decades, and does not offer a cure for these rare, but fatal, tumors. The field of immunotherapy has brought potent new drugs into the oncological armamentarium, and is becoming recognized as a potentially important arm in the treatment of glioblastoma for adults. Immune checkpoints are inhibitory receptors found on immune cells that, when stimulated, cause those immune cells to become quiescent. While this is a natural mechanism to prevent excessive inflammatory damage and autoimmunity in otherwise healthy tissues, cancer cells may utilize this process to grow in the absence of targeted immune destruction. Antibodies derived to block the stimulation of these negative checkpoints, allowing immune cells to remain activated and undergo effector function, are a growing area of immunotherapy. These therapies have seen much success in both the preclinical and clinical arenas for various tumors, particularly melanoma and nonsmall-cell lung cancer. Multiple clinical trials are underway to determine if these drugs have efficacy in glioblastoma. Here, we review the current evidence, from early preclinical data to lessons learned from clinical trials outside of glioblastoma, to assess the potential of immune checkpoint inhibition in the treatment of brain tumors and discuss how this therapy may be implemented with the present standard of care.

  View details for DOI 10.1007/s13311-017-0513-3

  View details for Web of Science ID 000417695200020

  View details for PubMedID 28258545

  View details for PubMedCentralID PMC5722751

• Targeting cytokines for treatment of neuropathic pain SCANDINAVIAN JOURNAL OF PAIN Hung, A. L., Lim, M., Doshi, T. L. 2017; 17: 287–93

  Abstract

  Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options.A literature review was performed to assess the role of pro-inflammatory and anti-inflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized.In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition.

  View details for DOI 10.1016/j.sjpain.2017.08.002

  View details for Web of Science ID 000419851500051

  View details for PubMedID 29229214

  View details for PubMedCentralID PMC5774983

• Long-term Treatment Response and Patient Outcomes for Vestibular Schwannoma Patients Treated with Hypofractionated Stereotactic Radiotherapy FRONTIERS IN ONCOLOGY Patel, M. A., Marciscano, A. E., Hu, C., Jusue-Torres, I., Garg, R., Rashid, A., Francis, H. W., Lim, M., Redmond, K. J., Rigamonti, D., Kleinberg, L. R. 2017; 7: 200

  Abstract

  The aim of this study is to evaluate long-term treatment outcome and toxicities among vestibular schwannoma (VS) patients treated with hypofractionated stereotactic radiotherapy (HSRT).383 patients with unilateral VS treated with HSRT (25 Gy, five fractions) between 1995 and 2007 were retrospectively reviewed. Treatment failure was defined as requiring salvage microsurgery. Posttreatment new/progressive clinical symptoms or increases in baseline tumor volume (BTV) due to treatment effect or progression were noted. Symptom outcomes were reported as baseline and posttreatment ± improvement, respectively. Symptoms were grouped by cranial nerve (CN) VII or CNVIII. Audiometry was assessed baseline and posttreatment hearing. Patients were grouped as having greater than serviceable hearing [Gardner Robertson (GR) score 1-2] or less than non-serviceable hearing (GR score 3-5) by audiometry.Median follow-up was 72.0 months. Nine (2.3%) experienced treatment failure. At last follow-up, 74 (19.3%) had new/progressive symptoms and were categorized as radiologic non-responders, whereas 300 (78.3%) had no tumor progression and were grouped as radiologic responders. Average pretreatment BTV for treatment failures, radiologic non-responders, and radiologic responders was 2.11, 0.44, and 1.87 cm3, respectively. Pretreatment CNVII and CNVIII symptoms were present in 9.4 and 93.4% of patients, respectively. Eight (24%) with pre-HSRT CNVII and 37 (10%) with pre-HSRT CNVIII symptoms recovered CN function post-HSRT. Thirty-five (9%) and 36 (9.4%) experienced new CNVII and CNVIII deficit, respectively, after HSRT. Of these, 20 (57%) and 18 (50%) recovered CNVII and CNVIII function, respectively, after HSRT. Evaluable audiograms were available in 199 patients. At baseline and at last follow-up, 65.8 and 36.2% had serviceable hearing, respectively. Fifty-one percent had preservation of serviceable hearing at last follow-up.Treatment of VS with HSRT is effective with treatment success in 97.7% and an acceptable toxicity profile. Less than one-third of patients experience any new CNVII or CNVIII deficit posttreatment. Greater than 50% of patients with serviceable hearing at baseline maintained hearing function. Improved methods to differentiate treatment effect and tumor progression are needed.

  View details for DOI 10.3389/fonc.2017.00200

  View details for Web of Science ID 000408986400001

  View details for PubMedID 28929084

  View details for PubMedCentralID PMC5591320

• Immunotherapy and radiation in glioblastoma JOURNAL OF NEURO-ONCOLOGY Sahebjam, S., Sharabi, A., Lim, M., Kesarwani, P., Chinnaiyan, P. 2017; 134 (3): 531–39

  Abstract

  Radiation therapy plays a central role in the management of glioblastoma. Although primarily thought of as modality to provide local tumor control through DNA damage, the capacity of ionizing radiation to modulate tumor immune response has long been recognized. The recent emergence of clinically active immunotherapies offers exciting potential for harnessing the immune modulatory effects or radiation through combinatorial strategies designed to enhance clinical outcomes. In this Review, we provide background describing the unique immune environment within the central nervous system, how ionizing radiation may modulate the tumor immune response, preclinical and clinical data testing the combination of radiation and immune modulating agents, and highlight some of the current challenges in extending these findings clinically.

  View details for DOI 10.1007/s11060-017-2413-0

  View details for Web of Science ID 000411370700008

  View details for PubMedID 28567588

• Amide proton transfer-weighted magnetic resonance image-guided stereotactic biopsy in patients with newly diagnosed gliomas EUROPEAN JOURNAL OF CANCER Jiang, S., Eberhart, C. G., Zhang, Y., Heo, H., Wen, Z., Blair, L., Qin, H., Lim, M., Quinones-Hinojosa, A., Weingart, J. D., Barker, P. B., Pomper, M. G., Laterra, J., van Zijl, P. M., Blakeley, J. O., Zhou, J. 2017; 83: 9–18

  Abstract

  Pathological assessment using World Health Organization (WHO) criteria is the gold standard for diagnosis of gliomas. However, the accuracy of diagnosis is limited by tissue sampling, particularly for infiltrating, heterogeneous tumours. We assessed the accuracy of amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI)-guided tissue sampling to identify regions of high-grade glioma via radiographic-histopathologic correlation in patients with newly suspected glioma.Twenty-four patients with previously undiagnosed gliomas underwent a volumetric APTw MRI prior to their first neurosurgical procedure. A total of 70 specimens were collected via APTw image-directed stereotactic biopsy. Cellularity, necrosis, proliferation and glioma WHO grade were analysed for all specimens and correlated with corresponding APTw signal intensities.Thirty-three specimens displayed grade-II pathology, 14 grade-III, 15 grade-IV, and eight specimens revealed only peritumoural oedema. Multiple glioma grades were found within a single lesion in six patients. APTw signal intensities of the biopsied sites and the maximum APTw values across all biopsied sites in each patient were significantly higher for high-grade versus low-grade specimens. APTw signal intensities were significantly positively correlated with cellularity (R = 0.757) and proliferation (R = 0.538). Multiple linear regression analysis showed that tumour cellularity and proliferation index were the best predictors of APTw signal intensities.APTw imaging identified tumour areas of higher cellularity and proliferation, allowing identification of high-grade regions within heterogeneous gliomas. APTw imaging can be readily translated for more widespread use and can assist diagnostic neurosurgical procedures by increasing the accuracy of tumour sampling in patients with infiltrating gliomas.

  View details for DOI 10.1016/j.ejca.2017.06.009

  View details for Web of Science ID 000408273800002

  View details for PubMedID 28704644

  View details for PubMedCentralID PMC5572540

• Clinical Trials Investigating Immune Checkpoint Blockade in Glioblastoma CURRENT TREATMENT OPTIONS IN ONCOLOGY Maxwell, R., Jackson, C. M., Lim, M. 2017; 18 (8): 51

  Abstract

  Immune checkpoint inhibitors have changed the landscape of cancer immunotherapy and are being integrated into the standard of care for a variety of solid and hematologic malignancies. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a grave prognosis despite advances in surgical resection, chemotherapy, and radiation therapy. Implementing immunotherapy for brain tumors mandates additional considerations due to the unique structural and immunologic milieu of the central nervous system (CNS). Nevertheless, strong data from preclinical studies have driven clinical trials of immune checkpoint blockade for newly diagnosed and recurrent GBM. The focus of this review is to discuss the ongoing clinical trials of checkpoint inhibitors in GBM and review the immunologic rationale for ongoing and future trial designs.

  View details for DOI 10.1007/s11864-017-0492-y

  View details for Web of Science ID 000407452300006

  View details for PubMedID 28785997

• Risk Factors for Preoperative Seizures and Loss of Seizure Control in Patients Undergoing Surgery for Metastatic Brain Tumors WORLD NEUROSURGERY Wu, A., Weingart, J. D., Gallia, G. L., Lim, M., Brem, H., Bettegowda, C., Chaichana, K. L. 2017; 104: 120–28

  Abstract

  Metastatic brain tumors are the most common brain tumors in adults. Patients with metastatic brain tumors have poor prognoses with median survival of 6-12 months. Seizures are a major presenting symptom and cause of morbidity and mortality. In this article, risk factors for the onset of preoperative seizures and postoperative seizure control are examined.Adult patients who underwent resection of one or more brain metastases at a single institution between 1998 and 2011 were reviewed retrospectively.Of 565 patients, 114 (20.2%) patients presented with seizures. Factors independently associated with preoperative seizures were preoperative headaches (P = 0.044), cognitive deficits (P = 0.031), more than 2 intracranial metastatic tumors (P = 0.013), temporal lobe location (P = 0.031), occipital lobe location (P = 0.010), and bone involvement by tumor (P = 0.029). Factors independently associated with loss of seizure control after surgical resection were preoperative seizures (P = 0.001), temporal lobe location (P = 0.037), lack of postoperative chemotherapy (P = 0.010), subtotal resection of tumor (P = 0.022), and local recurrence (P = 0.027). At last follow-up, the majority of patients (93.8%) were seizure-free. Thirty patients (5.30%) in total had loss of seizure control, and only 8 patients (1.41%) who did not have preoperative seizures presented with new-onset seizures after surgical resection of their metastases.The brain is a common site for metastases from numerous primary cancers, such as breast and lung. The identification of factors associated with onset of preoperative seizures as well as seizure control postoperatively could aid management strategies for patients with metastatic brain tumors. Patients with preoperative seizures who underwent resection tended to have good seizure control after surgery.

  View details for DOI 10.1016/j.wneu.2017.05.028

  View details for Web of Science ID 000407713100017

  View details for PubMedID 28512046

• Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy CLINICAL CANCER RESEARCH Bloch, O., Lim, M., Sughrue, M. E., Komotar, R. J., Abrahams, J. M., O'Rourke, D. M., D'Ambrosio, A., Bruce, J. N., Parsa, A. T. 2017; 23 (14): 3575–84

  Abstract

  Purpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8-30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575-84. ©2017 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-1369

  View details for Web of Science ID 000405678400013

  View details for PubMedID 28193626

  View details for PubMedCentralID PMC5511566

• Use of Stereotactic Radiosurgery in Elderly and Very Elderly Patients With Brain Metastases to Limit Toxicity Associated With Whole Brain Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, L., Shen, C., Redmond, K. J., Page, B. R., Kummerlowe, M., Mcnutt, T., Bettegowda, C., Rigamonti, D., Lim, M., Kleinberg, L. 2017; 98 (4): 939–47

  Abstract

  We evaluated the toxicity associated with stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) in elderly and very elderly patients with brain metastases, as the role of SRS in geriatric patients who would traditionally receive WBRT is unclear.We conducted a retrospective review of elderly patients (aged 70-79 years) and very elderly patients (aged ≥80 years) with brain metastases who underwent RT from 2010 to 2015 at Johns Hopkins Hospital. Patients received either upfront WBRT or SRS for metastatic solid malignancies, excluding small cell lung cancer. Acute central nervous system toxicity within 3 months of RT was graded using the Radiation Therapy Oncology Group acute radiation central nervous system morbidity scale. The toxicity data between age groups and treatment modalities were analyzed using Fisher's exact test and multivariate logistic regression analysis. Kaplan-Meier curves were used to estimate the median overall survival, and the Cox proportion hazard model was used for multivariate analysis.A total of 811 brain metastases received RT in 119 geriatric patients. The median overall survival from the diagnosis of brain metastases was 4.3 months for the patients undergoing WBRT and 14.4 months for the patients undergoing SRS. On multivariate analysis, WBRT was associated with worse overall survival in this cohort of geriatric patients (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9-7.0, P<.0001) and age ≥80 years was not. WBRT was associated with significantly greater rates of any grade 1 to 4 toxicity (OR 7.5, 95% CI 1.6-33.3, P=.009) and grade 2 to 4 toxicity (OR 2.8, 95% CI 1.0-8.1, P=.047) on multivariate analysis. Elderly and very elderly patients did not have significantly different statistically acute toxicity rates when stratified by age.WBRT was associated with increased toxicity compared with SRS in elderly and very elderly patients with brain metastases. SRS, rather than WBRT, should be prospectively evaluated in geriatric patients with the goal of minimizing treatment-related toxicity.

  View details for DOI 10.1016/j.ijrobp.2017.02.031

  View details for Web of Science ID 000403086600032

  View details for PubMedID 28602418

• Long-term Outcomes With Planned Multistage Reduced Dose Repeat Stereotactic Radiosurgery for Treatment of Inoperable High-Grade Arteriovenous Malformations: An Observational Retrospective Cohort Study NEUROSURGERY Marciscano, A. E., Huang, J., Tamargo, R. J., Hu, C., Khattab, M. H., Aggarwal, S., Lim, M., Redmond, K. J., Rigamonti, D., Kleinberg, L. R. 2017; 81 (1): 136–46

  Abstract

  There is no consensus regarding the optimal management of inoperable high-grade arteriovenous malformations (AVMs). This long-term study of 42 patients with high-grade AVMs reports obliteration and adverse event (AE) rates using planned multistage repeat stereotactic radiosurgery (SRS).To evaluate the efficacy and safety of multistage SRS with treatment of the entire AVM nidus at each treatment session to achieve complete obliteration of high-grade AVMs.Patients with high-grade Spetzler-Martin (S-M) III-V AVMs treated with at least 2 multistage SRS treatments from 1989 to 2013. Clinical outcomes of obliteration rate, minor/major AEs, and treatment characteristics were collected.Forty-two patients met inclusion criteria (n = 26, S-M III; n = 13, S-M IV; n = 3, S-M V) with a median follow-up was 9.5 yr after first SRS. Median number of SRS treatment stages was 2, and median interval between stages was 3.5 yr. Twenty-two patients underwent pre-SRS embolization. Complete AVM obliteration rate was 38%, and the median time to obliteration was 9.7 yr. On multivariate analysis, higher S-M grade was significantly associated ( P = .04) failure to achieve obliteration. Twenty-seven post-SRS AEs were observed, and the post-SRS intracranial hemorrhage rate was 0.027 events per patient year.Treatment of high-grade AVMs with multistage SRS achieves AVM obliteration in a meaningful proportion of patients with acceptable AE rates. Lower obliteration rates were associated with higher S-M grade and pre-SRS embolization. This approach should be considered with caution, as partial obliteration does not protect from hemorrhage.

  View details for DOI 10.1093/neuros/nyw041

  View details for Web of Science ID 000404929100043

  View details for PubMedID 28201783

• BRAF-V600 mutational status affects recurrence patterns of melanoma brain metastasis INTERNATIONAL JOURNAL OF CANCER Maxwell, R., Garzon-Muvdi, T., Lipson, E. J., Sharfman, W. H., Bettegowda, C., Redmond, K. J., Kleinberg, L. R., Ye, X., Lim, M. 2017; 140 (12): 2716–27

  Abstract

  Brain metastasis is common and carries a poor prognosis in melanoma. A single institution, retrospective cohort of 225 melanoma patients was analyzed to determine if BRAF-V600 mutational status was associated with brain metastasis. Eighty-three of the 225 patients (37%) had BRAF-V600 mutations. At initial diagnosis, BRAF-V600 mutations were associated with younger age (p ≤ 0.001), higher proportion of females (p = 0.0037), higher AJCC stage (p = 0.030), regional lymph node involvement (p = 0.047), and family history of cancer (p = 0.044). Compared to BRAF-WT, BRAF-V600 patients had an increased risk of brain metastasis in multivariate analysis (OR = 2.24; 95% CL = 1.10-4.58; p = 0.027). However, BRAF-V600 patients treated with a selective BRAF inhibitor (BRAFi) had a similar risk of brain metastasis compared to BRAF-WT patients (OR = 1.00; 95% CL = 0.37-2.65; p = 0.98). Moreover, treatment with BRAFi significantly prolonged the time from initial diagnosis to brain metastasis diagnosis (HR = 0.30; 95% CL = 0.11-0.79; p = 0.015). Compared to other tissues, the brain was the most frequent site of metastasis in BRAF-V600 patients without BRAFi (42% ± 7%). The frequency of brain metastasis was lower in BRAF-WT and BRAF-V600 patients with BRAFi (25% ± 4% and 25% ± 8%, respectively). The proportion of patients with brain metastasis as the only site was 40%, 60%, and 0% in the BRAF-WT, BRAF-V600 without BRAFi, and BRAF-V600 with BRAFi groups, respectively. This study provides evidence on the clinical importance of BRAF-V600 mutations and BRAF inhibition in the progression to melanoma brain metastasis.

  View details for DOI 10.1002/ijc.30241

  View details for Web of Science ID 000400158800011

  View details for PubMedID 27342756

• Biomarkers and Immunotherapeutic Targets in Glioblastoma WORLD NEUROSURGERY Hung, A. L., Garzon-Muvdi, T., Lim, M. 2017; 102: 494–506

  Abstract

  Glioblastoma (GBM) is an aggressive central nervous system cancer with poor prognosis despite maximal therapy. The recent advent of immunotherapy holds great promise for improving GBM survival and has already made great strides toward changing management strategies. A diverse set of biomarkers have been implicated as immunotherapeutic targets and prognostic indicators in other cancers. Some of the more extensively studied examples include cytokines (IL-4, IL-13, and TGF-β), checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, CD137, GITR, OX40), and growth/angiogenesis proteins (endoglin and EGFR). Emerging theories involving the tumor mutational landscape and microbiome have also been explored in relation to cancer treatment. Although identification of novel biomarkers may improve and help direct treatment of patients with GBM, the next step is to explore the role of biomarkers in precision medicine and selection of specific immunotherapeutic drugs in an individualized manner.

  View details for DOI 10.1016/j.wneu.2017.03.011

  View details for Web of Science ID 000405472500064

  View details for PubMedID 28300714

• The Potential of Cellular- and Viral-Based Immunotherapies for Malignant Glioma-Dendritic Cell Vaccines, Adoptive Cell Transfer, and Oncolytic Viruses CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Maxwell, R., Luksik, A. S., Garzon-Muvdi, T., Lim, M. 2017; 17 (6): 50

  Abstract

  Malignant gliomas, including glioblastoma and anaplastic astrocytoma, are the most frequent primary brain tumors and present with many treatment challenges. In this review, we discuss the potential of cellular- and viral-based immunotherapies in the treatment of malignant glioma, specifically focusing on dendritic cell vaccines, adoptive cell therapy, and oncolytic viruses.Diverse cellular- and viral-based strategies have been engineered and optimized to generate either a specific or broad antitumor immune response in malignant glioma. Due to their successes in the preclinical arena, many of these therapies have undergone phase I and II clinical testing. These early clinical trials have demonstrated the feasibility, safety, and efficacy of these immunotherapies. Dendritic cell vaccines, adoptive cell transfer, and oncolytic viruses may have a potential role in the treatment of malignant glioma. However, these modalities must be investigated in well-designed phase III trials to prove their efficacy.

  View details for DOI 10.1007/s11910-017-0754-x

  View details for Web of Science ID 000401256800005

  View details for PubMedID 28488122

• Histopathologic review of suspected disease progression in patients with recurrent glioblastoma (GBM) receiving nivolumab +/- ipilimumab: CheckMate 143. Sahebjam, S., Ramkissoon, S., Baehring, J. M., Mulholland, P., Grauer, O. M., Cloughesy, T., Reardon, D. A., Lim, M., Zwirtes, R. F., Latek, R., Strauss, L. C., Ligon, K. L. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.2001

  View details for Web of Science ID 000411895703171

• Spontaneous Intracranial Hypotension after Vestibular Schwannoma Resection Due to an Unexpected Pathology: Tarlov Cysts CUREUS Pross, S. E., Sharon, J. D., Lim, M., Moghekar, A., Rao, A., Carey, J. P. 2017; 9 (5): e1261

  Abstract

  While infrequent, cerebrospinal fluid (CSF) leaks are known to occur after surgical resection of vestibular schwannomas. Early signs of CSF leak often include headache and altered mental status. If untreated, life-threatening complications can occur, including brainstem herniation and meningitis. The appropriate surgical treatment for a CSF leak requires accurate localization of the source. While the most likely location of a CSF leak after lateral skull base surgery is through the aerated portions of the temporal bone, we present a unique case of a man with a prolonged CSF leak after an acoustic tumor removal who was ultimately found to have an occult spinal perineural (Tarlov) cyst as the source. Accurate localization was ultimately achieved with CT myelogram after empirically obliterating his mastoid failed to restore intracranial CSF volume. Tarlov cysts are the most common cause of idiopathic intracranial hypotension, and this case highlights the importance of considering this entity in the differential diagnosis of postoperative CSF leaks.

  View details for DOI 10.7759/cureus.1261

  View details for Web of Science ID 000453621500059

  View details for PubMedID 28652945

  View details for PubMedCentralID PMC5476477

• Efficacy of primary microvascular decompression versus subsequent microvascular decompression for trigeminal neuralgia JOURNAL OF NEUROSURGERY Theodros, D., Goodwin, C., Bender, M. T., Zhou, X., Garzon-Muvdi, T., De la Garza-Ramos, R., Abu-Bonsrah, N., Mathios, D., Blitz, A. M., Olivi, A., Carson, B., Bettegowda, C., Lim, M. 2017; 126 (5): 1691–97

  Abstract

  OBJECTIVE Trigeminal neuralgia (TN) is characterized by intermittent, paroxysmal, and lancinating pain along the distribution of the trigeminal nerve. Microvascular decompression (MVD) directly addresses compression of the trigeminal nerve. The purpose of this study was to determine whether patients undergoing MVD as their first surgical intervention experience greater pain control than patients who undergo subsequent MVD. METHODS A retrospective review of patient records from 1998 to 2015 identified a total of 942 patients with TN and 500 patients who underwent MVD. After excluding several cases, 306 patients underwent MVD as their first surgical intervention and 175 patients underwent subsequent MVD. Demographics and clinicopathological data and outcomes were obtained for analysis. RESULTS In patients who underwent subsequent MVD, surgical intervention was performed at an older age (55.22 vs 49.98 years old, p < 0.0001) and the duration of symptoms was greater (7.22 vs 4.45 years, p < 0.0001) than for patients in whom MVD was their first surgical intervention. Patients who underwent initial MVD had improved pain relief and no improvement in pain rates compared with those who had subsequent MVD (95.8% and 4.2% vs 90.3% and 9.7%, respectively, p = 0.0041). Patients who underwent initial MVD had significantly lower rates of facial numbness in the pre- and postoperative periods compared with patients who underwent subsequent MVD (p < 0.0001). The number of complications in both groups was similar (p = 0.4572). CONCLUSIONS The results demonstrate that patients who underwent other procedures prior to MVD had less pain relief and a higher incidence of facial numbness despite rates of complications similar to patients who underwent MVD as their first surgical intervention.

  View details for DOI 10.3171/2016.5.JNS151692

  View details for Web of Science ID 000400041400034

  View details for PubMedID 27419826

• Metastatic Atypical and Anaplastic Meningioma: A Case Series and Review of the Literature WORLD NEUROSURGERY Kessler, R. A., Garzon-Muvdi, T., Yang, W., Weingart, J., Olivi, A., Huang, J., Brem, H., Lim, M. 2017; 101: 47–56

  Abstract

  Atypical (World Health Organization grade II) and anaplastic (World Health Organization grade III) meningiomas are rare, accounting for less than 5% of all meningiomas. Histologic grading has a significant impact on prognosis, risk of recurrence, and the need for adjuvant radiation or chemotherapy. Extracranial metastases are even more infrequent and occur in 0.1% of all cases.Retrospective chart review of 168 patients with diagnosis of WHO grade II and III meningiomas was performed. Six patients with histologically confirmed metastatic disease were identified.We discuss the clinical, radiologic, and histopathologic clinical course of 6 patients with metastasis to the lung, liver, and spine from all patients with atypical or anaplastic meningioma treated at Johns Hopkins Hospital from 1993 to 2014.We reviewed the literature pertaining to this phenomenon and subsequently assessed the clinical benefits of adjuvant chemotherapeutic agents in patients with meningioma with metastatic disease.

  View details for DOI 10.1016/j.wneu.2017.01.070

  View details for Web of Science ID 000401932500008

  View details for PubMedID 28143726

• Progressive Low-Grade Glioma: Assessment of Prognostic Importance of Histologic Reassessment and MRI Findings WORLD NEUROSURGERY Narang, A. K., Chaichana, K. L., Weingart, J. D., Redmond, K. J., Lim, M., Olivi, A., Quinones-Hinojosa, A., Kleinberg, L. R. 2017; 99: 751–57

  Abstract

  In patients with progressive low-grade glioma (LGG), the presence of new magnetic resonance imaging (MRI) enhancement is commonly used as an indicator of malignant degeneration, but its accuracy in this setting is uncertain.We characterize the ability of new MRI enhancement to serve as a surrogate for histologic grade in patients with progressive LGG, and to explore the prognostic value of new MRI enhancement, pathologic grade, and extent of resection.Patients at our institution with World Health Organization grade II glioma diagnosed between 1994 and 2010 and who underwent repeat biopsy or resection at progression were retrospectively reviewed (n = 108). The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were characterized. A multivariable proportional hazards model was used to test associations with overall survival (OS), and Kaplan-Meier curves were constructed to compare OS between patient subsets.The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were 82%, 77%, 92%, and 57%, respectively. In patients without malignant degeneration, new MRI enhancement was associated with inferior median OS (92.5 months vs. not reached; P = 0.03). In patients with malignant degeneration, gross or near total resection was associated with improved median OS (58.8 vs. 28.8 months; P = 0.02).In patients with progressive LGG, new MRI enhancement and pathologic grade were discordant in greater than 20% of cases. Pathologic confirmation of grade should therefore be attempted, when safe, to dictate management. Beyond functioning as a surrogate for pathologic grade, new MRI enhancement may predict for worse outcomes, a concept that merits prospective investigation.

  View details for DOI 10.1016/j.wneu.2016.04.030

  View details for Web of Science ID 000397190100102

  View details for PubMedID 27108796

• 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. n., Chung, L. K., Macyszyn, L. n., Choy, W. n., Smith, Z. A., Dahdaleh, N. S., Bohnen, A. M., Cho, J. M., Colen, C. B., Duckworth, E. n., Germanwala, A. V., Kan, P. n., Khalessi, A. A., Kim, C. Y., Lam, S. n., Li, G. n., Lim, M. n., Sherman, J. H., Wang, V. Y., Zada, G. n., Yang, I. n. 2017; 8: 9

  View details for PubMedID 28217388

  View details for PubMedCentralID PMC5288991

• 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. n., Lagman, C. n., Chung, L. K., Khalessi, A. A., Zada, G. n., Smith, Z. A., Dahdaleh, N. S., Bohnen, A. M., Cho, J. M., Colen, C. B., Duckworth, E. n., Kan, P. n., Lam, S. n., Kim, C. Y., Li, G. n., Lim, M. n., Sherman, J. H., Wang, V. Y., Yang, I. n. 2017; 8: 52

  View details for PubMedID 28480114

  View details for PubMedCentralID PMC5402327

• Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma (vol 4, 28, 2016) JOURNAL FOR IMMUNOTHERAPY OF CANCER Patel, M. A., Kim, J. E., Theodros, D., Tam, A., Velarde, E., Kochel, C. M., Francica, B., Nirschl, T. R., Ghasemzadeh, A., Mathios, D., Harris-Bookman, S., Jackson, C. C., Jackson, C., Ye, X., Tran, P. T., Tyler, B., Coric, V., Selby, M., Brem, H., Drake, C. G., Pardoll, D. M., Lim, M. 2016; 4: 74

  Abstract

  [This corrects the article DOI: 10.1186/s40425-016-0132-2.].

  View details for DOI 10.1186/s40425-016-0181-6

  View details for Web of Science ID 000388043100001

  View details for PubMedID 27822377

  View details for PubMedCentralID PMC5096004

• ACT IV: AN INTERNATIONAL, DOUBLE-BLIND, PHASE 3 TRIAL OF RINDOPEPIMUT IN NEWLY DIAGNOSED, EGFRvIII-EXPRESSING GLIOBLASTOMA Weller, M., Butowski, N., Tran, D., Recht, L., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S., Iwamoto, F., Drappatz, J., O'Rourke, D., Wong, M., Finocchiaro, G., Perry, J., Wick, W., He, Y., Davis, T., Stupp, R., Sampson, J. OXFORD UNIV PRESS INC. 2016: 17–18

  View details for Web of Science ID 000398604101004

• The strategy of repeat stereotactic radiosurgery without whole brain radiation treatment for new brain metastases: Outcomes and implications for follow-up monitoring PRACTICAL RADIATION ONCOLOGY Shen, C. J., Rigamonti, D., Redmond, K. J., Kummerlowe, M. N., Lim, M., Kleinberg, L. R. 2016; 6 (6): 409–16

  Abstract

  Stereotactic radiosurgery (SRS) is widely used to treat brain metastases in place of whole brain radiation therapy (WBRT), with the goal of reducing treatment toxicity balanced against the risk of developing new metastases. We evaluated outcomes of repeated courses of SRS in the management of new brain metastases as an alternative to salvage WBRT.We conducted a single-institution retrospective review of 239 patients treated with SRS without WBRT for brain metastases from 2004 to 2014. Eighty-six patients received at least 2 courses of SRS for new brain metastases. Outcome metrics included survival, development of symptomatic new brain metastases, neurologic symptoms at death or last follow-up, and ultimate WBRT.Eighty-six patients (median age, 59 years) underwent a median of 2 courses of SRS (range, 2-6), with a median of 2 lesions treated initially and on retreatment. The median interval between SRS treatments was 5.8 months (range, 1.2-69.1). New brain metastases after initial radiosurgery were detected by routine imaging in 87% of cases. Median overall survival from repeat SRS was 13.0 months (range, 0.3-64.5) and from initial brain metastasis diagnosis 25.0 months (range, 2.0-68.1). On multivariate analysis, Eastern Cooperative Oncology Group performance status 0-1 (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.15-0.90; P=.029), controlled extracranial disease (HR, 0.35; 95% CI, 0.13-0.94; P=.038), and interval between initial and second SRS >6 months (HR, 0.49; 95% CI, 0.25-0.96; P=.037) correlated with improved overall survival from brain metastasis diagnosis. A total of 24.7% of patients had symptomatic intracranial metastatic disease at death or last follow-up, and 26.7% ultimately received WBRT.Repeated SRS is a reasonable option for patients with new brain metastases, as our results suggest favorable survival outcomes with this approach. New lesions infrequently caused neurologic symptoms before routine imaging detection, and a minority of patients had symptomatic intracranial disease at death or last follow-up.

  View details for DOI 10.1016/j.prro.2016.04.004

  View details for Web of Science ID 000387981000027

  View details for PubMedID 27687187

• NIVOLUMAB COMBINED WITH RADIOTHERAPY WITH OR WITHOUT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: RESULTS FROM PHASE 1 SAFETY COHORTS IN CHECKMATE 143 Omuro, A., Vlahovic, G., Baehring, J., Butowski, N., Reardon, D. A., Cloughesy, T., Sahebjam, S., Lim, M., Strauss, L., Latek, R., Zwirtes, R., Paliwal, P., Harbison, C., Sampson, J. OXFORD UNIV PRESS INC. 2016: 21

  View details for Web of Science ID 000398604101017

• PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB [DUR]) IN PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FOR COHORT B (DUR MONOTHERAPY), BEVACIZUMAB (BEV) NAIVE PATIENTS WITH RECURRENT GBM Reardon, D., Kaley, T., Dietrich, J., Lim, M., Dunn, G., Gan, H., Cloughesy, T., Clarke, J., Park, A., Macri, M., Ryan, A., Ricciardi, T., Reddy, V., Venhaus, R. OXFORD UNIV PRESS INC. 2016: 18

  View details for Web of Science ID 000398604101005

• MODULATING THE MYELOID COMPARTMENT TO POTENTIATE ANTI-PD1 MEDIATED IMMUNOTHERAPY AGAINST GLIOBLASTOMA Muvdi, T., Theodros, D., Carrera-Haro, M., Kim, E., Jackson, C., Luksik, A., Tyler, B., Brem, H., Padroll, D., Lim, M. OXFORD UNIV PRESS INC. 2016: 99

  View details for Web of Science ID 000398604102140

• Influence of Insurance Status on Survival of Adults With Glioblastoma Multiforme: A Population-Based Study CANCER Rong, X., Yang, W., Garzon-Muvdi, T., Caplan, J. M., Hui, X., Lim, M., Huang, J. 2016; 122 (20): 3157–65

  Abstract

  To the authors' knowledge, the impact of insurance status on the survival time of patients with glioblastoma multiforme (GBM) has not been fully understood. The objective of the current study was to clarify the association between insurance status and survival of patients with GBM by analyzing population-based data.The authors performed a cohort study using data from the Surveillance, Epidemiology, and End Results program. They included adult patients (aged ≥18 years) with GBM as their primary diagnosis from the years 2007 to 2012. Patients without information regarding insurance status were excluded. A survival analysis between insurance status and GBM-related death was performed using an accelerated failure time model. Demographic and clinical variables were included to adjust for confounding effects.Among the 13,665 adult patients in the study cohort, 558 (4.1%) were uninsured, 1516 (11.1%) had Medicaid coverage, and 11,591 (84.8%) had non-Medicaid insurance. Compared with patients who were uninsured, insured patients were more likely to be older, female, white, married, and with a smaller tumor size at diagnosis. Accelerated failure time analysis demonstrated that older age (hazard ratio [HR], 1.04; P<.001), male sex (HR, 1.08; P<.001), large tumor size at the time of diagnosis (HR, 1.26; P<.001), uninsured status (HR, 1.14; P =.018), and Medicaid insurance (HR, 1.10; P =.006) were independent risk factors for shorter survival among patients with GBM, whereas radiotherapy (HR, 0.40; P<.001) and married status (HR, 0.86; P<.001) indicated a better outcome. The authors discovered an overall yearly progressive improvement in survival in patients with non-Medicaid insurance who were diagnosed from 2007 through 2011 (P =.015), but not in uninsured or Medicaid-insured patients.Variations existed in insurance status within the GBM population. Uninsured status and Medicaid insurance suggested shorter survival compared with non-Medicaid insurance among a population of patients with GBM. Cancer 2016;122:3157-65. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30160

  View details for Web of Science ID 000388284500012

  View details for PubMedID 27500668

• Layered sellar reconstruction with avascular free grafts: Acceptable alternative to the nasoseptal flap for repair of low-volume intraoperative cerebrospinal fluid leak AMERICAN JOURNAL OF RHINOLOGY & ALLERGY Roxbury, C. R., Saavedra, T., Ramanathan, M., Lim, M., Ishii, M., Gallia, G. L., Reh, D. D. 2016; 30 (5): 367–71

  Abstract

  Although the nasoseptal flap has become the method of choice for reconstruction of intraoperative cerebrospinal fluid (CSF) leak in endoscopic minimally invasive surgery of the skull base, layered avascular graft techniques, including allografts and middle turbinate mucosal autografts, may provide comparable reconstructive success with decreased nasal morbidity.To describe a method of reconstruction of intraoperative CSF leak in endoscopic surgery of the sella turcica and analyze its postoperative success rate and associated comorbidities.A retrospective review of expanded endonasal sellar tumor resections from 2008-2014 was performed, and cases of layered intraoperative skull base reconstruction with avascular free grafts were identified. Demographic factors and comorbidities that predisposed to reconstruction failure (obstructive sleep apnea, obesity) were determined. Reconstruction-related nasal complications were also identified. Postoperative CSF leak rate was determined, and statistical analysis was performed to identify predictive factors for reconstructive failure.Seventy-three cases were identified. Layered closure with avascular free grafts was performed. There were five cases of postoperative CSF leak (6.85%). The mean follow-up was 19 months (range, 1-76 months). Intraoperative high-flow CSF leak was a significant predictor of reconstruction failure on univariate (odds ratio 22 [95% confidence interval, 2.26-214]; p = 0.008) and multivariate analysis (odds ratio 33.6 [95% confidence interval, 2.30-492]; p = 0.010). There were no significant differences in postoperative leak rates among bony overlay graft types. There were five patients (7.9%) who experienced persistent crusting after surgery. There were no significant differences in crusting rates between allografts and mucosal grafts. There were no postoperative mucoceles.In cases of low-volume intraoperative CSF leak, layered skull base repair with avascular free grafts was an acceptable alternative to the nasoseptal flap, which may reduce prolonged sinonasal healing and donor-site morbidities.

  View details for DOI 10.2500/ajra.2016.30.4356

  View details for Web of Science ID 000390854700018

  View details for PubMedID 27657903

• Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship CURRENT TREATMENT OPTIONS IN ONCOLOGY Shen, C. J., Lim, M., Kleinberg, L. R. 2016; 17 (9): 46

  Abstract

  With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed.

  View details for DOI 10.1007/s11864-016-0423-3

  View details for Web of Science ID 000381076500002

  View details for PubMedID 27447703

• Discussion on: Usefulness of an Osteotomy Template for Skull Tumorectomy and Simultaneous Skull Reconstruction JOURNAL OF CRANIOFACIAL SURGERY Gordon, C. R., Murphy, R. J., Armand, M., Liacouras, P., Weingart, J., Huang, J., Brem, H., Lim, M. 2016; 27 (6): 1568–70

  View details for DOI 10.1097/SCS.0000000000002999

  View details for Web of Science ID 000384271100078

  View details for PubMedID 27526253

  View details for PubMedCentralID PMC5014661

• Timely stereotactic body radiotherapy (SBRT) for spine metastases using a rapidly deployable automated planning algorithm SPRINGERPLUS Mian, O. Y., Thomas, O., Lee, J. Y., Le, Y., McNutt, T., Lim, M., Rigamonti, D., Wolinsky, J., Sciubba, D. M., Gokaslan, Z. L., Redmond, K., Kleinberg, L. 2016; 5: 1337

  Abstract

  The complex planning and quality assurance required for spine SBRT are a barrier to implementation in time-sensitive or limited resource clinical situations. We developed and validated an automated inverse planning algorithm designed to streamline planning and allow rapid delivery of conformal single fraction spine SBRT using widely available technology.The Rapid Spine (RaSp) automated script successfully generated single fraction SBRT plans for fourteen complex spinal lesions previously treated at a single high-volume institution. Automated RaSp plans were limited to 5 beams with a total of 15 segments (allowing calculation-based verification) and optimized based on RTOG 0631 objectives. Standard single fraction (16 Gy) stereotactic IMRT plans were generated for the same set of complex spinal lesions and used for comparison. A conservative 2 mm posterior isocenter shift was used to simulate minor set-up error.Automated plans were generated in under 5 min from target definition and had a mean dose to the PTV of 1663 cGy (SD 131.5), a dose to 90 % of PTV (D90) of 1358 cGy (SD 111.0), and a maximum point dose (Dmax) to the PTV of 2055 cGy (SD 195.2) on average. IMRT plans took longer to generate but yielded more favorable dose escalation with a mean dose to the PTV of 1891 cGy (SD 117.6), D90 of 1731 cGy (SD 126.5), and Dmax of 2218 cGy (SD 195.7). A 2 mm posterior shift resulted in a 20 % (SD 10.5 %) increase in cord dose for IMRT plans and a 10 % (SD 5.3 %) increase for RaSp plans. The 2 mm perturbation caused 3 cord dose violations for the IMRT plans and 1 violation for corresponding RaSp plans.The Rapid Spine plan method yields timely and dosimetrically reasonable SBRT plans which meet RTOG 0631 objectives and are suitable for rapid yet robust pretreatment quality assurance followed by expedited treatment delivery. RaSp plans reduce the tradeoff between rapid treatment and optimal dosimetry in urgent cases and limited resource situations.

  View details for DOI 10.1186/s40064-016-2961-3

  View details for Web of Science ID 000381642600022

  View details for PubMedID 27563532

  View details for PubMedCentralID PMC4981010

• A Systematic Analysis of the Reliability of Diffusion Tensor Imaging Tractography for Facial Nerve Imaging in Patients with Vestibular Schwannoma JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Ung, N., Mathur, M., Chung, L. K., Cremer, N., Pelargos, P., Frew, A., Thill, K., Mathur, I., Voth, B., Lim, M., Yang, I. 2016; 77 (4): 314–18

  Abstract

  Surgeons need to visualize the facial nerve reliably in relation to the vestibular schwannoma (VS) in surgical planning. Diffusion tensor imaging (DTI) tractography has enabled unprecedented in vivo preoperative visualization. We collected data to measure the accuracy of DTI for an accurate location of the nerve in preoperative VS resection planning. A PubMed search for relevant studies was conducted. Inclusion criteria were gross total resection of VS, preoperative DTI identification of the facial nerve, and intraoperative cranial nerve localization by the surgeon. Exclusion criteria were tumors other than VS and unsuccessful preoperative location of the cranial nerve. Accuracy rate was calculated by comparing the intraoperative and preoperative locations detailed by DTI. The query identified 38 cases of VS that fit our inclusion criteria. Overall, 89% had surgical findings that agreed with the DTI location of the facial nerve. Of these cases, 32 patients had a postoperative House-Brackmann grade I or II. Our findings suggest that DTI is a reliable method for facial nerve imaging. Implementation of this technique may help decrease facial nerve injury during surgery. Limitations and further studies are needed to better understand what factors correlate with successful location of the facial nerve and DTI in patients with VS.

  View details for DOI 10.1055/s-0035-1566303

  View details for Web of Science ID 000381047700010

  View details for PubMedID 27441156

  View details for PubMedCentralID PMC4949058

• Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Salzberg, S. L., Breitwieser, F. P., Kumar, A., Hao, H., Burger, P., Rodriguez, F. J., Lim, M., Quinones-Hinojosa, A., Gallia, G. L., Tornheim, J. A., Melia, M. T., Sears, C. L., Pardo, C. A. 2016; 3 (4): e251

  Abstract

  To determine the feasibility of next-generation sequencing (NGS) microbiome approaches in the diagnosis of infectious disorders in brain or spinal cord biopsies in patients with suspected CNS infections.In a prospective pilot study, we applied NGS in combination with a new computational analysis pipeline to detect the presence of pathogenic microbes in brain or spinal cord biopsies from 10 patients with neurologic problems indicating possible infection but for whom conventional clinical and microbiology studies yielded negative or inconclusive results.Direct DNA and RNA sequencing of brain tissue biopsies generated 8.3 million to 29.1 million sequence reads per sample, which successfully identified with high confidence the infectious agent in 3 patients for whom validation techniques confirmed the pathogens identified by NGS. Although NGS was unable to identify with precision infectious agents in the remaining cases, it contributed to the understanding of neuropathologic processes in 5 others, demonstrating the power of large-scale unbiased sequencing as a novel diagnostic tool. Clinical outcomes were consistent with the findings yielded by NGS on the presence or absence of an infectious pathogenic process in 8 of 10 cases, and were noncontributory in the remaining 2.NGS-guided metagenomic studies of brain, spinal cord, or meningeal biopsies offer the possibility for dramatic improvements in our ability to detect (or rule out) a wide range of CNS pathogens, with potential benefits in speed, sensitivity, and cost. NGS-based microbiome approaches present a major new opportunity to investigate the potential role of infectious pathogens in the pathogenesis of neuroinflammatory disorders.

  View details for DOI 10.1212/NXI.0000000000000251

  View details for Web of Science ID 000391168900003

  View details for PubMedID 27340685

  View details for PubMedCentralID PMC4907805

• Preface NEUROSURGERY CLINICS OF NORTH AMERICA Lee, J. K., Lim, M. 2016; 27 (3): IX

  View details for DOI 10.1016/j.nec.2016.05.001

  View details for Web of Science ID 000380577300001

  View details for PubMedID 27325004

• Stereotactic Radiosurgery: Treatment of Brain Metastasis Without Interruption of Systemic Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Shen, C. J., Kummerlowe, M. N., Redmond, K. J., Rigamonti, D., Lim, M. K., Kleinberg, L. R. 2016; 95 (2): 735–42

  Abstract

  To evaluate the prevalence, outcomes, and toxicities of concurrent delivery of systemic therapy with stereotactic radiosurgery (SRS) for treatment of brain metastases.We conducted a retrospective review of 193 patients treated at our institution with SRS without prior whole-brain radiation therapy (WBRT) for brain metastases between 2009 and 2014. Outcome metrics included administration of concurrent systemic therapy, myelosuppression, neurotoxicity, and survival.One hundred ninety-three patients with a median age of 61 years underwent a total of 291 SRS treatments. Thirty-seven percent of SRS treatments were delivered concurrently with systemic therapy, of which 46% were with conventional myelosuppressive chemotherapy, and 54% with targeted and immune therapy agents. Myelosuppression was minimal after treatment with both systemic therapy and SRS, with 14% grade 3-4 toxicity for lymphopenia and 4-9% for leukopenia, neutropenia, anemia, and thrombocytopenia. Neurotoxicity was also minimal after combined therapy, with no grade 4 and <5% grade 3 toxicity, 34% dexamethasone requirement, and 4% radiation necrosis, all similar to treatments with SRS alone. Median overall survival was similar after SRS alone (14.4 months) versus SRS with systemic therapy (12.9 months). In patients with a new diagnosis of primary cancer with brain metastasis, early treatment with concurrent systemic therapy and SRS correlated with improved survival versus SRS alone (41.6 vs 21.5 months, P<.05).Systemic therapy can be safely given concurrently with SRS for brain metastases: our results suggest minimal myelosuppression and neurotoxicity. Concurrent therapy is an attractive option for patients who have both intracranial and extracranial metastatic disease and may be particularly beneficial in patients with a new diagnosis of primary cancer with brain metastasis.

  View details for DOI 10.1016/j.ijrobp.2016.01.054

  View details for Web of Science ID 000375419800021

  View details for PubMedID 27034175

• Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 (durvalumab) in patients with glioblastoma (GBM). Reardon, D. A., Kaley, T., Dietrich, J., Lim, M., Dunn, G. P., Gan, H., Cloughesy, T., Clarke, J., Park, A. J., Macri, M. J., Ryan, A., Ricciardi, T., Reddy, V., Venhaus, R. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.TPS2080

  View details for Web of Science ID 000404665403067

• A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498. Sampson, J. H., Omuro, A., Preusser, M., Lim, M., Butowski, N. A., Cloughesy, T., Strauss, L. C., Latek, R., Paliwal, P., Weller, M., Reardon, D. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.TPS2079

  View details for Web of Science ID 000404665403066

• Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma JOURNAL FOR IMMUNOTHERAPY OF CANCER Patel, M. A., Kim, J. E., Theodros, D., Tam, A., Velarde, E., Kochel, C. M., Francica, B., Nirschl, T. R., Ghasemzadeh, A., Mathios, D., Harris-Bookman, S., Jackson, C. C., Jackson, C., Ye, X., Tran, P. T., Tyler, B., Coric, V., Selby, M., Brem, H., Drake, C. G., Pardoll, D. M., Lim, M. 2016; 4: 28

  Abstract

  Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.Mice received SRS and anti-GITR 10 days after implantation. The anti-GITR mAbs tested were formatted as mouse IgG1 D265A (anti-GITR (1)) and IgG2a (anti-GITR (2a)) isotypes. Mice were randomized to four treatment groups: (1) control; (2) SRS; (3) anti-GITR; (4) anti-GITR/SRS. SRS was delivered to the tumor in one fraction, and mice were treated with mAb thrice. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.Anti-GITR (1)/SRS significantly improved survival over either treatment alone (p < .0001) with a cure rate of 24 % versus 0 % in a T-lymphocyte-dependent manner. There was elevated intratumoral CD4+ effector cell infiltration relative to Treg infiltration in mice treated with anti-GITR (1)/SRS, as well as significantly elevated IFNγ and IL-2 production by CD4+ T-cells and elevated IFNγ and TNFα production by CD8+ T-cells. There was increased mRNA expression of M1 markers and decreased expression of M2 markers in tumor infiltrating mononuclear cells. The anti-GITR (2a)/SRS combination did not improve survival, induce tumor regression, or result in Treg depletion.These findings provide preclinical evidence for the use of anti-GITR (1) non-depleting antibodies in combination with SRS in GBM.

  View details for DOI 10.1186/s40425-016-0132-2

  View details for Web of Science ID 000376767800002

  View details for PubMedID 27190629

  View details for PubMedCentralID PMC4869343

• Current State of Immune-Based Therapies for Glioblastoma. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Lim, M., Weller, M., Chiocca, E. A. 2016: e132–e139

  Abstract

  Glioblastoma is one of the most aggressive solid tumors, and, despite treatment options such as surgery, radiation, and chemotherapy, its prognosis remains grim. Novel approaches are needed to improve survival. Immunotherapy has proven efficacy for melanoma, lung cancer, and kidney cancer and is now a focus for glioblastoma. In this article, glioblastoma-mediated immunosuppression will be discussed and two exciting immune approaches, checkpoint inhibitors and viral-based therapies, will be reviewed.

  View details for DOI 10.1200/EDBK_159084

  View details for PubMedID 30372353

• PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment (vol 121, pg 251, 2015) JOURNAL OF NEURO-ONCOLOGY Mathios, D., Ruzevick, J., Jackson, C. M., Xu, H., Shah, S. R., Taube, J. M., Burger, P. C., McCarthy, E. F., Quinones-Hinojosa, A., Pardoll, D. M., Lim, M. 2016; 128 (1): 183

  View details for DOI 10.1007/s11060-016-2130-0

  View details for Web of Science ID 000376095600022

  View details for PubMedID 27161248

• Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines PLOS ONE Binder, Z. A., Wilson, K. M., Salmasi, V., Orr, B. A., Eberhart, C. G., Siu, I., Lim, M., Weingart, J. D., Quinones-Hinojosa, A., Bettegowda, C., Kassam, A. B., Olivi, A., Brem, H., Riggins, G. J., Gallia, G. L. 2016; 11 (3)

  Abstract

  Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants.Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling.Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors.We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

  View details for DOI 10.1371/journal.pone.0150271

  View details for Web of Science ID 000373116500004

  View details for PubMedID 27028405

  View details for PubMedCentralID PMC4814135

• Laser speckle imaging to improve clinical outcomes for patients with trigeminal neuralgia undergoing radiofrequency thermocoagulation JOURNAL OF NEUROSURGERY Ringkamp, M., Wooten, M., Carson, B. S., Lim, M., Hartke, T., Guarnieri, M. 2016; 124 (2): 422–28

  Abstract

  Percutaneous treatments for trigeminal neuralgia are safe, simple, and effective for achieving good pain control. Procedural risks could be minimized by using noninvasive imaging techniques to improve the placement of the radiofrequency thermocoagulation probe into the trigeminal ganglion. Positioning of a probe is crucial to maximize pain relief and to minimize unwanted side effects, such as denervation in unaffected areas. This investigation examined the use of laser speckle imaging during probe placement in an animal model.This preclinical safety study used nonhuman primates, Macaca nemestrina (pigtail monkeys), to examine whether real-time imaging of blood flow in the face during the positioning of a coagulation probe could monitor the location and guide the positioning of the probe within the trigeminal ganglion.Data from 6 experiments in 3 pigtail monkeys support the hypothesis that laser imaging is safe and improves the accuracy of probe placement.Noninvasive laser speckle imaging can be performed safely in nonhuman primates. Because improved probe placement may reduce morbidity associated with percutaneous rhizotomies, efficacy trials of laser speckle imaging should be conducted in humans.

  View details for DOI 10.3171/2015.1.JNS14408

  View details for Web of Science ID 000368866300023

  View details for PubMedID 26274997

• Current State of Immune-Based Therapies for Glioblastoma. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Lim, M., Weller, M., Chiocca, E. A. 2016; 35: e132–9

  Abstract

  Glioblastoma is one of the most aggressive solid tumors, and, despite treatment options such as surgery, radiation, and chemotherapy, its prognosis remains grim. Novel approaches are needed to improve survival. Immunotherapy has proven efficacy for melanoma, lung cancer, and kidney cancer and is now a focus for glioblastoma. In this article, glioblastoma-mediated immunosuppression will be discussed and two exciting immune approaches, checkpoint inhibitors and viral-based therapies, will be reviewed.

  View details for DOI 10.14694/EDBK_159084

  View details for PubMedID 27249715

• Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model INTERNATIONAL JOURNAL OF CANCER Mathios, D., Park, C., Marcus, W. D., Alter, S., Rhode, P. R., Jeng, E. K., Wong, H. C., Pardoll, D. M., Lim, M. 2016; 138 (1): 187–94

  Abstract

  Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.

  View details for DOI 10.1002/ijc.29686

  View details for Web of Science ID 000363203600023

  View details for PubMedID 26174883

  View details for PubMedCentralID PMC4696021

• Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium JOURNAL OF IMMUNOLOGY RESEARCH Kim, E. S., Kim, J. E., Patel, M. A., Mangraviti, A., Ruzevick, J., Lim, M. 2016; 2016: 4683607

  Abstract

  Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.

  View details for DOI 10.1155/2016/4683607

  View details for Web of Science ID 000368461900001

  View details for PubMedID 26881264

  View details for PubMedCentralID PMC4736366

• Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM) Reardon, D. A., Dietrich, J., Kaley, T., Gan, H., Dunn, G. P., Cloughesy, T., Lim, M., Clarke, J., Park, A., Pang, L., Lai, D. W., Karakunnel, J., Robbins, P., Narwal, R., Venhaus, R. AMER ASSOC CANCER RESEARCH. 2016

  View details for DOI 10.1158/2326-6074.CRICIMTEATIAACR15-A046

  View details for Web of Science ID 000375484400041

• Ganetespib radiosensitization for liver cancer therapy CANCER BIOLOGY & THERAPY Chettiar, S. T., Malek, R., Annadanam, A., Nugent, K. M., Kato, Y., Wang, H., Cades, J. A., Taparra, K., Belcaid, Z., Ballew, M., Manmiller, S., Proia, D., Lim, M., Anders, R. A., Herman, J. M., Tran, P. T. 2016; 17 (4): 457–66

  Abstract

  Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33-1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.

  View details for DOI 10.1080/15384047.2016.1156258

  View details for Web of Science ID 000375583500016

  View details for PubMedID 26980196

  View details for PubMedCentralID PMC4910914

• Oligometastatic Adenocarcinoma of the Lung: A Therapeutic Opportunity for Long-Term Survival CUREUS Yarchoan, M., Lim, M., Brahmer, J. R., Ettinger, D. 2015; 7 (12): e409

  Abstract

  We report a case of oligometastatic non-small-cell lung cancer (NSCLC) in a 60-year-old male that was treated with both local and systemic therapies with an exceptional response to therapy. This case provides evidence that oligometastatic lung cancer, when treated with curative intent, may be an opportunity for long-term survival in select patients.

  View details for DOI 10.7759/cureus.409

  View details for Web of Science ID 000453608700017

  View details for PubMedID 26824009

  View details for PubMedCentralID PMC4725613

• Reduced CSF leak in complete calvarial reconstructions of microvascular decompression craniectomies using calcium phosphate cement JOURNAL OF NEUROSURGERY Eseonu, C. I., Goodwin, C., Zhou, X., Theodros, D., Bender, M. T., Mathios, D., Bettegowda, C., Lim, M. 2015; 123 (6): 1476–79

  Abstract

  Calcium phosphate cement provides a biomaterial that can be used for calvarial reconstruction in a retrosigmoid craniectomy for microvascular decompression (MVD). This study evaluates the outcomes of postoperative CSF leak and wound infection for patients undergoing a complete cranioplasty using calcium phosphate cement versus incomplete cranioplasty using polyethylene titanium mesh following a retrosigmoid craniectomy for MVD.The authors evaluated 211 cases involving patients who underwent first-time retrosigmoid craniectomies performed by a single attending surgeon fortrigeminal neuralgia from October 2008 to June 2014. From this patient population, 111 patients underwent calvarial reconstruction after retrosigmoid craniectomy using polyethylene titanium mesh, and 100 patients had reconstructions using calcium phosphate cement. A Pearson's chi-square test was used to compare postoperative complications of CSF leak and wound infection in these 2 types of cranioplasties.The polyethylene titanium mesh group included 5 patients (4.5%) with postoperative CSF leak or pseudomeningocele and 3 patients (2.7%) with wound infections. In the calcium phosphate cement group, no patients had a CSF leak, and 2 patients (2%) had wound infections. This represented a statistically significant reduction of postoperative CSF leak in patients who underwent calcium phosphate reconstructions of their calvarial defect compared with those who underwent polyethylene titanium mesh reconstructions (p = 0.03). No significant difference was seen between the 2 groups in the number of patients with postoperative wound infections.Calcium phosphate cement provides a viable alternative biomaterial for calvarial reconstruction of retrosigmoid craniectomy defects in patients who have an MVD. The application of this material provides a biocompatible barrier that reduces the incidence of postoperative CSF leaks.

  View details for DOI 10.3171/2015.1.JNS142102

  View details for Web of Science ID 000365372100016

  View details for PubMedID 26230465

  View details for PubMedCentralID PMC4856008

• Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy JOURNAL OF NEUROSURGERY-SPINE Puvanesarajah, V., Lo, S., Aygun, N., Liauw, J. A., Jusue-Torres, I., Lina, I. A., Hadelsberg, U., Elder, B. D., Bydon, A., Bettegowda, C., Sciubba, D. M., Wolinsky, J., Rigamonti, D., Kleinberg, L. R., Gokaslan, Z. L., Witham, T. F., Redmond, K. J., Lim, M. 2015; 23 (5): 620–29

  Abstract

  OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher.

  View details for DOI 10.3171/2015.2.SPINE14618

  View details for Web of Science ID 000363439600012

  View details for PubMedID 26230422

  View details for PubMedCentralID PMC4733601

• Immunomodulation: checkpoint blockade etc. NEURO-ONCOLOGY Curry, W. T., Lim, M. 2015; 17: 26–31

  Abstract

  The immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Checkpoint inhibitors manipulate the co-stimulatory response between antigen-presenting cells and immune cells-or between the tumor and immune cells-to elicit an antitumor immune response that would have otherwise been suppressed. Checkpoint inhibitors have shown great promise in the clinics, and some inhibitors such as anti-CTLA-4 antibodies and anti-PD-1 antibodies have gained FDA approval for certain tumors. Here we will discuss the current state of checkpoint inhibitors, biomarker strategies, and management of associated toxicities in glioblastoma.

  View details for DOI 10.1093/neuonc/nov174

  View details for Web of Science ID 000368421200006

  View details for PubMedID 26516223

  View details for PubMedCentralID PMC4625892

• Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy LANCET ONCOLOGY Sharabi, A. B., Lim, M., DeWeese, T. L., Drake, C. G. 2015; 16 (13): E498–E509

  Abstract

  Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.

  View details for DOI 10.1016/S1470-2045(15)00007-8

  View details for Web of Science ID 000361946300018

  View details for PubMedID 26433823

• Prospects of immune checkpoint modulators in the treatment of glioblastoma NATURE REVIEWS NEUROLOGY Preusser, M., Lim, M., Hafler, D. A., Reardon, D. A., Sampson, J. H. 2015; 11 (9): 504–14

  Abstract

  Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

  View details for DOI 10.1038/nrneurol.2015.139

  View details for Web of Science ID 000360967300005

  View details for PubMedID 26260659

  View details for PubMedCentralID PMC4782584

• Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wang, Y., Springer, S., Zhang, M., McMahon, K., Kinde, I., Dobbyn, L., Ptak, J., Brem, H., Chaichana, K., Gallia, G. L., Gokaslan, Z. L., Groves, M. L., Jallo, G. I., Lim, M., Olivi, A., Quinones-Hinojosa, A., Rigamonti, D., Riggins, G. J., Sciubba, D. M., Weingart, J. D., Wolinsky, J., Ye, X., Oba-Shinjo, S., Marie, S. N., Holdhoff, M., Agrawal, N., Diaz, L. A., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Bettegowda, C. 2015; 112 (31): 9704–9

  Abstract

  Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

  View details for DOI 10.1073/pnas.1511694112

  View details for Web of Science ID 000358930600069

  View details for PubMedID 26195750

  View details for PubMedCentralID PMC4534284

• Risk of surgical site infection in 401 consecutive patients with glioblastoma with and without carmustine wafer implantation NEUROLOGICAL RESEARCH Chaichana, K. L., Kone, L., Bettegowda, C., Weingart, J. D., Olivi, A., Lim, M., Quinones-Hinojosa, A., Gallia, G. L., Brem, H. 2015; 37 (8): 717–26

  Abstract

  Patients with glioblastoma (GBM) have an inherently shortened survival because of their disease. It has been recently shown that carmustine wafers in addition to other therapies (surgery, temozolomide, and radiation) can further extend survival. There is concern, however, that these therapies may increase infection risk. The goals of this study were to calculate the incidence of postoperative infection, evaluate if carmustine wafers changes the risk of infection and identify factors independently associated with an infection following GBM surgery.All patients who underwent non-biopsy, surgical resection of an intracranial GBM from 2007 to 2011 at a single institution were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify factors associated with infection, including the use of carmustine wafers. Variables with P < 0.05 were considered statistically significant.Four hundred and one patients underwent resection of an intracranial GBM during the reviewed period, and 21 (5%) patients developed an infection at a median time of 40 [28-286] days following surgery. The incidence of infection was not higher in patients who had carmustine wafers, and this remained true in multivariate analyses to account for differences in treatment cohorts. The factors that remained significantly associated with an increased risk of infection were prior surgery [RR (95% CI); 2.026 (1.473-4.428), P = 0.01], diabetes mellitus [RR (95% CI); 6.090 (1.380-9.354)], P = 0.02], and increasing duration of hospital stay [RR (95% CI); 1.048 (1.006-1.078); P = 0.02], where the greatest risk occurred with hospital stays > 5 days [RR (95% CI); 3.904 (1.003-11.620), P = 0.05].These findings may help guide treatment regimens aimed at minimizing infection for patients with GBM.

  View details for DOI 10.1179/1743132815Y.0000000042

  View details for Web of Science ID 000356891600009

  View details for PubMedID 25916669

• Immunosuppressive mechanisms of malignant gliomas: parallels at non-CNS sites FRONTIERS IN ONCOLOGY Perng, P., Lim, M. 2015; 5: 153

  Abstract

  The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa.

  View details for DOI 10.3389/fonc.2015.00153

  View details for Web of Science ID 000359149000001

  View details for PubMedID 26217588

  View details for PubMedCentralID PMC4492080

• Combining immunotherapy with radiation for the treatment of glioblastoma. Journal of neuro-oncology Chow, K. K., Hara, W., Lim, M., Li, G. 2015; 123 (3): 459-464

  Abstract

  Glioblastoma is a devastating cancer with universally poor outcomes in spite of current standard multimodal therapy. Immunotherapy is an attractive new treatment modality given its potential for exquisite specificity and its favorable side effect profile; however, clinical trials of immunotherapy in GBM have thus far shown modest benefit. Optimally combining radiation with immunotherapy may be the key to unlocking the potential of both therapies given the evidence that radiation can enhance anti-tumor immunity. Here we review this evidence and discuss considerations for combined therapy.

  View details for DOI 10.1007/s11060-015-1762-9

  View details for PubMedID 25877468

• Technical note: Orbitozygomatic craniotomy using an ultrasonic osteotome for precise osteotomies CLINICAL NEUROLOGY AND NEUROSURGERY Ruzevick, J., Raza, S. M., Recinos, P. F., Chaichana, K., Pradilla, G., Kim, J. E., Olivi, A., Weingart, J., Evans, J., Quinones-Hinojosa, A., Lim, M. 2015; 134: 24–27

  Abstract

  The orbitozygomatic craniotomy is a fundamental procedure in neurosurgery, allowing access to orbital and skull base pathology.Determine the feasibility of using an ultrasonic osteotome to safely perform orbitozygomatic osteotomies in patients with intracranial pathology.The medical records of patients undergoing orbitozygomatic craniotomy using an ultrasonic osteotome (Aesculap BoneScalpel™) for tumor resection at Johns Hopkins Hospital between November 2009 and March 2013 were retrospectively reviewed.Six patients underwent orbitozygomatic craniotomy for tumor resection using an ultrasonic osteotome at the Johns Hopkins Hospital during the study period. All patients were female and the average age was 53.2 years. Patients were followed for an average of 375 days. There were two cases of transient diplopia. There were no cases of periorbital violation, orbital injury, enophthalmos, or orbital hematoma. Post-operative imaging showed the cuts were well opposed and no cosmetic issues were encountered.Use of an ultrasonic osteotome allows for precise cuts under direct visualization with minimal risk to critical adjacent structures in our cohort of patients undergoing a two-piece orbitozygomatic craniotomy. This appears to be a safe instrument for osteotomy creation in skull base approaches.

  View details for DOI 10.1016/j.clineuro.2015.04.005

  View details for Web of Science ID 000356550300006

  View details for PubMedID 25935127

  View details for PubMedCentralID PMC4696035

• The role of checkpoints in the treatment of GBM JOURNAL OF NEURO-ONCOLOGY Kim, J. E., Lim, M. 2015; 123 (3): 413–23

  Abstract

  Targeted immunotherapy is founded on the principle that augmentation of effector T cell activity in the tumor microenvironment can translate to tumor regression. Targeted checkpoint inhibitors in the form of agonist or antagonist monoclonal antibodies have come to the fore as a promising strategy to activate systemic immunity and enhance T cell activity by blocking negative signals, enhancing positive signals, or altering the cytokine milieu. This review will examine several immune checkpoints and checkpoint modulators that play a role in cancer pathogenesis, with an emphasis on malignant gliomas.

  View details for DOI 10.1007/s11060-015-1747-8

  View details for Web of Science ID 000358160000011

  View details for PubMedID 25749875

  View details for PubMedCentralID PMC4750481

• Introduction: brain tumor immunotherapy JOURNAL OF NEURO-ONCOLOGY Lim, M., Liau, L. M. 2015; 123 (3): 321–22

  View details for DOI 10.1007/s11060-015-1848-4

  View details for Web of Science ID 000358160000001

  View details for PubMedID 26113108

  View details for PubMedCentralID PMC4515570

• Immediate Single-Stage Cranioplasty Following Calvarial Resection for Benign and Malignant Skull Neoplasms Using Customized Craniofacial Implants JOURNAL OF CRANIOFACIAL SURGERY Berli, J. U., Thomaier, L., Zhong, S., Huang, J., Quinones, A., Lim, M., Weingart, J., Brem, H., Gordon, C. R. 2015; 26 (5): 1456–62

  Abstract

  Craniectomy defects following resection of calvarial lesions are most often reconstructed using on-table manufacturing. With the advent of computer-aided design/manufacturing and customized craniofacial implants (CCIs), there seems to be more suited alternatives. In this study, the authors report their institutional experience and outcome using immediate, single-stage, CCI-based reconstruction for benign and malignant skull neoplasm defects.A retrospective review of a prospectively maintained database of all implant cranioplasties performed between 2011 and 2014, by a single craniofacial surgeon at a tertiary academic medical institution was performed. Preoperative and postoperative computed tomography scans with 3D reconstruction were performed for the purpose of assessing adequate resection and reconstructive outcomes. Primary endpoints included length of surgery, predicted defect versus postoperative implant surface area, contour irregularities, and complications.Of the 108 patients with cranioplasty identified, 7 patients were found to undergo immediate CCI-based reconstruction for calvarial neoplasms; 4 patients (4/7, 57%) presented with malignant pathology. All defects were >5  cm2. As compared with their original size, all implants were modified intraoperatively between 0.2% and 40.8%, with a mean of 13.8%. With follow-up ranging between 1 and 16 months, there were no implant-related complications identified. The immediate and long-term aesthetic results, as well as patient satisfaction, were ideal.With this preliminary experience, the authors have successfully demonstrated that immediate customized implant reconstructive techniques, by way of intraoperative modification, are both safe and feasible for benign and malignant skull neoplasms. The authors believe that with wider acceptance of this multidisciplinary approach and increased surgeon familiarity, this technique will soon become the reconstructive standard of care.

  View details for DOI 10.1097/SCS.0000000000001816

  View details for Web of Science ID 000369611000047

  View details for PubMedID 26163837

• Immunotherapy for glioblastoma: are we finally getting closer? NEURO-ONCOLOGY Lim, M. 2015; 17 (6): 771–72

  View details for DOI 10.1093/neuonc/nov070

  View details for Web of Science ID 000356265100002

  View details for PubMedID 25964313

  View details for PubMedCentralID PMC4483131

• Phase II study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM). Reardon, D. A., Dietrich, J., Kaley, T., Gan, H., Dunn, G. P., Cloughesy, T., Lim, M., Clarke, J., Park, A. J., Pan, L. S., Lai, D. W., Karakunnel, J., Robbins, P. B., Narwal, R., Venhaus, R. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.tps2077

  View details for Web of Science ID 000358036904674

• Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy Bloch, O., Raizer, J. J., Lim, M., Sughrue, M., Komotar, R., Abrahams, J., O'Rourke, D., D'Ambrosio, A., Bruce, J. N., Parsa, A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.2011

  View details for Web of Science ID 000358036900470

• Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. Sampson, J. H., Vlahovic, G., Sahebjam, S., Omuro, A., Baehring, J. M., Hafler, D. A., Voloschin, A., Paliwal, P., Grosso, J., Coric, V., Cloughesy, T. F., Lim, M., Reardon, D. A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.3010

  View details for Web of Science ID 000358036900644

• Stereotactic Radiation Therapy Combined With Immunotherapy: Augmenting the Role of Radiation in Local and Systemic Treatment ONCOLOGY-NEW YORK Sharabi, A. B., Tran, P. T., Lim, M., Drake, C. G., DeWeese, T. L. 2015; 29 (5): 331–40

  Abstract

  Stereotactic radiosurgery and stereotactic body radiation therapy are two contemporary radiation modalities that can treat tumors in any area of the body using highly focused radiation. Recently, immunotherapy has established itself as a viable and powerful anticancer treatment. In this review we detail the rationale supporting a combination of immunotherapy and stereotactic radiation. Additionally, we discuss the evidence for the immune stimulatory effects of focused radiation and the role that radiation may play in enhancing the systemic treatment effects of immunotherapy.

  View details for Web of Science ID 000355064600002

  View details for PubMedID 25979541

  View details for PubMedCentralID PMC4814161

• Neurosurgery concepts: Key perspectives on dendritic cell vaccines, metastatic tumor treatment, and radiosurgery. Surgical neurology international Li, G. n., Sherman, J. H., Cho, J. M., Lim, M. n., Khalessi, A. A., Colen, C. B., Kim, C. Y., Wang, V. Y., Zada, G. n., Smith, Z. A., Yang, I. n. 2015; 6: 6

  Abstract

  This is a laboratory study to investigate the effect of adding brain-derived-neurotrophic factor (BDNF) in a poly (N-isopropylacrylamide-g-poly (ethylene glycol) scaffold and its effect on spinal cord injury in a rat model.This is a laboratory investigation of a spinal cord injury in a rat model. A dorsolateral funiculotomy was used to disrupt the dorsolateral funiculus and rubrospinal tract. Animals were then injected with either the scaffold polymer or scaffold polymer with BDNF. Postoperatively, motor functions were assessed with single pellet reach to grasp task, stair case reaching task and cylinder task. Histological study was also performed to look at extent of glial scar and axonal growth.Animals received BDNF containing polymer had an increased recovery rate of fine motor function of forelimb, as assessed by stair case reaching task and single pellet reach to grasp task compared with control animals that received the polymer only. There is no significant difference in the glial scar formation. BDNF treated animals also had increased axon growth including increase in the number and length of the rubrospinal tract axons.BDNF delivered via a scaffold polymer results in increased recovery rate in forelimb motor function in an experimental model of spinal cord injury, possibly through a promotion of growth of axons of the rubrospinal tract.

  View details for DOI 10.4103/2152-7806.149389

  View details for PubMedID 25657859

• Neurocytoma of the Spinal Cord NEUROSURGERY CLINICS OF NORTH AMERICA Kim, J. E., Lim, M. 2015; 26 (1): 109-+

  Abstract

  This article presents an overview of spinal neurocytomas. A rare manifestation of an uncommon tumor, extraventricular neurocytomas (EVNs) should be included in the differential for spinal intradural and intramedullary tumors. Spinal EVNs are generally benign with an indolent pathologic course but may display a variety of acute or chronic clinical behaviors, depending on their anatomic location. Only a handful of spinal EVNs have been described in the literature, often in the form of individual case reports or small case series. Discussion includes a review of the literature and an overview of the clinical, pathologic, and radiologic features of this rare tumor type, as well as the differential diagnosis, treatment options, and general prognosis.

  View details for DOI 10.1016/j.nec.2014.09.005

  View details for Web of Science ID 000346620900015

  View details for PubMedID 25432190

• PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment JOURNAL OF NEURO-ONCOLOGY Mathios, D., Ruzevick, J., Jackson, C. M., Xu, H., Shah, S., Taube, J. M., Burger, P. C., McCarthy, E. F., Quinones-Hinojosa, A., Pardoll, D. M., Lim, M. 2015; 121 (2): 251–59

  Abstract

  Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

  View details for DOI 10.1007/s11060-014-1637-5

  View details for Web of Science ID 000349010200003

  View details for PubMedID 25349132

  View details for PubMedCentralID PMC4322919

• Pituitary adenomas: historical perspective, surgical management and future directions. CNS oncology Theodros, D., Patel, M., Ruzevick, J., Lim, M., Bettegowda, C. 2015; 4 (6): 411–29

  Abstract

  Pituitary adenomas are among the most common central nervous system tumors. They represent a diverse group of neoplasms that may or may not secrete hormones based on their cell of origin. Epidemiologic studies have documented the incidence of pituitary adenomas within the general population to be as high as 16.7%. A growing body of work has helped to elucidate the pathogenesis of these tumors. Each subtype has been shown to demonstrate unique cellular changes potentially leading to tumorigenesis. Surgical advancements over several decades have included microsurgery and the employment of the endoscope for surgical resection. These advancements increase the likelihood of gross-total resection and have resulted in decreased patient morbidity.

  View details for DOI 10.2217/cns.15.21

  View details for PubMedID 26497533

• Metastatic Extrapulmonary Small Cell Carcinoma to the Cerebellopontine Angle: A Case Report and Review of the Literature CASE REPORTS IN ONCOLOGICAL MEDICINE Theodros, D., Goodwin, C., Crane, G. M., Liauw, J., Kleinberg, L., Lim, M. 2015: 847058

  Abstract

  Extrapulmonary small cell carcinomas (EPSCC) are rare malignancies with poor patient prognoses. We present the case of a 63-year-old male who underwent surgical resection of a poorly differentiated small cell carcinoma, likely from a small intestinal primary tumor that metastasized to the cerebellopontine angle (CPA). A 63-year-old male presented with mild left facial paralysis, hearing loss, and balance instability. MRI revealed a 15 mm mass in the left CPA involving the internal auditory canal consistent with a vestibular schwannoma. Preoperative MRI eight weeks later demonstrated marked enlargement to 35 mm. The patient underwent a suboccipital craniectomy and the mass was grossly different visually and in consistency from a standard vestibular schwannoma. The final pathology revealed a poorly differentiated small cell carcinoma. Postoperative PET scan identified avid uptake in the small intestine suggestive of either a small intestinal primary tumor or additional metastatic disease. The patient underwent whole brain radiation therapy and chemotherapy and at last follow-up demonstrated improvement in his symptoms. Surgical resection and radiotherapy are potential treatment options to improve survival in patients diagnosed with NET brain metastases. We present the first documented case of skull base metastasis of a poorly differentiated small cell carcinoma involving the CPA.

  View details for DOI 10.1155/2015/847058

  View details for Web of Science ID 000365497100001

  View details for PubMedID 25810937

  View details for PubMedCentralID PMC4355812

• Antiangiogenic Therapies and Extracranial Metastasis in Glioblastoma: A Case Report and Review of the Literature CASE REPORTS IN ONCOLOGICAL MEDICINE Khattab, M. H., Marciscano, A. E., Lo, S. S., Lim, M., Laterra, J. J., Kleinberg, L. R., Redmond, K. J. 2015: 431819

  Abstract

  We present a case report of a patient with glioblastoma multiforme (GBM) complicated by extracranial metastasis (ECM) whose survival of nearly four years surpassed the anticipated life expectancy given numerous negative prognostic factors including EGFRvIII-mutation, unmethylated MGMT promoter status, and ECM. Interestingly, while this patient suffered from locally aggressive disease with multiple intracranial recurrences, the proximal cause of death was progressive extracranial disease and complications related to pulmonary metastases. Herein, we review potential mechanisms of ECM with an emphasis upon glioblastoma molecular and genetic profiles and the potential implications of targeted agents such as bevacizumab.

  View details for DOI 10.1155/2015/431819

  View details for Web of Science ID 000365498300001

  View details for PubMedID 26199775

  View details for PubMedCentralID PMC4493308

• The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy CANCERS Patel, M. A., Kim, J. E., Ruzevick, J., Li, G., Lim, M. 2014; 6 (4): 1953-1985

  Abstract

  The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

  View details for DOI 10.3390/cancers6041953

  View details for Web of Science ID 000209950800005

• Management of Cerebral Brain Metastasis CURRENT SURGERY REPORTS Patel, M. A., Ruzevick, J., Lim, M. 2014; 2 (12)

  View details for DOI 10.1007/s40137-014-0074-x

  View details for Web of Science ID 000218721500001

• PD-1 BLOCKADE SHOWS SYNERGISTIC SURVIVAL, ANTI-TUMOR IMMUNE RESPONSE AND LONG-TERM MEMORY WITH INTERSTITIAL BUT NOT SYSTEMIC CHEMOTHERAPY: STUDY IN A MURINE GLIOBLASTOMA MODEL Mathios, D., Phallen, J., Park, C., Jackson, C., Nicholas, S., Tyler, B., Pardoll, D., Brem, H., Lim, M. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou258.19

  View details for Web of Science ID 000350452200459

• Planning Evaluation of C-Arm Cone Beam CT Angiography for Target Delineation in Stereotactic Radiation Surgery of Brain Arteriovenous Malformations INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Kang, J., Huang, J., Gailloud, P., Rigamonti, D., Lim, M., Bernard, V., Ehtiati, T., Ford, E. C. 2014; 90 (2): 430–37

  Abstract

  Stereotactic radiation surgery (SRS) is one of the therapeutic modalities currently available to treat cerebral arteriovenous malformations (AVM). Conventionally, magnetic resonance imaging (MRI) and MR angiography (MRA) and digital subtraction angiography (DSA) are used in combination to identify the target volume for SRS treatment. The purpose of this study was to evaluate the use of C-arm cone beam computed tomography (CBCT) in the treatment planning of SRS for cerebral AVMs.Sixteen consecutive patients treated for brain AVMs at our institution were included in this retrospective study. Prior to treatment, all patients underwent MRA, DSA, and C-arm CBCT. All images were coregistered using the GammaPlan planning system. AVM regions were delineated independently by 2 physicians using either C-arm CBCT or MRA, resulting in 2 volumes: a CBCT volume (VCBCT) and an MRA volume (VMRA). SRS plans were generated based on the delineated regions.The average volume of treatment targets delineated using C-arm CBCT and MRA were similar, 6.40 cm(3) and 6.98 cm(3), respectively (P=.82). However, significant regions of nonoverlap existed. On average, the overlap of the MRA with the C-arm CBCT was only 52.8% of the total volume. In most cases, radiation plans based on VMRA did not provide adequate dose to the region identified on C-arm CBCT; the mean minimum dose to VCBCT was 29.5%, whereas the intended goal was 45% (P<.001). The mean volume of normal brain receiving 12 Gy or more in C-arm CBCT-based plans was not greater than in the MRA-based plans.Use of C-arm CBCT images significantly alters the delineated regions of AVMs for SRS planning, compared to that of MRA/MRI images. CT-based planning can be accomplished without increasing the dose to normal brain and may represent a more accurate definition of the nidus, increasing the chances for successful obliteration.

  View details for DOI 10.1016/j.ijrobp.2014.05.035

  View details for Web of Science ID 000341994400028

  View details for PubMedID 25015197

  View details for PubMedCentralID PMC4857200

• Selective cerebral hypothermia induced via hypothermic retrograde jugular vein saline flush in a porcine model NEUROLOGICAL RESEARCH Chen, C., Puvanesarajah, V., Lo, S. L., Cheng, T., Cheng, C., Lim, M., Lin, H. 2014; 36 (10): 897–902

  Abstract

  Multiple methods of selective brain cooling have been used to prevent cerebral ischemia secondary to trauma and pathological or iatrogenic cerebral blood flow restriction. In this study, we tested the efficacy of hypothermic retrograde jugular vein flush (HRJVF) in eliciting selective brain hypothermia in a porcine model.Twelve swine were divided into two groups: retrograde jugular vein infusion (RJVI) with cold saline (4°C RJVI, n  =  6) and with room temperature saline (24°C RJVI, n  =  6). For 90 minutes, the following parameters were measured: brain parenchymal temperature, rectal temperature, intracranial pressure (ICP), mean arterial pressure, and heart rate (HR).Swine receiving 4°C RJVI experienced a drop in mean brain parenchymal temperature of 1·1 ± 0·1°C, compared to 0·1 ± 0·1°C in swine receiving 24°C RJVI. At 90 minutes, mean brain parenchymal temperature in the 4°C RJVI treatment group was 35·5 ± 0·2°C, as compared to 37·1 ± 0·2°C in the 24°C RJVI treatment group (P < 0·001). In the 4°C RJVI group, the brain-systemic temperature gradient peaked 10 minutes after initiation of cooling and remained significantly different when comparing the two experimental groups (P < 0·001) throughout the duration of the 90 minutes experiment. Of note, ICP, mean arterial pressure, and HR remained constant without any significant changes or differences between treatment groups.These results suggest that HRJVF is an effective method for selective brain hypothermia in a large animal model. Clinical application may prove effective in delaying neural ischemia.

  View details for DOI 10.1179/1743132814Y.0000000374

  View details for Web of Science ID 000341397500007

  View details for PubMedID 24725291

• TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting CANCER RESEARCH Herrmann, A., Cherryholmes, G., Schroeder, A., Phallen, J., Alizadeh, D., Xin, H., Wang, T., Lee, H., Lahtz, C., Swiderski, P., Armstrong, B., Kowolik, C., Gallia, G. L., Lim, M., Brown, C., Badie, B., Forman, S., Kortylewski, M., Jove, R., Yu, H. 2014; 74 (18): 5218–28

  Abstract

  Understanding supports for cancer stem-like cells in malignant glioma may suggest therapeutic strategies for their elimination. Here, we show that the Toll-like receptor TLR9 is elevated in glioma stem-like cells (GSC) in which it contributes to glioma growth. TLR9 overexpression is regulated by STAT3, which is required for GSC maintenance. Stimulation of TLR9 with a CpG ligand (CpG ODN) promoted GSC growth, whereas silencing TLR9 expression abrogated GSC development. CpG-ODN treatment induced Frizzled4-dependent activation of JAK2, thereby activating STAT3. Targeted delivery of siRNA into GSC was achieved via TLR9 using CpG-siRNA conjugates. Through local or systemic treatment, administration of CpG-Stat3 siRNA to silence STAT3 in vivo reduced GSC along with glioma growth. Our findings identify TLR9 as a functional marker for GSC and a target for the delivery of efficacious therapeutics for glioma treatment. Cancer Res; 74(18); 5218-28. ©2014 AACR.

  View details for DOI 10.1158/0008-5472.CAN-14-1151

  View details for Web of Science ID 000342358300024

  View details for PubMedID 25047528

  View details for PubMedCentralID PMC4167470

• Technical Nuances of Microvascular Decompression of the Posterior Fossa Cranial Nerves: 3-Dimensional Operative Video OPERATIVE NEUROSURGERY Binning, M. J., Veznedaroglu, E. 2014; 10 (3): 487

  View details for Web of Science ID 000209565600040

  View details for PubMedID 24983440

• Immunotherapy for Brain Cancer: Recent Progress and Future Promise CLINICAL CANCER RESEARCH Jackson, C. M., Lim, M., Drake, C. G. 2014; 20 (14): 3651–59

  Abstract

  Immunotherapy is emerging as the newest pillar of cancer treatment, with the potential to assume a place alongside surgical debulking, radiotherapy, and chemotherapy. Early experiences with antitumor vaccines demonstrated the feasibility and potential efficacy of this approach, and newer agents, such as immune checkpoint blocking antibodies and modern vaccine platforms, have ushered in a new era. These efforts are headlined by work in melanoma, prostate cancer, and renal cell carcinoma; however, substantial progress has been achieved in a variety of other cancers, including high-grade gliomas. A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiotherapy and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also use an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas, and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology.

  View details for DOI 10.1158/1078-0432.CCR-13-2057

  View details for Web of Science ID 000339611500006

  View details for PubMedID 24771646

  View details for PubMedCentralID PMC4729210

• Focal Radiation Therapy Combined with 4-1BB Activation and CTLA-4 Blockade Yields Long-Term Survival and a Protective Antigen-Specific Memory Response in a Murine Glioma Model PLOS ONE Belcaid, Z., Phallen, J. A., Zeng, J., See, A. P., Mathios, D., Gottschalk, C., Nicholas, S., Kellett, M., Ruzevick, J., Jackson, C., Albesiano, E., Durham, N. M., Ye, X., Tran, P. T., Tyler, B., Wong, J. W., Brem, H., Pardoll, D. M., Drake, C. G., Lim, M. 2014; 9 (7): e101764

  Abstract

  Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model.GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors.Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response.Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.

  View details for DOI 10.1371/journal.pone.0101764

  View details for Web of Science ID 000339378400036

  View details for PubMedID 25013914

  View details for PubMedCentralID PMC4094423

• Identifying Better Surgical Candidates Among Recursive Partitioning Analysis Class 2 Patients who Underwent Surgery for Intracranial Metastases WORLD NEUROSURGERY Chaichana, K. L., Acharya, S., Flores, M., Wijesekera, O., Rigamonti, D., Weingart, J. D., Olivi, A., Bettegowda, C., Gallia, G. L., Brem, H., Lim, M., Quinones-Hinojosa, A. 2014; 82 (1-2): E267–E275

  Abstract

  The management of patients with brain metastases is typically dependent on their prognosis. Recursive partitioning analysis (RPA) is the most commonly used method for prognosticating survival, but has limitations for patients in the intermediate class. The aims of this study were to ascertain preoperative risk factors associated with survival, develop a preoperative prognostic grading system, and evaluate the utility of this system in predicting survival for RPA class 2 patients.Adult patient who underwent intracranial metastatic tumor surgery at an academic tertiary care institution from 1997 to 2011 were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify preoperative factors associated with survival. The identified associations were then used to develop a grading system. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analyses.A total of 421 (59%) of 708 patients were RPA class 2. The preoperative factors found to be associated with poorer survival were: male gender (P < 0.0001), motor deficit (P = 0.0007), cognitive deficit (P = 0.0004), nonsolitary metastases (P = 0.002), and tumor size >2 cm (P = 0.003). Patients having 0-1, 2, and 3-5 of these variables were assigned a preoperative grade of A, B, and C, respectively. Patients with a preoperative grade of A, B, and C had a median survival of 17.0, 10.3, and 7.3 months, respectively. These grades had distinct survival times (P < 0.05).The present study devised a preoperative grading system that may provide prognostic information for RPA class 2 patients, which may also guide medical and surgical therapies before any intervention is pursued.

  View details for DOI 10.1016/j.wneu.2013.08.031

  View details for Web of Science ID 000342911400070

  View details for PubMedID 24076052

  View details for PubMedCentralID PMC3995859

• DIFFERENTIAL EXPRESSION OF PD-L1 ON HEMATOPOIETIC VERSUS TUMOR CELLS IN MEDULLOBLASTOMA Martin, A. M., Nirschl, C., Polanczyk, M., Bell, R., Martinez, D., Sullivan, L. M., Santi, M., Burger, P. C., Taube, J. M., Drake, C. G., Pardoll, D. M., Lim, M. OXFORD UNIV PRESS INC. 2014: 89

  View details for Web of Science ID 000337924200339

• Multidisciplinary Approach for Improved Outcomes in Secondary Cranial Reconstruction: Introducing the Pericranial-Onlay Cranioplasty Technique OPERATIVE NEUROSURGERY Gordon, C. R., Fisher, M., Liauw, J., Lina, I., Puvanesarajah, V., Susarla, S., Coon, A., Lim, M., Quinones-Hinojosa, A., Weingart, J., Colby, G., Olivi, A., Huang, J. 2014; 10 (2): 179–89

  Abstract

  Although materials for secondary cranial reconstruction have evolved with time, the overall approach in terms of bone flap/implant reconstruction after necessary delay has remained constant.To present our cases series of 50 consecutive secondary cranial reconstruction patients and to describe a multidisciplinary cranioplasty approach developed to reduce morbidity, to minimize infection, and to improve aesthetic appearance.Standard technique teaches us to place the bone flap and/or alloplastic implant directly over the dura or dural protectant after scalp flap re-elevation. However, this procedure is fraught with high complication rates, including infection. While raising the previously incised scalp flap overlying the full-thickness calvarial defect, the dissection is performed within the loose areolar tissue plane beneath the galea aponeurosis, thus leaving vascularized pericranium intact over the dura.A total of 50 consecutive patients were treated by the senior author encompassing 46 cranioplasties using the pericranial-onlay approach, along with 4 isolated temporal soft tissue reconstructions with liquid poly-methyl-methacrylate. Of the 46 cranioplasties (> 5 cm), only 1 autologous bone flap developed deep infection necessitating bone flap removal (1 of 46, 2.17%; 95% confidence interval, 0.003-11.3). None of the alloplastic custom implants placed have developed any infection requiring removal.This multidisciplinary approach illustrated in our case series, including our "pericranial-onlay" technique described here for the first time, has the potential to improve patient outcomes, to decrease perioperative morbidity, and to minimize costs associated with postoperative infections after secondary cranial reconstruction.

  View details for DOI 10.1227/NEU.0000000000000296

  View details for Web of Science ID 000489098100013

  View details for PubMedID 24448187

  View details for PubMedCentralID PMC4703091

• Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression? FUTURE ONCOLOGY Walker, A. J., Ruzevick, J., Malayeri, A. A., Rigamonti, D., Lim, M., Redmond, K. J., Kleinberg, L. 2014; 10 (7): 1277–97

  Abstract

  A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms--acute, subacute and late--and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem.

  View details for DOI 10.2217/fon.13.271

  View details for Web of Science ID 000337946000020

  View details for PubMedID 24947265

  View details for PubMedCentralID PMC4325371

• alpha 5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth ACTA NEUROPATHOLOGICA Sengupta, S., Weeraratne, S. D., Sun, H., Phallen, J., Rallapalli, S. K., Teider, N., Kosaras, B., Amani, V., Pierre-Francois, J., Tang, Y., Brian Nguyen, B., Yu, F., Schubert, S., Balansay, B., Mathios, D., Lechpammer, M., Archer, T. C., Phuoc Tran, P., Reimer, R. J., Cook, J. M., Lim, M., Jensen, F. E., Pomeroy, S. L., Cho, Y. 2014; 127 (4): 593-603

  Abstract

  Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.

  View details for DOI 10.1007/s00401-013-1205-7

  View details for Web of Science ID 000332957400010

• Invasive adenoma and pituitary carcinoma: a SEER database analysis NEUROSURGICAL REVIEW Hansen, T. M., Batra, S., Lim, M., Gallia, G. L., Burger, P. C., Salvatori, R., Wand, G., Quinones-Hinojosa, A., Kleinberg, L., Redmond, K. J. 2014; 37 (2): 279–85

  Abstract

  Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5 years (p = 0.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas (p = 0.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30 years (p = 0.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches.

  View details for DOI 10.1007/s10143-014-0525-y

  View details for Web of Science ID 000333027200024

  View details for PubMedID 24526366

  View details for PubMedCentralID PMC4322934

• The role of regulatory T-cells in glioma immunology CLINICAL NEUROLOGY AND NEUROSURGERY Ooi, Y., Tran, P., Ung, N., Thill, K., Trang, A., Fong, B. M., Nagasawa, D. T., Lim, M., Yang, I. 2014; 119: 125–32

  Abstract

  Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients may be attributed to the immunosuppressed microenvironment that is characteristic of invasive glioma. Regulatory T-cells (Tregs) are immunosuppressive T-cells that normally prevent autoimmunity when the human immune response is evoked; however, there have been strong correlations between glioma-induced immunosuppression and Tregs. In fact, induction of Treg activity has been correlated with glioma development in both murine models and patients. While the exact mechanisms by which regulatory T-cells function require further elucidation, various cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TFG-β) have been implicated in these processes and are currently under investigation. In addition, hypoxia is characteristic of tumor development and is also correlated with downstream induction of Tregs. Due to the poor prognosis associated with immunosuppression in glioma patients, Tregs remain a promising area for immunotherapeutic research.

  View details for DOI 10.1016/j.clineuro.2013.12.004

  View details for Web of Science ID 000334138000026

  View details for PubMedID 24582432

• STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications CANCERS Kim, J. E., Patel, M., Ruzevick, J., Jackson, C. M., Lim, M. 2014; 6 (1): 376–95

  Abstract

  Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.

  View details for DOI 10.3390/cancers6010376

  View details for Web of Science ID 000209950500020

  View details for PubMedID 24518612

  View details for PubMedCentralID PMC3980601

• Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies SCIENCE TRANSLATIONAL MEDICINE Bettegowda, C., Sausen, M., Leary, R. J., Kinde, I., Wang, Y., Agrawal, N., Bartlett, B. R., Wang, H., Luber, B., Alani, R. M., Antonarakis, E. S., Azad, N. S., Bardelli, A., Brem, H., Cameron, J. L., Lee, C. C., Fecher, L. A., Gallia, G. L., Gibbs, P., Le, D., Giuntoli, R. L., Goggins, M., Hogarty, M. D., Holdhoff, M., Hong, S., Jiao, Y., Juhl, H. H., Kim, J. J., Siravegna, G., Laheru, D. A., Lauricella, C., Lim, M., Lipson, E. J., Marie, S., Netto, G. J., Oliner, K. S., Olivi, A., Olsson, L., Riggins, G. J., Sartore-Bianchi, A., Schmidt, K., Shih, I., Oba-Shinjo, S., Siena, S., Theodorescu, D., Tie, J., Harkins, T. T., Veronese, S., Wang, T., Weingart, J. D., Wolfgang, C. L., Wood, L. D., Xing, D., Hruban, R. H., Wu, J., Allen, P. J., Schmidt, C., Choti, M. A., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Papadopoulos, N., Diaz, L. A. 2014; 6 (224): 224ra24

  Abstract

  The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

  View details for DOI 10.1126/scitranslmed.3007094

  View details for Web of Science ID 000331476700004

  View details for PubMedID 24553385

  View details for PubMedCentralID PMC4017867

• Current Vaccine Trials in Glioblastoma: A Review JOURNAL OF IMMUNOLOGY RESEARCH Xu, L., Chow, K. K., Lim, M., Li, G. 2014

  Abstract

  Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.

  View details for DOI 10.1155/2014/796856

  View details for Web of Science ID 000334230200001

  View details for PubMedID 24804271

  View details for PubMedCentralID PMC3996322

• Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma NEURO-ONCOLOGY Chaichana, K. L., Jusue-Torres, I., Navarro-Ramirez, R., Raza, S. M., Pascual-Gallego, M., Ibrahim, A., Hernandez-Hermann, M., Gomez, L., Ye, X., Weingart, J. D., Olivi, A., Blakeley, J., Gallia, G. L., Lim, M., Brem, H., Quinones-Hinojosa, A. 2014; 16 (1): 113–22

  Abstract

  Surgery is first-line therapy for glioblastoma, and there is evidence that gross total resection is associated with improved survival. Gross total resection, however, is not always possible, and relationships among extent (percent) of resection (EOR), residual volume (RV), and survival are unknown. The goals were to evaluate whether there is an association between EOR and RV with survival and recurrence and to establish minimum EOR and maximum RV thresholds.Adult patients who underwent primary glioblastoma surgery from 2007 to 2011 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate proportional hazards regression analysis was used to evaluate the relationship between EOR and RV with survival and recurrence.Of 259 patients, 203 (78%) died and 156 (60%) had tumor recurrence. The median survival and progression-free survival were 13.4 and 8.9 months, respectively. The median (interquartile range) pre- and postoperative tumor volumes were 32.2 (14.0-56.3) and 2.1 (0.0-7.9) cm(3), respectively. EOR was independently associated with survival (hazard ratio [HR], 0.995; 95% confidence interval [CI]: 0.990-0.998; P = .008) and recurrence (HR [95% CI], 0.992 [0.983-0.998], P = .005). The minimum EOR threshold for survival (P = .0006) and recurrence (P = .005) was 70%. RV was also associated with survival (HR [95% CI], 1.019 [1.006-1.030], P = .004) and recurrence (HR [95% CI], 1.024 [1.001-1.044], P = .03). The maximum RV threshold for survival (P = .01) and recurrence (P = .01) was 5 cm(3).This study shows for the first time that both EOR and RV are significantly associated with survival and recurrence, where the thresholds are 70% and 5 cm(3), respectively. These findings may help guide surgical and adjuvant therapies aimed at optimizing outcomes for glioblastoma patients.

  View details for DOI 10.1093/neuonc/not137

  View details for Web of Science ID 000329135900014

  View details for PubMedID 24285550

  View details for PubMedCentralID PMC3870832

• The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers Patel, M. A., Kim, J. E., Ruzevick, J., Li, G., Lim, M. 2014; 6 (4): 1953-1985

  Abstract

  The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

  View details for DOI 10.3390/cancers6041953

  View details for PubMedID 25268164

• The Transconjunctival Transorbital Approach: A Keyhole Approach to the Midline Anterior Skull Base WORLD NEUROSURGERY Raza, S. M., Quinones-Hinojosa, A., Lim, M., Boahene, K. 2013; 80 (6): 864–71

  Abstract

  To report an initial experience with a medial transorbital approach to the midline skull base performed via a transconjunctival incision.The authors retrospectively reviewed their clinical experience with this approach in the management of benign cranial base pathology. Preoperative imaging, intraoperative records, hospitalization charts, and postoperative records were reviewed for relevant data.During the period 2009-2011, six patients underwent a transconjunctival craniotomy performed by a neurosurgeon and otolaryngologist-head and neck surgeon working together. The indications for surgery were esthesioneuroblastoma in one patient, juvenile angiofibroma in one patient, Paget disease in one patient, and recalcitrant cerebrospinal fluid leaks in three patients. Three patients had prior cranial base surgery (either open craniotomy or an endonasal approach) done at another institution. The mean length of stay was 3.8 days; mean follow-up was 6 months. Surgery was considered successful in all cases (negative margins or no leak recurrence); diplopia was noted in one patient postoperatively.The transconjunctival medial orbital craniectomy provides a minimally invasive keyhole approach to lesions located anteriorly along the anterior cranial fossa that are in the midline with lateral extension over the orbital roof. Based on our initial experience with this technique, the working space afforded limits complex surgical dissection; this approach is primarily well suited for less extensive pathology.

  View details for DOI 10.1016/j.wneu.2012.06.027

  View details for Web of Science ID 000329733300086

  View details for PubMedID 22722037

  View details for PubMedCentralID PMC4696057

• Patients undergoing surgery of intracranial metastases have different outcomes based on their primary pathology NEUROLOGICAL RESEARCH Chaichana, K. L., Gadkaree, S., Rao, K., Link, T., Rigamonti, D., Purtell, M., Browner, I., Weingart, J., Olivi, A., Gallia, G., Bettegowda, C., Brem, H., Lim, M., Quinones-Hinojosa, A. 2013; 35 (10): 1059–69

  Abstract

  Patients with a variety of different primary cancers can develop intracranial metastases. Patients who develop intracranial metastases are often grouped into the same study population, and therefore an understanding of outcomes for patients with different primary cancers remain unclear.Adults who underwent intracranial metastatic tumor surgery from 1997-2011 at a single institution were retrospectively reviewed. Primary pathologies were compared using Fisher's exact and Student's t-test, and Cox regression analysis was used to identify factors associated with survival.About 708 patients underwent surgery during the reviewed period, where 269 (38%) had non-small cell lung cancer (NSCLC), 106 (15%) breast cancer (BC), 72 (10%) gastrointestinal (GI) cancers, 88 (12%) renal cell cancer (RCC), and 88 (12%) melanoma. The most notable differences were that NSCLC patients were older, BC younger, BC had more primary tumor control, and NSCLC less extracranial spread. BC had longer survival, RCC had longer local progression free survival (PFS), and NSCLC had longer distal PFS. The factors independently associated with survival for NSCLC (female, recursive partitioning analysis (RPA) class, primary tumor control, solitary metastasis, tumor size, adenocarcinoma, radiation, discharge to home), BC (age, no skull base involvement, radiation), GI cancer (age, RPA class, Karnofsky performance scale (KPS), lack of preoperative motor deficit, non-esophageal tumors, non-hemorrhagic tumors, avoidance of new deficits), melanoma (preoperative seizures, solitary metastasis, smaller tumor size, discharge to home, chemotherapy), and RCC (KPS, chemotherapy) were distinctly different.These differences between patients with different primary cancers support the fact that patients with intracranial disease are not all the same and should be studied by their primary pathology.

  View details for DOI 10.1179/1743132813Y.0000000253

  View details for Web of Science ID 000328144300010

  View details for PubMedID 24070329

  View details for PubMedCentralID PMC3994530

• Glycerol rhizotomy via a retrosigmoid approach as an alternative treatment for trigeminal neuralgia CLINICAL NEUROLOGY AND NEUROSURGERY Goodwin, C., Yang, J. X., Bettegowda, C., Hwang, B., James, C., Biser, A., Raza, S., Bender, M., Carson, B., Lee, J. K., Lim, M. 2013; 115 (12): 2454–56

  Abstract

  Trigeminal neuralgia is a sensory nerve disorder characterized by lancinating pain and treated most commonly with carbamazepine, rhizotomy treatment, or open surgical management with microvascular decompression. We describe a novel technique to complement surgical treatment for trigeminal neuralgia via direct injection of the trigeminal nerve with glycerin in the cisternal portion of the nerve.We performed a retrospective analysis of patients who received standard microvascular decompression and injection of glycerin to the inferior third of the cisternal portion of the nerve anterior to the root entry zone with lack of a compressive vessel on MRI as the primary indication. Fourteen patients were identified and demographic information, post-operative course and complications were recorded.There were eleven females and three males with an average age at time of surgery of 54.8 years. 100% of patients reported that their trigeminal pain was significantly improved following surgical intervention. Four out of fourteen patients reported a 50-80% decrease from the pre-surgery baseline pain at one month and three month follow up. One patient developed a CSF leak, and no surgical site infections or motor deficits were observed.Intra-operative glycerin rhizotomy in conjunction with microvascular decompression can be used to safely treat patients suffering from trigeminal neuralgia.

  View details for DOI 10.1016/j.clineuro.2013.09.009

  View details for Web of Science ID 000330417500008

  View details for PubMedID 24161889

• AMIDE PROTON TRANSFER MRI OF MALIGNANT GLIOMAS FOR DETECTING ACTIVE VERSUS INACTIVE TUMOR Wolf, D., Ye, X., Lim, M., Zhu, H., Wang, M., Quinones-Hinojosa, A., Weingart, J., Olivi, A., van Zijl, P., Laterra, J., Zhou, J., Blakeley, J. OXFORD UNIV PRESS INC. 2013: 204

  View details for Web of Science ID 000327456200803

• Three-Dimensional Amide Proton Transfer MR Imaging of Gliomas: Initial Experience and Comparison With Gadolinium Enhancement JOURNAL OF MAGNETIC RESONANCE IMAGING Zhou, J., Zhu, H., Lim, M., Blair, L., Quinones-Hinojosa, A., Messina, S. A., Eberhart, C. G., Pomper, M. G., Laterra, J., Barker, P. B., van Zijl, P. M., Blakeley, J. O. 2013; 38 (5): 1119–28

  Abstract

  To investigate the feasibility of a three-dimensional amide-proton-transfer (APT) imaging sequence with gradient- and spin-echo readouts at 3 Tesla in patients with high- or low-grade gliomas.Fourteen patients with newly diagnosed gliomas were recruited. After B0 inhomogeneity correction on a voxel-by-voxel basis, APT-weighted images were reconstructed using a magnetization-transfer-ratio asymmetry at offsets of ±3.5 ppm with respect to the water resonance. Analysis of variance post hoc tests were used for statistical evaluations, and results were validated with pathology.In six patients with gadolinium-enhancing high-grade gliomas, enhancing tumors on the postcontrast T1 -weighted images were consistently hyperintense on the APT-weighted images. Increased APT-weighted signal intensity was also clearly visible in two pathologically proven, high-grade gliomas without gadolinium enhancement. The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001). In six low-grade gliomas, including two with gadolinium enhancement, APT-weighted imaging showed iso-intensity or mild punctate hyperintensity within all the lesions, which was significantly lower than that seen in the high-grade gliomas (P < 0.001).The proposed three-dimensional APT imaging sequence can be incorporated into standard brain MRI protocols for patients with malignant gliomas.

  View details for DOI 10.1002/jmri.24067

  View details for Web of Science ID 000326146900015

  View details for PubMedID 23440878

  View details for PubMedCentralID PMC3664658

• THE ROLE OF PD-1 PATHWAY IN CHORDOMAS Mathios, D., Lim, M., Ruzevick, J., Nicholas, S., Polanczyk, M., Jackson, C., Taube, J., Burger, P., Martin, A., Xu, H. OXFORD UNIV PRESS INC. 2013: 64–65

  View details for Web of Science ID 000327456200269

• DEFERRED RADIATION IS AN APPROPRIATE OPTION FOR PATIENTS PRESENTING FOR TREATMENT OF NON-FUNCTIONING PITUITARY MACROADENOMAS WITH RESIDUAL POST SURGICAL TUMOR Nicholas, S., Salvatori, R., Lim, M., Redmond, K., Quinones, A., Gallia, G., Rigamonti, D., Kleinberg, L. OXFORD UNIV PRESS INC. 2013: 185

  View details for Web of Science ID 000327456200727

• 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

• Survival and Recurrence for Patients Undergoing Surgery of Skull Base Intracranial Metastases JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Chaichana, K. L., Flores, M., Acharya, S., Sampognaro, P., Bettegowda, C., Rigamonti, D., Weingart, J. D., Olivi, A., Gallia, G. L., Brem, H., Lim, M., Quinones-Hinojosa, A. 2013; 74 (4): 228–35

  Abstract

  Objective Skull base metastases (SBMs) are rare lesions in close proximity to critical neural and vasculature structures. This rarity and complexity have led many to only offer nonsurgical therapies. The surgical outcomes for patients with SBM therefore remain unknown. Design Retrospective, comparison analyses. Setting Johns Hopkins Hospital. Participants All patients who underwent intracranial metastatic tumor surgery. Main Outcome Measure Survival and recurrence. Results Of the 708 patients who underwent intracranial metastatic tumor surgery, 29 (4%) had SBM: 3 (10%) involved the anterior skull base, 7 (24%) the sella, 6 (21%) the orbit, 2 (7%) the sphenoid wing, 3 (10%) the clivus, 4 (14%) the petrous bone, and 4 (14%) the paranasal sinuses. Following surgery, 6 (50%) had improvements in vision and 14 (88%) had improvement and/or maintenance of their cranial nerve symptoms. Three (10%), 0(0%), and 1(3%) developed a new motor, language, and vision deficit, respectively. There were no differences in median survival (10.0 versus 9.2 months, p = 0.48) and local progression-free survival (PFS) (p = 0.52), but there was improved distal PFS (p = 0.04) between patients with and without SBM. Conclusions Patients with SBM are relatively rare. These patients can tolerate surgery with minimal morbidity and mortality, and they have similar prognoses to patients without SBM.

  View details for DOI 10.1055/s-0033-1342925

  View details for Web of Science ID 000322366600007

  View details for PubMedID 24436917

  View details for PubMedCentralID PMC3715603

• Postoperative Anticoagulation in Patients with Mechanical Heart Valves Following Surgical Treatment of Subdural Hematomas NEUROCRITICAL CARE Amin, A. G., Ng, J., Hsu, W., Pradilla, G., Raza, S., Quinones-Hinojosa, A., Lim, M. 2013; 19 (1): 90–94

  Abstract

  Thromboembolic events and anticoagulation-associated bleeding events represent frequent complications following cardiac mechanical valve replacement. Management guidelines regarding the timing for resuming anticoagulation therapy following a surgically treated subdural hematoma (SDH) in patients with mechanical valves remains to be determined.To determine optimal anticoagulation management in patients with mechanical heart valves following treatment of SDH.Outcomes were retrospectively reviewed for 12 patients on anticoagulation therapy for thromboembolic prophylaxis for mechanical cardiac valves who underwent surgical intervention for a SDH at the Johns Hopkins Hospital between 1995 and 2010.The mean age at admission was 71 years. All patients had St. Jude's mechanical heart valves and were receiving anticoagulation therapy. All patients had their anticoagulation reversed with vitamin K and fresh frozen plasma and underwent surgical evacuation. Anticoagulation was withheld for a mean of 14 days upon admission and a mean of 9 days postoperatively. The average length of stay was 19 days. No deaths or thromboembolic events occurred during the hospitalization. Average follow-up time was 50 months, during which two patients had a recurrent SDH. No other associated morbidities occurred during follow-up.Interruptions in anticoagulation therapy for up to 3 weeks pose minimal thromboembolic risk in patients with mechanical heart valves. Close follow-up after discharge is highly recommended, as recurrent hemorrhages can occur several weeks after the resumption of anticoagulation.

  View details for DOI 10.1007/s12028-012-9704-2

  View details for Web of Science ID 000322140000014

  View details for PubMedID 22528281

  View details for PubMedCentralID PMC4613758

• Increased Subventricular Zone Radiation Dose Correlates With Survival in Glioblastoma Patients After Gross Total Resection INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, L., Guerrero-Cazares, H., Ye, X., Ford, E., McNutt, T., Kleinberg, L., Lim, M., Chaichana, K., Quinones-Hinojosa, A., Redmond, K. 2013; 86 (4): 616–22

  Abstract

  Neural progenitor cells in the subventricular zone (SVZ) have a controversial role in glioblastoma multiforme (GBM) as potential tumor-initiating cells. The purpose of this study was to examine the relationship between radiation dose to the SVZ and survival in GBM patients.The study included 116 patients with primary GBM treated at the Johns Hopkins Hospital between 2006 and 2009. All patients underwent surgical resection followed by adjuvant radiation therapy with intensity modulated radiation therapy (60 Gy/30 fractions) and concomitant temozolomide. Ipsilateral, contralateral, and bilateral SVZs were contoured on treatment plans by use of coregistered magnetic resonance imaging and computed tomography. Multivariate Cox regression was used to examine the relationship between mean SVZ dose and progression-free survival (PFS), as well as overall survival (OS). Age, Karnofsky Performance Status score, and extent of resection were used as covariates. The median age was 58 years (range, 29-80 years).Of the patients, 12% underwent biopsy, 53% had subtotal resection (STR), and 35% had gross total resection (GTR). The Karnofsky Performance Status score was less than 90 in 54 patients and was 90 or greater in 62 patients. The median ipsilateral, contralateral, and bilateral mean SVZ doses were 48.7 Gy, 34.4 Gy, and 41.5 Gy, respectively. Among patients who underwent GTR, a mean ipsilateral SVZ dose of 40 Gy or greater was associated with a significantly improved PFS compared with patients who received less than 40 Gy (15.1 months vs 10.3 months; P=.028; hazard ratio, 0.385 [95% confidence interval, 0.165-0.901]) but not in patients undergoing STR or biopsy. The subgroup of GTR patients who received an ipsilateral dose of 40 Gy or greater also had a significantly improved OS (17.5 months vs 15.6 months; P=.027; hazard ratio, 0.385 [95% confidence interval, 0.165-0.895]). No association was found between SVZ radiation dose and PFS and OS among patients who underwent STR or biopsy.A mean radiation dose of 40 Gy or greater to the ipsilateral SVZ was associated with a significantly improved PFS and OS in patients with GBM after GTR.

  View details for DOI 10.1016/j.ijrobp.2013.02.014

  View details for Web of Science ID 000320590200013

  View details for PubMedID 23540348

  View details for PubMedCentralID PMC3996451

• Factors associated with survival for patients with glioblastoma with poor pre-operative functional status JOURNAL OF CLINICAL NEUROSCIENCE Chaichana, K. L., Martinez-Gutierrez, J., De la Garza-Ramos, R., Weingart, J. D., Olivi, A., Gallia, G. L., Lim, M., Brem, H., Quinones-Hinojosa, A. 2013; 20 (6): 818–23

  Abstract

  Patients with glioblastoma (GB) are known to have poor prognoses, and among these patients, those with poor neurological function have an even poorer prognosis. Consequently, aggressive surgeries and adjuvant therapies are often withheld because of this dismal outlook. The effects of aggressive therapies in this small subset of patients remain unknown. The goal of this study was to evaluate outcomes and factors associated with survival for poor functioning patients who underwent aggressive resection of their GB. Adult patients who underwent surgical resection of an intracranial primary GB at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score of ≤60 were included. A total of 100 patients with primary GB met the inclusion criteria. The average age (± standard deviation) and KPS score of this cohort were 54 ± 15 years and 53 ± 12, respectively. No patient (0%) experienced perioperative mortality, and 0 (0%), 10 (10%), and 3 (3%) of patients incurred a new or increasing language, motor, and visual deficit, respectively. At last follow-up, 88 (88%) patients died with a median survival of 6.6 months. The factors associated with improved survival were age <65 year (p = 0.005), tumor size >2 cm (p = 0.01), radical tumor resection (p=0.01), and temozolomide (p = 0.001). This study identifies a subset of patients with poor functional status who may benefit from aggressive surgical resection.

  View details for DOI 10.1016/j.jocn.2012.07.016

  View details for Web of Science ID 000320352800010

  View details for PubMedID 23639620

  View details for PubMedCentralID PMC3994533

• Metastatic Melanoma to the Brain: Surgery and Radiation Is Still the Standard of Care CURRENT TREATMENT OPTIONS IN ONCOLOGY Nicholas, S., Mathios, D., Jackson, C., Lim, M. 2013; 14 (2): 264–79

  Abstract

  Malignant melanoma with brain metastases remains a difficult disease to treat. Patients presenting with disease affecting the central nervous system (CNS) have a poor prognosis. Treatment depends on a number of factors, including the size and number of lesions, performance status, comorbidities, and presenting symptoms. Physicians and patients must weigh risks and benefits of treatments, with the main goal of palliating symptoms and decreasing the risk of neurological death. Opinions throughout the country vary, but first-line treatment for brain metastases is local therapy involving either craniotomy or stereotactic radiosurgery (SRS) using CyberKnife or Gamma Knife, with or without whole brain radiation therapy (WBRT). Clinical trials remain another option for patients, with chemotherapy reserved for patients who have exhausted other options. There has been a recent surge in knowledge regarding the pathophysiology and treatment of metastatic melanoma leading to recent FDA approval in 2011 of new drugs: ipilimumab, a novel immune therapy, and vemurafenib, which blocks the MAP Kinase pathway. These drugs have the potential to treat patients with metastatic melanoma to the brain but are still undergoing clinical investigation. Despite these recent advances, the prognosis is poor, with few patients able to achieve durable and long-lasting response. Treatment for patients with brain metastases continues to lag behind treatment of other diseases, partly due to their exclusion from early clinical trials.

  View details for DOI 10.1007/s11864-013-0228-6

  View details for Web of Science ID 000318842700011

  View details for PubMedID 23504304

• Current trends in glioblastoma multiforme treatment: radiation therapy and immune checkpoint inhibitors. Brain tumor research and treatment Nicholas, S., Mathios, D., Ruzevick, J., Jackson, C., Yang, I., Lim, M. 2013; 1 (1): 2–8

  Abstract

  Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body's adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration.

  View details for DOI 10.14791/btrt.2013.1.1.2

  View details for PubMedID 24904882

• Multiple resections for patients with glioblastoma: prolonging survival Clinical article JOURNAL OF NEUROSURGERY Chaichana, K. L., Zadnik, P., Weingart, J. D., Olivi, A., Gallia, G. L., Blakeley, J., Lim, M., Brem, H., Quistones-Hinojosa, A. 2013; 118 (4): 812–20

  Abstract

  Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival.The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis.Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423-4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525-0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388-0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238-0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05).Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.

  View details for DOI 10.3171/2012.9.JNS1277

  View details for Web of Science ID 000316715700024

  View details for PubMedID 23082884

  View details for PubMedCentralID PMC3700339

• MYC AMPLIFICATION STATUS INFLUENCES TUMOR IMMUNE EVASION IN MEDULLOBLASTOMA Martin, A., Nirschl, C., Polanczyk, M., Cohen, K., Pardoll, D., Drake, C., Lim, M. OXFORD UNIV PRESS INC. 2013: 15–16

  View details for Web of Science ID 000318570500058

• Seizure Control for Patients Undergoing Meningioma Surgery WORLD NEUROSURGERY Chaichana, K. L., Pendleton, C., Zaidi, H., Olivi, A., Weingart, J. D., Gallia, G. L., Lim, M., Brem, H., Quinones-Hinojosa, A. 2013; 79 (3-4): 515–24

  Abstract

  Seizures are common among patients with meningiomas and are a significant cause of morbidity and poor quality of life. The factors associated with the onset of seizures as well as factors associated with seizure control remains poorly understood.Adult patients who underwent primary resection of a supratentorial World Health Organization grade I meningioma at a single institution between 1996 and 2006 were retrospectively reviewed. Multivariate logistical regression analyses were used to identify associations with preoperative seizures, and multivariate proportional hazards regression analyses were used to identify associations with prolonged seizure control after surgical resection.Of the 626 patients in this series, 84 (13%) presented with seizures. The factors independently associated with preoperative seizures were Karnofsky performance score ≤ 80 (P< 0.0001), absence of headaches (P = 0.0006), and vasogenic edema (P = 0.007). At 48 months postoperatively, 90% were Engel class I, 3% were class II, 0 were class III, and 7% were class IV. The factors independently associated with decreased seizure control after surgical resection were uncontrolled preoperative seizures (P = 0.04), parasagittal tumors (P = 0.03), and tumors along the sphenoid wing (P = 0.05). The association between seizure recurrence and tumor recurrence trended toward but did not achieve statistical significance (P = 0.11).With the widespread availability of various neuroimaging modalities, there will be increased detection of intracranial meningiomas. The identification and consideration of factors associated with seizure onset and prolonged seizure control may help guide treatment strategies aimed at improving the quality of life for patients with meningiomas.

  View details for DOI 10.1016/j.wneu.2012.02.051

  View details for Web of Science ID 000318262600030

  View details for PubMedID 22469524

• Deep venous thrombosis and pulmonary embolisms in adult patients undergoing craniotomy for brain tumors NEUROLOGICAL RESEARCH Chaichana, K. L., Pendleton, C., Jackson, C., Martinez-Gutierrez, J., Diaz-Stransky, A., Aguayo, J., Olivi, A., Weingart, J., Gallia, G., Lim, M., Brem, H., Quinones-Hinojosa, A. 2013; 35 (2): 206–11

  Abstract

  The development of venothromboembolisms (VTEs), including deep vein thrombosis (DVT) and pulmonary emboli (PE), is common in brain tumor patients. Their development can be catastrophic. Studies evaluating pre-operative clinical factors that predispose patients to the development of VTE are few and limited. An understanding may help risk stratify patients and guide subsequent therapy aimed at reducing the risk of DVTs/PEs.All adult patients who underwent surgery for an intracranial tumor at an academic tertiary care institution between 1998 and 2008 were retrospectively reviewed. Stepwise multivariate logistical regression analysis was used to identify pre-operative factors associated with the development of peri-operative (within 30 days of surgery) DVTs/PEs among patients who underwent surgery of their intracranial tumor.Of the 4293 patients in this study, 126 (3%) patients developed DVT and/or PE in the peri-operative period. The pre-operative factors independently associated with the development of DVTs/PEs were: poorer Karnofsky performance scale (KPS) [odds ratio (OR), 1·040; 95% confidence interval (CI), 1·026-1·052; P<0·0001], high grade glioma (OR, 1·702; 95% CI, 1·176-2·465; P = 0·005), older age (OR, 1·033; 95% CI, 1·020-1·046; P<0·0001), hypertension (OR, 1·785; 95% CI, 1·180-2·699; P = 0·006), and motor deficit (OR, 1·854; 95% CI, 1·244-2·763; P = 0·002). Eighty six per cent of the patients with DVTs/PEs were treated with either unfractionated or low molecular weight heparin, and 4% of these patients developed intracranial hemorrhage.The present study found that poorer functional status, older age, pre-operative motor deficit, high grade glioma, and hypertension each independently increased the risk of developing peri-operative DVTs/PEs. These findings may provide patients and physicians with prognostic information that may guide therapies aimed at minimizing the development of peri-operative DVTs/PEs.

  View details for DOI 10.1179/1743132812Y.0000000126

  View details for Web of Science ID 000315773800018

  View details for PubMedID 23336127

  View details for PubMedCentralID PMC3991124

• Vaccine strategies for glioblastoma: progress and future directions IMMUNOTHERAPY Jackson, C., Ruzevick, J., Brem, H., Lim, M. 2013; 5 (2): 155–67

  Abstract

  Recent advances in glioblastoma therapy have led to optimism that more effective therapies will improve outcomes. Immunotherapy is a promising approach that has demonstrated the potential to eradicate cancer cells with cellular-level accuracy while minimizing damage to surrounding healthy tissue. Several vaccination strategies have been evaluated for activity against glioblastoma in clinical trials. These include peptide vaccines, polyvalent dendritic cell vaccines, heat shock protein vaccines and adoptive immunotherapy. In this review, we highlight clinical trials representative of each of these approaches and discuss strategies for integrating these therapies into routine patient care.

  View details for DOI 10.2217/IMT.12.155

  View details for Web of Science ID 000314674800013

  View details for PubMedID 23413907

  View details for PubMedCentralID PMC4086484

• Glycerol rhizotomy and radiofrequency thermocoagulation for trigeminal neuralgia in multiple sclerosis JOURNAL OF NEUROSURGERY Bender, M. T., Pradilla, G., Batra, S., See, A. P., James, C., Pardo, C. A., Carson, B. S., Lim, M. 2013; 118 (2): 329–36

  Abstract

  Patients with trigeminal neuralgia due to multiple sclerosis (TN-MS) and idiopathic TN (ITN) who underwent glycerol rhizotomy (GR) and radiofrequency thermocoagulation with glycerol rhizotomy (RFTC-GR) were compared to investigate the effectiveness of these percutaneous ablative procedures in the TN-MS population.Between 1998 and 2010, 822 patients with typical TN were evaluated; 63 (8%) had TN-MS and 759 (92%) had ITN. Pain relief comparisons were made between 22 GR procedures in patients with TN-MS and 470 GR procedures in patients with ITN; 50 RFTC-GR procedures in patients with TN-MS and 287 RFTC-GR procedures in patients with ITN were compared. Analysis of time to recurrence included only procedures that achieved complete pain relief without medications.After 15 of the GR procedures (68%) in patients with TN-MS and 315 of the procedures (67%) in those with ITN, the patients were pain free without medications (p = 0.736). After 36 of the RFTC-GR procedures (72%) in patients with TN-MS and 210 of the procedures (73%) in those with ITN, the patients were pain free without medications (p = 0.657). The difference in pain relief between GR and RFTC-GR for patients with TN-MS was not significant (p = 0.447). The median time to failure of GR was 20 months in patients with TN-MS compared with 25 months in those with ITN (p = 0.403). The median time to failure of RFTC-GR was 26 months in the TN-MS population compared with 21 months in the ITN population (p = 0.449). Patients with TN-MS experienced similar times to recurrence whether they were treated with GR or RFTC-GR (p = 0.431).Pain relief and durability of relief outcomes of GR and RFTC-GR were similar in patients with TN-MS and ITN, reinforcing their use as preferred treatments of TN-MS. The GR and RFTC-GR achieved comparable outcomes in patients with TN-MS, suggesting that both can be used to good effect.

  View details for DOI 10.3171/2012.9.JNS1226

  View details for Web of Science ID 000313937900016

  View details for PubMedID 23121430

• A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain CASE REPORTS IN ONCOLOGICAL MEDICINE Ruzevick, J., Nicholas, S., Redmond, K., Kleinberg, L., Lipson, E. J., Lim, M. 2013: 946392

  Abstract

  Cancers, such as melanoma, that are associated with immune deficiencies are a major cause of morbidity and mortality in HIV-infected patients. Once patients develop melanoma metastases to the brain, treatment is often limited to palliative surgery and/or radiation. Ipilimumab, a CTLA-4 antagonist, has been shown to improve the median survival of patients with metastatic melanoma. However, available data regarding the safety and efficacy of ipilimumab in HIV-infected patients who develop intracranial melanoma metastases is limited. Here we report our experience administering ipilimumab to a patient with HIV-AIDS who developed multiple intracranial melanoma metastases. Following treatment, our patient showed improvement in systemic tumor control without any apparent interference with antiretroviral treatment.

  View details for DOI 10.1155/2013/946392

  View details for Web of Science ID 000215599700103

  View details for PubMedID 24383025

  View details for PubMedCentralID PMC3870634

• Handbook of Radiosurgery in CNS Disease Preface HANDBOOK OF RADIOSURGERY IN CNS DISEASE Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: IX-X

  View details for Web of Science ID 000319780500001

• Technology and Techniques of Cranial Radiosurgery HANDBOOK OF RADIOSURGERY IN CNS DISEASE Ruzevick, J., Lim, M., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: 13–25

  View details for Web of Science ID 000319780500003

• Skull-Base Tumors C. Stereotactic Radiosurgery for Glomus Jugulare Tumors HANDBOOK OF RADIOSURGERY IN CNS DISEASE Guss, Z. D., Amin, A. G., Lim, M., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: 77–81

  View details for Web of Science ID 000319780500009

• Skull-Base Tumors D. Radiosurgery for Vestibular Schwannomas HANDBOOK OF RADIOSURGERY IN CNS DISEASE Ruzevick, J., Lim, M., Rigamonti, D., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: 83–91

  View details for Web of Science ID 000319780500010

• Radiosurgery for Arteriovenous Malformations HANDBOOK OF RADIOSURGERY IN CNS DISEASE Ruzevick, J., Batra, S., Lim, M., Rigamonti, D., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: 123–35

  View details for Web of Science ID 000319780500014

• Immune Modulation and Stereotactic Radiation: Improving Local and Abscopal Responses BIOMED RESEARCH INTERNATIONAL Zeng, J., Harris, T. J., Lim, M., Drake, C. G., Tran, P. T. 2013; 2013: 658126

  Abstract

  New and innovative treatment strategies for cancer patients in the fields of immunotherapy and radiotherapy are rapidly developing in parallel. Among the most promising preclinical treatment approaches is combining immunotherapy with radiotherapy where early data suggest synergistic effects in several tumor model systems. These studies demonstrate that radiation combined with immunotherapy can result in superior efficacy for local tumor control. More alluring is the emergence of data suggesting an equally profound systemic response also known as "abscopal" effects with the combination of radiation and certain immunotherapies. Studies addressing optimal radiation dose, fractionation, and modality to be used in combination with immunotherapy still require further exploration. However, recent anecdotal clinical reports combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic sustained clinical responses, both local and abscopal. Technologic advances in clinical radiation therapy has made it possible to deliver hypofractionated regimens anywhere in the body using stereotactic radiation techniques, facilitating further clinical investigations. Thus, stereotactic radiation in combination with immunotherapy agents represents an exciting and potentially fruitful new space for improving cancer therapeutic responses.

  View details for DOI 10.1155/2013/658126

  View details for Web of Science ID 000327353300001

  View details for PubMedID 24324970

  View details for PubMedCentralID PMC3845488

• The role of STAT3 activation in modulating the immune microenvironment of GBM JOURNAL OF NEURO-ONCOLOGY See, A. P., Han, J. E., Phallen, J., Binder, Z., Gallia, G., Pan, F., Jinasena, D., Jackson, C., Belcaid, Z., Jeong, S., Gottschalk, C., Zeng, J., Ruzevick, J., Nicholas, S., Kim, Y., Albesiano, E., Pardoll, D. M., Lim, M. 2012; 110 (3): 359–68

  Abstract

  Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.

  View details for DOI 10.1007/s11060-012-0981-6

  View details for Web of Science ID 000311208300006

  View details for PubMedID 23096132

  View details for PubMedCentralID PMC3700337

• Predictors of Visual Outcome Following Surgical Resection of Medial Sphenoid Wing Meningiomas JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Chaichana, K. L., Jackson, C., Patel, A., Miller, N. R., Subramanian, P., Lim, M., Gallia, G., Olivi, A., Weingart, J., Brem, H., Quinones-Hinojosa, A. 2012; 73 (5): 321–26

  Abstract

  Objective Medial sphenoid wing meningiomas (SWMs) are relatively common tumors that are associated with significant morbidity and mortality, primarily from their anatomic proximity to many critical neurological and vascular structures. A major complication is visual deterioration. This study aimed to identify predictors of visual outcome following medial SWM resection. Design Retrospective, stepwise multivariate proportional hazards regression analysis. Setting Johns Hopkins Hospital. Participants All patients who underwent medial SWM resection from 1998 to 2009. Main Outcome Measures Visual function. Results Sixty-five medial SWM resections were performed. After multivariate proportional hazards regression analysis, preoperative visual decline (relative risk [RR] 95% confidence interval [CI]; 13.431 [2.601 to 46.077], p = 0.006), subtotal resection (RR [95% CI]; 3.717 [1.204 to 13.889], p = 0.02), and repeat surgery (RR [95% CI]; 5.681 [1.278 to 19.802], p = 0.03) were found to be independent predictors of visual decline at last follow-up. Tumor recurrence and postoperative radiation therapy trended toward, but did not reach statistical significance. Conclusion These findings advocate for early and aggressive surgical intervention for patients with medial SWMs to maximize the likelihood of subsequent visual preservation. This may provide patients and physicians with prognostic information that may guide medical and surgical therapy for patients with medial SWMs.

  View details for DOI 10.1055/s-0032-1321510

  View details for Web of Science ID 000321270900005

  View details for PubMedID 24083123

  View details for PubMedCentralID PMC3578636

• ONCOGENIC DRIVERS OF MEDULLOBLASTOMA MAY DETERMINE A NOVEL IMMUNE PHENOTYPE Martin, A. M., Nirschl, C., Polanczyk, M., Cohen, K. J., Pardoll, D. M., Drake, C. G., Lim, M. OXFORD UNIV PRESS INC. 2012: 41

  View details for Web of Science ID 000310971300172

• A PROSPECTIVE STUDY OF MOTOR DYSFUNCTION FOLLOWING CRANIAL IRRADIATION FOR PEDIATRIC BRAIN TUMORS Redmond, K. J., Mahone, E. M., Kleinberg, L., Terezakis, S., McNutt, T., Agbahiwe, H., Cohen, K., Lim, M., Wharam, M., Horska, A. OXFORD UNIV PRESS INC. 2012: 137

  View details for Web of Science ID 000310971300541

• INCREASED RADIATION DOSE TO THE SVZ IMPROVES PROGRESSION FREE SURVIVAL IN GBM PATIENTS Chen, L., Guerrero-Cazares, H., Ford, E., McNutt, T., Kleinberg, L., Lim, M., Quinones-Hinojosa, A., Redmond, K. OXFORD UNIV PRESS INC. 2012: 139

  View details for Web of Science ID 000310971300549

• Real-Time Imaging with the O-Arm for Skull Base Applications: A Cadaveric Feasibility Study JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Raza, S. M., See, A. P., Lim, M. 2012; 73 (5): 293–301

  Abstract

  Introduction Although intraoperative imaging/navigation has established its critical role in neurosurgery, its role in cranial base surgery is currently limited. Due to issues such as poor bony resolution and accuracy, surgeons have to rely on anatomic landmarks that can be distorted by pathology when drilling out critical structures. Though originally developed for spinal application, we hypothesized that the O-Arm could address the above issues for use in cranial base procedures. Methods A cadaveric study was performed in which heads underwent a preprocedure scan via the O-Arm, a fluoroscopic device capable of providing three-dimensional images through the use of cone-beam technology. Preprocedure scans were taken and then registered to a Stealth S7 machine (Medtronic, Inc., Minneapolis, MN, USA). Key cranial base landmarks were identified on these scans and then subsequently identified under direct visualization after (1) endoscopic endonasal dissection and (2) a middle fossa approach. We then quantified the difference in distance between the preplanned and identified structure during surgery. This difference was considered the error. Results For anterior cranial fossa structures, the mean error was 0.25 mm (anterior septum), 0.27 mm (left septum), and 0.32 mm (right septum). For middle fossa structures, the errors were: 0.11 mm (foramen spinosum), 0.44 mm (foramen rotundum), and 0.21 mm (foramen ovale). Conclusion Based on this preliminary cadaveric study, we feel the O-Arm can provide the necessary imaging resolution at the skull base to be employed for intraoperative navigation during cranial base approaches (open and endoscopic). This study warrants further investigation into its clinical use in patients undergoing similar surgical procedures.

  View details for DOI 10.1055/s-0032-1321505

  View details for Web of Science ID 000321270900001

  View details for PubMedID 24083119

  View details for PubMedCentralID PMC3578634

• Subependymoma: clinical features and surgical outcomes NEUROLOGICAL RESEARCH Jain, A., Amin, A. G., Jain, P., Burger, P., Jallo, G. I., Lim, M., Bettegowda, C. 2012; 34 (7): 677–84

  Abstract

  Subependymomas are rare, indolent neoplasms that have been described in the brain and the spinal cord. The purpose of this study is to report the clinical and radiolographic features, and surgical outcomes of this entity.Twenty-six patients with pathologically-verified subependymomas were treated from 1990 through 2009, with a mean follow-up of 39 months. The clinical and radiological records were reviewed and outcomes analyzed.There were 15 fourth ventricle tumors, 6 lateral ventricle tumors, and 5 spinal tumors. For the intracranial tumors, headaches, changes in vision, and difficulties with balance were the most common symptoms. Most tumors were heterogeneously enhancing and hypointense or isointense to gray matter on T1-imaging and hyperintense on T2-imaging. All patients with tumors in the fourth ventricle underwent a suboccipital craniotomy and seven patients received an additional C1 laminectomy. Patients with lateral ventricular tumors underwent craniotomy with primarily a transcallosal resection. Patients with spinal tumors underwent laminectomy with intramedullary tumor resection. All tumors were resected employing microsurgical techniques. Overall, six patients had a sub-total resection. No recurrence of tumor or symptoms was noted at last follow-up for any patient, suggesting that maximal safe resection is often sufficient to provide symptomatic relief. Three patients had long-term complications from surgery. Tumor location was not associated with age at presentation, resection achieved, or development of complications.Subependymomas are indolent tumors that when symptomatic can present with cerebrospinal fluid (CSF) obstructive symptoms in the brain and myelopathy in the spinal cord. There is no one symptom diagnostic for subependymomas. Surgical treatment can provide long term tumor control.

  View details for DOI 10.1179/1743132812Y.0000000064

  View details for Web of Science ID 000307532500008

  View details for PubMedID 22747714

  View details for PubMedCentralID PMC4618470

• 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

• Potential Role for STAT3 Inhibitors in Glioblastoma NEUROSURGERY CLINICS OF NORTH AMERICA Jackson, C., Ruzevick, J., Amin, A. G., Lim, M. 2012; 23 (3): 379-+

  Abstract

  Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that translocates to the nucleus to modulate the expression of a variety of genes associated with cell survival, differentiation, proliferation, angiogenesis, and immune function. Several cancers induce constitutive STAT3 activation. Most studies have reported that STAT3 inhibition has antineoplastic activity; however, emerging evidence suggests that the role of STAT3 activity in GBM may be more nuanced than initially appreciated. The authors review the roles of STAT3 in GBM and discuss potential strategies for targeting STAT3.

  View details for DOI 10.1016/j.nec.2012.04.002

  View details for Web of Science ID 000307024800004

  View details for PubMedID 22748651

• Clinical Trials with Immunotherapy for High-Grade Glioma NEUROSURGERY CLINICS OF NORTH AMERICA Ruzevick, J., Jackson, C., Phallen, J., Lim, M. 2012; 23 (3): 459-+

  Abstract

  Immunotherapy is a potential new therapeutic option in patients with high-grade gliomas (HGGs). Phase I/II trials have assessed the efficacy of increasing immune activity using vaccines made from lymphokine-activated killer cells, cytotoxic T cells, autologous tumor cells, or dendritic cells. Studies to decrease tumor immunoresistance have focused on cytokine modulation of known immunosuppressive factors in the tumor microenvironment. Several early studies have reported a survival benefit using different forms of immunotherapy. This article discusses past clinical trials using immunotherapy in HGGs, their efficacy, limits, and biologic and clinical design challenges that must be overcome to advance immunotherapy for patients with HGGs.

  View details for DOI 10.1016/j.nec.2012.04.003

  View details for Web of Science ID 000307024800011

  View details for PubMedID 22748658

• LEVERAGING EXPRESSION OF A5/GABA-A RECEPTOR IN MEDULLOBLASTOMA AS A NOVEL THERAPEUTIC TARGET 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) Sengupta, S., Weeraratne, S. D., Phallen, J., Sun, H., Rallapalli, S., Amani, V., Pierre-Francois, J., Teider, N., Cook, J., Jensen, F., Lim, M., Pomeroy, S., Cho, Y. OXFORD UNIV PRESS INC. 2012: 105–105

  View details for Web of Science ID 000308394400397

• NOVEL IMMUNE CHARACTERISTICS OF MEDULLOBLASTOMA CORRELATE WITH MYC AMPLIFICATION STATUS Martin, A., Nirschl, C., Polanczyk, M., Cohen, K. J., Pardoll, D. M., Drake, C. G., Lim, M. OXFORD UNIV PRESS INC. 2012: 93

  View details for Web of Science ID 000308394400350

• Effectiveness of Repeat Glycerol Rhizotomy in Treating Recurrent Trigeminal Neuralgia NEUROSURGERY Bender, M., Pradilla, G., Batra, S., See, A., Bhutiani, N., James, C., Carson, B. S., Lim, M. 2012; 70 (5): 1125–33

  Abstract

  Percutaneous glycerol rhizotomy (GR) is used to treat trigeminal neuralgia (TN), with satisfactory pain relief lasting 2 to 3 years in most patients after the first intervention. The efficacy of subsequent GRs, however, has not been studied.To compare the pain relief and durability achieved by the first GR with those obtained after subsequent GRs in a retrospective cohort of TN patients.Between 1998 and 2010, 548 patients with TN underwent 708 GRs. After exclusions, 430 initial GRs (GR1) and 114 subsequent GRs (GR2+) were compared in terms of initial pain relief, durability, sensory change, and complications. Durability was assessed by determining median time to treatment failure for all GRs achieving complete pain relief without medications (n = 375: 264 failures, 111 censored). Predictors of initial pain relief were assessed by logistic regression, and predictors of failure were assessed by Cox regression analysis.After GR1, pain relief results were as follows: 285 patients (66%) were pain free without medications, 26 (6%) were pain free with medications, 66 (15%) improved, and 53 (12%) were unchanged. After GR2+, results were as follows: 90 patients (79%) were pain free without medications, 6 (5%) were pain free with medications, 7 (6%) improved, and 11 (10%) were unchanged (P = .03). Median time to treatment failure was 26 months after GR1 and 25 months after GR2+ (P = .34). On multivariate analysis, prior GR was a positive predictor of initial pain relief (odds ratio, 2.067; 95% confidence interval, 1.243-3.437; P = .005) and had no effect on durability.TN patients experienced greater pain relief and equivalent durability after GR2+ beyond the initial treatment.

  View details for DOI 10.1227/NEU.0b013e31823f5eb6

  View details for Web of Science ID 000303390400027

  View details for PubMedID 22067421

• Overall Survival and Prognostic Factors for Overall Survival Vary by Histology and Performance Status for Patients with Newly Diagnosed Brain Metastases Treated with Gamma Knife Todd, A., Lawrence, K., Aizik, W., Sachin, B., Borletto, P., Chettan, B., Beatriz, A., Laurie, B., Coy, S., Redmond, K., Lim, M., Rigamonti, D. LIPPINCOTT WILLIAMS & WILKINS. 2012: 201–2

  View details for Web of Science ID 000301956300067

• 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

  View details for PubMedCentralID PMC3385070

• Stereotactic Radiosurgery of Cranial Arteriovenous Malformations and Dural Arteriovenous Fistulas NEUROSURGERY CLINICS OF NORTH AMERICA See, A. P., Raza, S., Tamargo, R. J., Lim, M. 2012; 23 (1): 133-+

  Abstract

  Cranial arteriovenous malformations (AVM) and cranial dural arteriovenous fistulas (AVF) carry a significant risk of morbidity and mortality when they hemorrhage. Current treatment options include surgery, embolization, radiosurgery, or a combination of these treatments. Radiosurgery is thought to reduce the risk hemorrhage in AVMs and AVFs by obliterating of the nidus of abnormal vasculature over the course of 2 to 3 years. Success in treating AVMs is variable depending on the volume of the lesion, the radiation dose, and the pattern of vascular supply and drainage. This article discusses the considerations for selecting radiosurgery as a treatment modality in patients who present with AVMs and AVFs.

  View details for DOI 10.1016/j.nec.2011.09.011

  View details for Web of Science ID 000298312000013

  View details for PubMedID 22107864

• Immunotherapy for glioma: promises and challenges. Neurosurgery clinics of North America Han, S. J., Zygourakis, C. n., Lim, M. n., Parsa, A. T. 2012; 23 (3): 357–70

  Abstract

  Novel immunotherapeutic modalities are being pursed in the treatment of high-grade gliomas. This article explains how tumors suppress immune function in the brain. It specifically describes the ways in which tumors limit effective communication with immune cells, secrete immune-inhibitory cytokines and molecules, and express molecules that induce apoptosis of immune cells. It also defines 3 different immunotherapeutic approaches to counteract this tumor-associated immunosuppression: cytokine therapy, passive immunotherapy (either serotherapy or adoptive immunotherapy), and active immunotherapy. Although immunotherapeutic approaches have met with mixed success so far, immunotherapy continues to be actively pursued because of its potential to attack infiltrating high-grade gliomas.

  View details for DOI 10.1016/j.nec.2012.05.001

  View details for PubMedID 22748649

• Surgical treatment of pediatric trigeminal neuralgia: case series and review of the literature CHILDS NERVOUS SYSTEM Bender, M. T., Pradilla, G., James, C., Raza, S., Lim, M., Carson, B. S. 2011; 27 (12): 2123–29

  Abstract

  Pediatric trigeminal neuralgia (TN) is a rare entity. The purpose of this study was to retrospectively analyze a small series of pediatric patients diagnosed with TN and surgically treated with microvascular decompression (MVD) at a single center.Nine patients were identified who presented with TN symptoms that began before the age of 18. Four were excluded because of delayed surgical intervention or successful medical management. We retrospectively reviewed the charts of 5 patients with classical TN who underwent MVD at or before the age of 18.Patient ages ranged from 3 to 18 years (average, 11.7) at the time of procedure. All five patients were female. Four patients underwent a single procedure and one had bilateral MVDs. In all six cases, vascular compression of the trigeminal nerve was found during surgery. Compression was venous in three cases, arterial in two, and both in one. Pain relief was complete following the procedure in five of six cases. Pain relief was incomplete but substantial in one patient, allowing her to discontinue anticonvulsant medications. Follow-up duration ranges from 9.1 to 24.8 months with an average of 15.3 (± 6.1) and a median of 12.7 months follow-up. There were no complications such as CSF leak, infection, or cranial nerve deficits.Until now, there had been no reports on the effectiveness of MVD performed before the age of 18 to treat TN. These preliminary results suggest MVD may be performed with good pain relief and minimal side effects in the pediatric population.

  View details for DOI 10.1007/s00381-011-1593-8

  View details for Web of Science ID 000297164300018

  View details for PubMedID 21965150

• 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

• DEVELOPMENT AND VALIDATION OF A PRE-OPERATIVE PROGNOSTIC SCORING SYSTEM FOR PATIENTS WITH GLIOBLASTOMA 16th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO)/AANS/CNS Section on Tumors Chaichana, K., Pendleton, C., Chambless, L., Nathan, J., Camara-Quintana, J., Li, G., Harsh, G., Thompson, R., Lim, M., Quinones-Hinojosa, A. OXFORD UNIV PRESS INC. 2011: 154–155

  View details for Web of Science ID 000297026600606

• MEDULLOBLASTOMA: A COMPARISON OF PEDIATRIC AND ADULT PATIENTS TREATED AT THE JOHNS HOPKINS HOSPITAL Ishaq, O., Montgomery, J., Terezakis, S., Wharam, M., Lim, M., Holdhoff, M., Kleinberg, L., Redmond, K. OXFORD UNIV PRESS INC. 2011: 29

  View details for Web of Science ID 000297026600120

• STEREOTACTIC RADIOSURGERY COMBINED WITH DOUBLE IMMUNOTHERAPY WITH ANTI-CTLA-4 AND ANTI-4-1BB YIELDS LONG-TERM SURVIVAL AND PROTECTIVE ANTITUMOR RESPONSE IN A MOUSE ORTHOTOPIC GLIOBLASTOMA MODEL Belcaid, Z., Phallen, J. A., Zeng, J., See, A. P., Albesiano, E., Durham, N. M., Tyler, B., Brem, H., Pardoll, D. M., Drake, C., Lim, M. OXFORD UNIV PRESS INC. 2011: 32

  View details for Web of Science ID 000297026600133

• COMBINING ANTI-PD-1 (B7-H1) IMMUNOTHERAPY WITH STEREOTACTIC RADIOSURGERY IN A MOUSE ORTHOTOPIC GLIOBLASTOMA MODEL Zeng, J., See, A. P., Phallen, J., Belcaid, Z., Durham, N., Meyer, C., Albesiano, E., Pradilla, G., Ford, E., Hammers, H., Tyler, B., Brem, H., Tran, P. T., Pardoll, D., Drake, C. G., Lim, M. OXFORD UNIV PRESS INC. 2011: 37–38

  View details for Web of Science ID 000297026600152

• GENOME-WIDE ANALYSIS OF CLINICALLY SIGNIFICANT CPG METHYLATION SITES IN GLIOBLASTOMA MULTIFORME See, A., Hwang, T., Shin, D., Shin, J., Gao, Y., Lim, M. OXFORD UNIV PRESS INC. 2011: 79

  View details for Web of Science ID 000297026600320

• Delivery of stereotactic radiosurgery: a cross-platform comparison NEUROLOGICAL RESEARCH Trang Nguyen, Hsu, W., Lim, M., Naff, N. 2011; 33 (8): 787–91

  Abstract

  Stereotactic radiosurgery is a modern addition to the armamentarium of treatment options for intracranial and extracranial lesions. It is increasingly being used as an adjuvant to surgery, conventional radiation therapy, and chemotherapy as well as being used as primary treatment. Since the introduction of the Gamma Knife (Elekta, Stockholm, Sweden) system, many more stereotactic radiosurgery machines have become available. The objective of this review is to compare and contrast the various currently available stereotactic radiosurgery platforms.

  View details for DOI 10.1179/016164111X13123658647409

  View details for Web of Science ID 000295973600002

  View details for PubMedID 22004701

• Endoscopic Transvestibular Paramandibular Exploration of the Infratemporal Fossa and Parapharyngeal Space: A Minimally Invasive Approach to the Middle Cranial Base LARYNGOSCOPE Chan, J. K., Li, R. J., Lim, M., Hinojosa, A., Boahene, K. D. 2011; 121 (10): 2075–80

  Abstract

  To describe a novel transvestibular endoscopic approach for the exposure, exploration, and resection of lesions in the infratemporal fossa (ITF) and parapharyngeal space (PPS).Surgical technique and clinical feasibilty of a novel approach to the middle cranial base.The transvestibular endoscopic approach was applied to four patients with lesions involving the ITF and PPS. Through a vertical oral mucosal incision along the ascending ramus of the mandible, an optical corridor to the ITF and PPS was created and maintained with the aid of a Hardy speculum. The contents of the ITF and PPS were explored with the aid of a 0-degree 4-mm rigid endoscope.Four patients underwent exploration of their right-sided ITF and PPS. The approach provided exposure and access from the middle cranial base at the level of the foramen ovale to the mid-PPS. Branches of the trigeminal nerve in the ITF were safely explored and preserved. Exposure and visualization of the internal maxillary artery and branches were achieved. Of the four patients, two underwent resection of a primary and a recurrent pleomorphic adenoma, one had chronic pain relief from a large synovial chondromatosis, and one had debulking of a recurrent mucoepidermoid carcinoma. The only complications were self-limiting hypoesthesia of the lip in one patient and transient dysphagia in another patient.The transvestibular endoscopic approach to the ITF and PPS offers direct and minimally invasive access to select lesions within this region. Further use of this approach will allow us to determine its potential and limitations.

  View details for DOI 10.1002/lary.22159

  View details for Web of Science ID 000295228800006

  View details for PubMedID 21898443

• Nelfinavir induces radiation sensitization in pituitary adenoma cells CANCER BIOLOGY & THERAPY Zeng, J., See, A. P., Aziz, K., Thiyagarajan, S., Salih, T., Gajula, R. P., Armour, M., Phallen, J., Terezakis, S., Kleinberg, L., Redmond, K., Hales, R. K., Salvatori, R., Quinones-Hinojosa, A., Tran, P. T., Lim, M. 2011; 12 (7): 657–63

  Abstract

  Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p < 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT-mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies.

  View details for DOI 10.4161/cbt.12.7.17172

  View details for Web of Science ID 000295470800011

  View details for PubMedID 21811091

  View details for PubMedCentralID PMC5724381

• Clinical Outcomes after Treatment of Germ Cell Tumors NEUROSURGERY CLINICS OF NORTH AMERICA Jackson, C., Jallo, G., Lim, M. 2011; 22 (3): 385-+

  Abstract

  Intracranial GCTs are a heterogeneous group of neoplasms most commonly diagnosed in the pediatric population. Germinomas are exquisitely radiosensitive with long-term survival rates in excess of 90% with radiotherapy alone. NGGCTs are associated with a poorer prognosis and are typically treated with a combination of radiation and chemotherapy. Given the young age of these patients, achieving optimal outcomes will ultimately require a careful balance of maximizing disease control while minimizing adverse treatment effects. Here we review the management of intracranial GCTs and discuss the clinical outcomes of patients who undergo treatment for these rare and fascinating tumors.

  View details for DOI 10.1016/j.nec.2011.04.002

  View details for Web of Science ID 000294372100009

  View details for PubMedID 21801987

• Heat shock protein-peptide complex in the treatment of glioblastoma EXPERT REVIEW OF VACCINES See, A. P., Pradilla, G., Yang, I., Han, S., Parsa, A. T., Lim, M. 2011; 10 (6): 721–31

  Abstract

  Vaccination immunotherapies offer the promise of long-term tumor control, and preclinical trials have found promising results. Active immunotherapy uses the adaptive immune response to specifically kill tumor cells. Tumor-specific antigens are processed by antigen-presenting cells and recognized by specific effector lymphocytes. However, basic vaccination strategies with tumor lysates have been unsuccessful in inducing antiglioma immunity in clinical trials. Gliomas are known to modulate the activity of antigen-presenting cells to reduce antitumor immune activity. Recently, tumor-derived heat shock proteins have been found to more effectively activate the immune response. Widely expressed, heat shock proteins are thought to present protein peptide fragments in a format conducive to processing by antigen-presenting cells. As a part of the protein synthesis machinery, peptides complexed with heat shock proteins are effectively representative of antigens expressed by the cell; these peptides convey the specificity of this vaccination strategy. The heat shock protein-peptide vaccine is one of many promising immunotherapeutic strategies being evaluated in clinical trials. These can be broadly classified as active, passive and adoptive, each with advantages and disadvantages. Here, we compare and contrast heat shock protein-peptide vaccines with other immunotherapies and describe the outcomes of clinical trials to date.

  View details for DOI 10.1586/ERV.11.49

  View details for Web of Science ID 000293115800010

  View details for PubMedID 21692695

• THE RADIOSURGICAL TREATMENT OF ARTERIOVENOUS MALFORMATIONS: OBLITERATION, MORBIDITIES, AND PERFORMANCE STATUS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Sun, D. Q., Carson, K. A., Raza, S. M., Batra, S., Kleinberg, L. R., Lim, M., Huang, J., Rigamonti, D. 2011; 80 (2): 354–61

  Abstract

  This study examined the single-center treatment outcomes of arteriovenous malformations (AVMs) of the brain using stereotactic radiosurgery, with regard to obliteration, predictive factors, morbidities, and patient performance status.127 patients were treated between 1990 and 2008 by use of linear accelerator or Gamma Knife. Their median age was 37 years, the median AVM volume was 7.3 cc (range, 0.014-113.13 cc), and the median follow-up duration was 42 months (range, 6-209 months). Forty-two percent of patients presented with intracranial hemorrhage, 31% received embolization, and 8% underwent prior resection. Thirty-one percent of patients received more than one round of radiosurgery.64% of patients had complete obliteration confirmed by magnetic resonance imaging or angiography. Positive predictors of obliteration included pretreatment hemorrhage (p = 0.042), smaller AVM volume (odds ratio = 1.25; 95% CI, 1.03-1.52), and larger marginal dose (odds ratio = 0.292; 95% CI, 0.100-0.820), whereas embolization (p < 0.001) was a negative predictor . The annual risk of hemorrhage after radiosurgery was 2.2%, and the risk of death as a result of hemorrhage was 0.6-1.3%. Eleven percent of patients reported new or worsened neurologic symptoms. Radiosurgery was effective in treating AVM-related headaches (p < 0.001) but did not improve the performance status of patients.Stereotactic radiosurgery is an effective tool in the treatment of AVMs and amelioration of AVM-related headaches, but it did not affect the patients' performance status. Factors affecting obliteration include prior hemorrhage, marginal dose, prior embolization, and AVM volume. Risk of hemorrhage persists in the latency period after radiosurgery, and it remains finite even after complete obliteration.

  View details for DOI 10.1016/j.ijrobp.2010.01.049

  View details for Web of Science ID 000290837100006

  View details for PubMedID 20400239

• Treatment of pituitary adenomas using radiosurgery and radiotherapy: a single center experience and review of literature NEUROSURGICAL REVIEW Sun, D. Q., Cheng, J. J., Frazier, J. L., Batra, S., Wand, G., Kleinberg, L. R., Rigamonti, D., Quinones-Hinojosa, A., Salvatori, R., Lim, M. 2011; 34 (2): 181–89

  Abstract

  Fractionated radiotherapy (FRT) and gamma knife stereotactic radiosurgery (GKSRS) are used as adjuvant therapies to surgical resection for functional and non-functional pituitary adenomas, although their optimum role in the treatment algorithm, as well as long-term safety and efficacy, still awaits further study. We report a single center experience with 33 patients with non-functional (16 patients), ACTH- (five patients), GH- (four patients), or prolactin-secreting (eight patients) tumors treated with FRT or SRS. The median tumor diameter was 1.9 cm, and the median follow-up was 36 months. For GKSRS, the median dosage was 16 Gy for non-functional adenomas and 23 Gy for hormone-secreting tumors. The median total dose for FRT was 50.4 Gy over 28 fractions (median). Two patients (6%) demonstrated radiographic evidence of tumor progression, three patients (9%) demonstrated radiation-induced visual field deficits on neuro-ophthalmic evaluation, and two patients (6%) suffered from radiation-induced hypopituitarism. Biochemical control, defined as normalized hormone values in the absence of medical therapy, was achieved in five out of eight prolactinoma patients and two out of five patients with Cushing's disease, but none of the four patients with acromegaly. These results are presented with a review of the relevant literature on the differential characteristics of FRT versus SRS in the treatment of functional and non-functional pituitary adenomas and validate postoperative irradiation as a potentially safe and effective means for tumor control.

  View details for DOI 10.1007/s10143-010-0285-2

  View details for Web of Science ID 000288510600011

  View details for PubMedID 20838838

• Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series RADIATION ONCOLOGY See, A. P., Zeng, J., Tran, P. T., Lim, M. 2011; 6: 25

  Abstract

  There is little data on the safety of combining radiation therapy and human immunodeficiency virus (HIV) protease inhibitors to treat cancers in HIV-positive patients. We describe acute toxicities observed in a series of HIV-positive patients receiving modern radiation treatments, and compare patients receiving HIV protease inhibitors (PI) with patients not receiving HIV PIs.By reviewing the clinical records beginning January 1, 2009 from the radiation oncology department, we identified 29 HIV-positive patients who received radiation therapy to 34 body sites. Baseline information, treatment regimen, and toxicities were documented by review of medical records: patient age, histology and source of the primary tumor, HIV medication regimen, pre-radiation CD4 count, systemic chemotherapy, radiation therapy dose and fractionation, irradiated body region, toxicities, and duration of follow-up. Patients were grouped according to whether they received concurrent HIV PIs and compared using Pearson's chi-square test.At baseline, the patients in the two groups were similar with the exception of HIV medication regimens, CD4 count and presence of AIDS-defining malignancy. Patients taking concurrent PIs were more likely to be taking other HIV medications (p = 0.001) and have CD4 count >500 (p = 0.006). Patients taking PIs were borderline less likely to have an AIDS-defining malignancy (p = 0.06). After radiation treatment, 100 acute toxicities were observed and were equally common in both groups (64 [median 3 per patient, IQR 1-7] with PIs; 36 [median 3 per patient, IQR 2-3] without PIs). The observed toxicities were also equally severe in the two groups (Grades I, II, III respectively: 30, 30, 4 with PIs; 23, 13, 0 without PIs: p = 0.38). There were two cases that were stopped early, one in each group; these were not attributable to toxicity.In this study of recent radiotherapy in HIV-positive patients taking second generation PIs, no difference in toxicities was observed in patients taking PIs compared to patients not taking PIs during radiation therapy. This suggests that it is safe to use unmodified doses of PIs and radiation therapy in HIV cancer patients, and that it is feasible to use PIs as a radiosensitizer in cancer therapy, as has been suggested by pre-clinical results.

  View details for DOI 10.1186/1748-717X-6-25

  View details for Web of Science ID 000288816200001

  View details for PubMedID 21414215

  View details for PubMedCentralID PMC3064638

• Predictors of Inpatient Death and Complications among Postoperative Elderly Patients with Metastatic Brain Tumors ANNALS OF SURGICAL ONCOLOGY Grossman, R., Mukherjee, D., Chang, D. C., Purtell, M., Lim, M., Brem, H., Quinones-Hinojosa, A. 2011; 18 (2): 521–28

  Abstract

  Risks of brain surgery in elderly patients with brain metastases are not well defined. This study was designed to quantify the postoperative risk for these patients after brain surgery for metastatic disease to the brain.We performed a retrospective analysis of the Nationwide Inpatient Sample (1998-2005). Patients aged 65 years or older who underwent tumor resection of brain metastases were identified by ICD-9 coding. Primary outcome was inpatient death. Other outcomes included systemic postoperative complications, length of stay (LOS), and total charges.A total of 4,907 patients (53.6% men) were identified. Mean age was 72.1 years. Mean Charlson comorbidity score was 7.8. Inpatient mortality was 4%. The most common adverse events were pulmonary complications (3.4%). Mean length of stay was 9.2 days. Mean total charges were $57,596.39. In multivariate analysis, patients up to age 80 years had no significantly greater odds of inpatient death, relative to their 65- to 69-year-old counterparts. Each 1-point increase in Charlson score was associated with 12% increased odds of death, 0.52 days increased LOS, and $1,710.61 higher hospital charges. Postoperative pulmonary complications, stroke, or thromboembolic events increased LOS and total charges by up to 9.6 days and $57,664.42, respectively. These associations were statistically significant (P < 0.05).Surgical resection of brain metastases among the elderly up to the ninth decade of life is feasible. Age older than 80 years and higher Charlson comorbidity scores were found to be important prognostic factors for inpatient outcome. Incorporating these factors into preoperative decision making may help to select appropriately those elderly candidates for neurosurgical intervention.

  View details for DOI 10.1245/s10434-010-1299-2

  View details for Web of Science ID 000286938600035

  View details for PubMedID 20809176

  View details for PubMedCentralID PMC4859207

• Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment CLINICAL & DEVELOPMENTAL IMMUNOLOGY Jackson, C., Ruzevick, J., Phallen, J., Belcaid, Z., Lim, M. 2011: 732413

  Abstract

  Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment.

  View details for DOI 10.1155/2011/732413

  View details for Web of Science ID 000298701200001

  View details for PubMedID 22190972

  View details for PubMedCentralID PMC3235820

• ESTABLISHMENT OF GBM SUSPENSION CELL LINES Binder, Z. A., Salmasi, V., Lim, M., Weingart, J., Brem, H., Olivi, A., Riggins, G. J., Gallia, G. L. OXFORD UNIV PRESS INC. 2010: 134

  View details for Web of Science ID 000285082400570

• THE ROLE OF STAT3 ACTIVATION IN MODULATING THE IMMUNE MICROENVIRONMENT OF GLIOMAS Albesiano, E., Han, J. E., See, A., Jackson, C., Lim, M. OXFORD UNIV PRESS INC. 2010: 31

  View details for Web of Science ID 000285082400139

• STAT3 INHIBITION ALTERS THE IMMUNE PROFILE IN MURINE GLIOMAS Han, J. E., Albesiano, E., Pradilla, G., Lim, M. OXFORD UNIV PRESS INC. 2010: 16–17

  View details for Web of Science ID 000285082400074

• ADJUVANT STEREOTACTIC RADIOSURGERY INCREASES TUMOR CONTROL RATES IN PATIENTS WITH CEREBRAL METASTASES AFTER SURGICAL RESECTION Jackson, C. M., Amin, A., See, P., Pradilla, G., Tryggestad, E., Lim, M. OXFORD UNIV PRESS INC. 2010: 112

  View details for Web of Science ID 000285082400477

• PODOCALYXIN EXPRESSION CORRELATES WITH ASTROCYTOMA TUMOR GRADE Binder, Z. A., Orr, B., Lim, M., Weingart, J. D., Brem, H., Olivi, A., Riggins, G. J., Gallia, G. L. OXFORD UNIV PRESS INC. 2010: 119–20

  View details for Web of Science ID 000285082400507

• Immunologic Consequences of Signal Transducers and Activators of Transcription 3 Activation in Human Squamous Cell Carcinoma CANCER RESEARCH Albesiano, E., Davis, M., See, A. P., Han, J. E., Lim, M., Pardoll, D. M., Kim, Y. 2010; 70 (16): 6467–76

  Abstract

  Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.

  View details for DOI 10.1158/0008-5472.CAN-09-4058

  View details for Web of Science ID 000280887000009

  View details for PubMedID 20682796

  View details for PubMedCentralID PMC2922407

• Transpalpebral Orbitofrontal Craniotomy: A Minimally Invasive Approach to Anterior Cranial Vault Lesions SKULL BASE-AN INTERDISCIPLINARY APPROACH Boahene, K., Lim, M., Chu, E., Quinones-Hinojosa, A. 2010; 20 (4): 237–44

  Abstract

  To describe a minimally invasive approach to anterior cranial vault pathology using a transpalpebral exposure with a miniorbitofrontal craniotomy.Case series.Tertiary referral hospital with multidisciplinary skull base program. Participants include patients with intra-axial and extra-axial anterior skull base lesions who underwent the transpalpebral minicraniotomy approach.Feasibility of the approach to permit adequate exposure of targeted lesion. We applied this approach in seven patients for the repair of persistent cerebrospinal fluid leaks, pneumocephalus, and the biopsy or resection of midline brain tumors along the anterior cranial base. The approach allowed bimanual instrumentation working with either endoscopic or microscopic visualization for tumor resection and repair of dural and cranial base defects. We measured an average working distance of 4 cm to the sella. The transpalpebral miniorbitofrontal craniotomy approach to the anterior cranial base is quick, adequate, and safe and should be considered as an alternative to extended bifrontal approaches and/or pterional craniotomies for select anterior cranial vault pathology.

  View details for DOI 10.1055/s-0030-1249247

  View details for Web of Science ID 000279573800003

  View details for PubMedID 21311616

  View details for PubMedCentralID PMC3023318

• STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF BRAIN METASTASES: AN INSTITUTIONAL RETROSPECTIVE ANALYSIS OF SURVIVAL INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Frazier, J. L., Batra, S., Kapor, S., Vellimana, A., Gandhi, R., Carson, K. A., Shokek, O., Lim, M., Kleinberg, L., Rigamonti, D. 2010; 76 (5): 1486–92

  Abstract

  The objective of this study was to report our experience with stereotactic radiosurgery performed with the Gamma Knife (GK) in the treatment of patients with brain metastases and to compare survival for those treated with radiosurgery alone with survival for those treated with radiosurgery and whole-brain radiotherapy.Prospectively collected demographic and clinical characteristics and treatment and survival data on 237 patients with intracranial metastases who underwent radiosurgery with the GK between 2003 and 2007 were reviewed. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare survival by demographic and clinical characteristics and treatment.The mean age of the patient population was 56 years. The most common tumor histologies were non-small-cell lung carcinoma (34.2%) and breast cancer (13.9%). The median overall survival time was 8.5 months from the time of treatment. The median survival times for patients with one, two/three, and four or more brain metastases were 8.5, 9.4, and 6.7 months, respectively. Patients aged 65 years or greater and those aged less than 65 years had median survival times of 7.8 and 9 months, respectively (p = 0.008). The Karnofsky Performance Score (KPS) at the time of treatment was a significant predictor of survival: those patients with a KPS of 70 or less had a median survival of 2.9 months compared with 10.3 months (p = 0.034) for those with a KPS of 80 or greater. There was no statistically significant difference in survival between patients treated with radiosurgery alone and those treated with radiosurgery plus whole-brain radiotherapy.Radiosurgery with the GK is an efficacious treatment modality for brain metastases. A KPS greater than 70, histology of breast cancer, smaller tumor volume, and age less than 65 years were associated with a longer median survival in our study.

  View details for DOI 10.1016/j.ijrobp.2009.03.028

  View details for Web of Science ID 000276675300033

  View details for PubMedID 19619958

• Stereotactic Radiosurgery for Spine Tumors: Review of Current Literature STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Hsu, W., Nguyen, T., Kleinberg, L., Ford, E. C., Rigamonti, D., Gokaslan, Z. L., Lim, M. 2010; 88 (5): 315–21

  Abstract

  Stereotactic radiosurgery (SR) is increasingly utilized for the treatment of intracranial and extracranial pathology. It is considered an important adjuvant to surgery, chemotherapy or fractionated radiotherapy, and the role of SR as a primary treatment modality continues to be explored. Although SR for spinal lesions is in its infancy, there is a growing body of literature supporting its efficacy. The purpose of this review is to summarize the pertinent literature regarding the use of SR for lesions of the spine and spinal cord. Particular emphasis will be placed on large clinical series of both primary and secondary spine tumors.

  View details for DOI 10.1159/000319959

  View details for Web of Science ID 000281966000008

  View details for PubMedID 20714211

• Biologic Principles of Immunotherapy for Malignant Gliomas NEUROSURGERY CLINICS OF NORTH AMERICA Han, S. J., Kaur, G., Yang, I., Lim, M. 2010; 21 (1): 1-+

  Abstract

  The most common primary brain neoplasm is glioblastoma multiforme, which is associated with a dismal prognosis. Despite the recommended treatment regimen of aggressive surgical resection, radiation, and chemotherapy, the median survival remains approximately only 14 months. Due to these minimal improvements in survival of patients despite recent advances in conventional treatments, new modalities such as immunotherapy are being investigated and studied. A hurdle to developing effective immunotherapy is the immunosuppressive characteristics that are the hallmark of malignant gliomas. Effective therapeutic strategies will require overcoming these mechanisms, by augmenting tumor antigen presentation, perhaps in a setting isolated from the tumor microenvironment. The heterogeneity of potential glioma antigens warrants potential targeting of multiple tumor-specific antigens, and discovery and investigation of additional antigens. This article describes the current strategies and principles of immunotherapy for malignant gliomas.

  View details for DOI 10.1016/j.nec.2009.08.001

  View details for Web of Science ID 000278059500002

  View details for PubMedID 19944962

• Immunotherapy Preface NEUROSURGERY CLINICS OF NORTH AMERICA Yang, I., Lim, M. 2010; 21 (1): XV

  View details for DOI 10.1016/j.nec.2009.09.006

  View details for Web of Science ID 000278059500001

  View details for PubMedID 19944961

• Mechanisms of Local Immunoresistance in Glioma NEUROSURGERY CLINICS OF NORTH AMERICA Albesiano, E., Han, J. E., Lim, M. 2010; 21 (1): 17-+

  Abstract

  Even though the central nervous system (CNS) was conventionally defined as "immunologically privileged", new discoveries have demonstrated the role of the immune system in neurologic disease and illness, including gliomas. Brain tumor immunotherapy is an exciting and revived area of research, in which neurosurgeons have taken a major position. Despite the ability to induce a tumor-specific systemic immune response, the challenge to effectively eradicate intracranial gliomas remains mainly because of tumor-induced immunoresistance. This article gives an overview of the immunologic responses that occur in the CNS and their potential role in brain tumors. The main cellular and molecular mechanisms that mediate tumor escape from natural immune surveillance are also covered in this article. Glioma cells have been shown to diminish the expression of danger signals necessary for immune activation and to increase the concentration of immunosuppressive factors in the tumor microenvironment, which results in T-cell anergy or apoptosis. Finally, the authors discuss most of the over-expressed oncogenic signaling pathways that cause tumor tolerance.

  View details for DOI 10.1016/j.nec.2009.08.008

  View details for Web of Science ID 000278059500003

  View details for PubMedID 19944963

• Immunotherapy Combined with Chemotherapy in the Treatment of Tumors NEUROSURGERY CLINICS OF NORTH AMERICA Frazier, J. L., Han, J. E., Lim, M., Olivi, A. 2010; 21 (1): 187-+

  Abstract

  This article provides a broad overview of the data, including laboratory and clinical studies, currently available on the combination of immunotherapy and chemotherapy for treating cancer. The various forms of immunotherapy combined with chemotherapy include monoclonal antibodies, adoptive lymphocyte transfer, or active specific immunotherapy, such as tumor proteins, irradiated tumor cells, tumor cell lysates, dendritic cells pulsed with peptides or lysates, or tumor antigens expressed in plasmids or viral vectors. This discussion is not limited to malignant brain tumors, because many of the studies have been conducted on various cancer types, thereby providing a comprehensive perspective that may encourage further studies that combine chemotherapy and immunotherapy for treating brain tumors.

  View details for DOI 10.1016/j.nec.2009.09.003

  View details for Web of Science ID 000278059500017

  View details for PubMedID 19944977

• 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

• A NEUROSURGEON'S GUIDE TO STEM CELLS, CANCER STEM CELLS, AND BRAIN TUMOR STEM CELLS NEUROSURGERY Cheshier, S. H., Kalani, M. Y., Lim, M., Ailles, L., Huhn, S. L., Weissman, I. L. 2009; 65 (2): 237-249

  Abstract

  Stem cells and their potential applications have become the forefront of scientific, political, and ethical discourse. Whereas stem cells were long accepted as units of development and evolution, it is now becoming increasingly clear that they are also units of oncogenesis. Although the field of stem cell biology is expanding at an astounding rate, the data attained are not readily translatable for the physicians who may eventually deliver these tools to patients. Herein, we provide a brief review of stem cell and cancer stem cell biology and highlight the scientific and clinical implications of recent findings regarding the presence of cancer-forming stem cells in brain tumors.

  View details for DOI 10.1227/01.NEU.0000349921.14519.2A

  View details for Web of Science ID 000268523200005

  View details for PubMedID 19625901

• NONISOCENTRIC RADIOSURGICAL RHIZOTOMY FOR TRIGEMINAL NEURALGIA NEUROSURGERY Adler, J. R., Bower, R., Gupta, G., Lim, M., Efron, A., Gibbs, I. C., Chang, S. D., Soltys, S. G. 2009; 64 (2): A84-A90

  Abstract

  Although stereotactic radiosurgery is an established procedure for treating trigeminal neuralgia (TN), the likelihood of a prompt and durable complete response is not assured. Moreover, the incidence of facial numbness remains a challenge. To address these limitations, a new, more anatomic radiosurgical procedure was developed that uses the CyberKnife (Accuray, Inc., Sunnyvale, CA) to lesion an elongated segment of the retrogasserian cisternal portion of the trigeminal sensory root. Because the initial experience with this approach resulted in an unacceptably high incidence of facial numbness, a gradual dose and volume de-escalation was performed over several years. In this single-institution prospective study, we evaluated clinical outcomes in a group of TN patients who underwent lesioning with seemingly optimized nonisocentric radiosurgical parameters.Forty-six patients with intractable idiopathic TN were treated between January 2005 and June 2007. Eligible patients were either poor surgical candidates or had failed previous microvascular decompression or destructive procedures. During a single radiosurgical session, a 6-mm segment of the affected nerve was treated with a mean marginal prescription dose of 58.3 Gy and a mean maximal dose of 73.5 Gy. Monthly neurosurgical follow-up was performed until the patient became pain-free. Longer-term follow-up was performed both in the clinic and over the telephone. Outcomes were graded as excellent (pain-free and off medication), good (>90% improvement while still on medication), fair (50-90% improvement), or poor (no change or worse). Facial numbness was assessed using the Barrow Neurological Institute Facial Numbness Scale score.Symptoms disappeared completely in 39 patients (85%) after a mean latency of 5.2 weeks. In most of these patients, pain relief began within the first week. TN recurred in a single patient after a pain-free interval of 7 months; all symptoms abated after a second radiosurgical procedure. Four additional patients underwent a repeat rhizotomy after failing to respond adequately to the first operation. After a mean follow-up period of 14.7 months, patient-reported outcomes were excellent in 33 patients (72%), good in 11 patients (24%), and poor/no improvement in 2 patients (4%). Significant ipsilateral facial numbness (Grade III on the Barrow Neurological Institute Scale) was reported in 7 patients (15%).Optimized nonisocentric CyberKnife parameters for TN treatment resulted in high rates of pain relief and a more acceptable incidence of facial numbness than reported previously. Longer follow-up periods will be required to establish whether or not the durability of symptom relief after lesioning an elongated segment of the trigeminal root is superior to isocentric radiosurgical rhizotomy.

  View details for DOI 10.1227/01.NEU.0000341631.49154.62

  View details for Web of Science ID 000262797700016

  View details for PubMedID 19165079

• A VIRTUAL FRAME SYSTEM FOR STEREOTACTIC RADIOSURGERY PLANNING INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Ford, E., Purger, D., Tryggestad, E., McNutt, T., Christodouleas, J., Rigamonti, D., Shokek, O., Won, S., Zhou, J., Lim, M., Wong, J., Kleinberg, L. 2008; 72 (4): 1244-1249

  Abstract

  We describe a computerized (or virtual) model of a stereotactic head frame to enable planning prior to the day of radiosurgery. The location of the virtual frame acts as a guide to frame placement on the day of the procedure.The software consists of a triangular mesh representation of the essential frame hardware that can be overlaid with any MR scan of the patient and manipulated in three dimensions. The software calculates regions of the head that will actually be accessible for treatment, subject to the geometric constraints of the Leksell Gamma Knife hardware. DICOM-compliant MR images with virtual fiducial markers overlaid onto the image can then be generated for recognition by the treatment planning system.Retrospective evaluation of the software on 24 previously treated patients shows a mean deviation of the position of the virtual frame from the actual frame position of 1.6 +/- 1.3 mm. Initial clinical use on five patients indicates an average discrepancy of the virtual frame location and the actual frame location of <1 mm. MR images with virtual fiducial markers can be imported into radiosurgical treatment planning software and used to generate an initial treatment plan.The virtual frame provides a tool for prospective determination of lesion accessibility, optimization of the frame placement, and treatment planning before the day of the procedure. This promises to shorten overall treatment times, improve patient comfort, and reduce the need for repeat treatments due to suboptimally placed frames.

  View details for DOI 10.1016/j.ijrobp.2008.06.1934

  View details for Web of Science ID 000260592600039

  View details for PubMedID 18954719

• Suprasellar giant cell ependymoma: a rare neoplasm in a unique location HUMAN PATHOLOGY Sangoi, A. R., Lim, M., Dulai, M. S., Vogel, H., Chang, S. D. 2008; 39 (9): 1396-1401

  Abstract

  Ependymomas are glial tumors that usually present in the posterior fossa in children and in the spinal cord in adults. Giant cell ependymoma, a rare ependymal subtype only recently recognized as a diagnostic entity in the last decade, demonstrates pleomorphic giant cells admixed with features of typical ependymoma. Although only 8 giant cell ependymomas have been reported to date, none have been reported in the suprasellar space. Moreover, as these neoplasms demonstrate a high incidence of anaplastic grade, recognition of this ependymal subtype is paramount. We describe the presentation and pertinent radiologic, histologic, immunologic, and ultrastructural findings in conjunction with relevant clinical implications of the first reported case of a suprasellar giant cell ependymoma occurring in a 34-year-old female 7 years after an initial diagnosis of a medullary ependymoma with rare atypical giant cells, a potential tumor seeding culprit.

  View details for DOI 10.1016/j.humpath.2008.01.007

  View details for PubMedID 18602668

• Cyberknife radiosurgery for trigeminal neuralgia treatment: A preliminary multicenter experience NEUROSURGERY Villavicencio, A. T., Lim, M., Burneikiene, S., Romanelli, P., Adler, J. R., McNeely, L., Chang, S. D., Fariselli, L., McIntyre, M., Bower, R., Broggi, G., Thramann, J. J. 2008; 62 (3): 647-654

  Abstract

  Radiosurgery has gained acceptance as a treatment option for trigeminal neuralgia. We report our preliminary multicenter experience treating trigeminal neuralgia with the CyberKnife (Accuray, Inc., Sunnyvale, CA).A total of 95 patients were treated for idiopathic trigeminal neuralgia between May 2002 and October 2005. Radiosurgical dose and volume parameters were retrospectively analyzed in relation to pain response, complications, and recurrence of symptoms. Optimal treatment parameters were identified for patients who had excellent and sustained pain relief with no complications, including severe or moderate hypesthesia.Excellent pain relief was initially experienced by 64 out of 95 patients (67%). The median time to pain relief was 14 days (range, 0.3-180 d). Posttreatment numbness occurred in 45 (47%) of the patients treated. Using higher radiation doses and treating longer segments of the nerve led to both better pain relief and a higher incidence of hypesthesia. The presence of posttreatment numbness was predictive of better pain relief. The overall rate of complications was 18%. At the mean follow-up time of 2 years, 47 of the 95 patients (50%) had sustained pain relief, all of whom were completely off pain medications.The results of this study suggest the following optimal radiosurgical treatment parameters for treatment of idiopathic trigeminal neuralgia: a median maximal dose of 78 Gy (range, 70-85.4 Gy) and a median length of the nerve treated of 6 mm (range, 5-12 mm).

  View details for DOI 10.1227/01.NEU.0000297129.08066.137

  View details for Web of Science ID 000255268500023

  View details for PubMedID 18425011

• Radiosurgery for glomus Jugulare tumors TECHNOLOGY IN CANCER RESEARCH & TREATMENT Lim, M., Bower, R., Nangiana, J. S., Adler, J. R., Chang, S. D. 2007; 6 (5): 419-423

  Abstract

  Results for treating glomus jugulare tumors with radiosurgery have been limited by short follow-up and small number of patients. We report our experience using LINAC or CyberKnife in 21 tumors with a median follow-up of 66 months (Mean follow-up of 60 months). In addition, we have a subset of eight patients that were followed out for more than 10 years. Patients were treated with doses ranging from 1400 cGy to 2700 cGy. We retrospectively assessed patients for efficacy and post treatment side effects. All patients had stable neurological symptoms, and two patients experienced transient ipsilateral tongue weakness and hearing loss, both of which subsequently resolved. One patient experienced transient ipsilateral vocal cord paresis; however, this patient received previous external beam radiotherapy. All tumors remained stable or decreased in size by MRI exam. Our results support radiosurgery as an effective and safe method of treatment for glomus jugulare tumors with low morbidity as evidenced by a larger number of patients and long term follow-up.

  View details for Web of Science ID 000250211600007

  View details for PubMedID 17877430

• 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

• Anti-angiogenic targeted therapy in a rat model for glioblastoma multiforme tumor with temporal MRI and pet studies 7th Congress of the European-Association-for-Neuro-Oncology (EANO) Lim, M., Yang, Y., Sims, L., Choi, S., Wang, Y., Guccione, S. OXFORD UNIV PRESS INC. 2006: 415–15

  View details for Web of Science ID 000240877301092

• Growth of human glioblastoma multiforme and medulloblastoma tumors in RAG 2 and common cytokine receptor gamma chain double knockout mice: A new model for in vivo study of GBM Cheshier, S. H., Ailles, L., Tse, V., Skirboll, S., Huhn, S., Weissman, I. DUKE UNIV PRESS. 2006: 471

  View details for Web of Science ID 000240877301308

• Flow cytometric analysis of neural stem cell markers on pediatric brain tumors 7th Congress of the European-Association-for-Neuro-Oncology (EANO) Cheshier, S. H., Ailles, L. E., Lim, M., Laddis, P., Tse, V., Weissman, I. L., Huhn, S. OXFORD UNIV PRESS INC. 2006: 466–66

  View details for Web of Science ID 000240877301290

• CD90 expression segregates tumor-sphere forming cells in human glioblastoma multiforme 7th Congress of the European-Association-for-Neuro-Oncology (EANO) Cheshier, S. H., Ailles, L., Higgins, D. M., Lim, M., Kalani, M. Y., Bababeygy, S., Weissman, I. L. OXFORD UNIV PRESS INC. 2006: 471–71

  View details for Web of Science ID 000240877301309

• New vessel formation in the central nervous system during tumor growth, vascular malformations, and Moyamoya CURRENT NEUROVASCULAR RESEARCH Lim, M., Cheshier, S., Steinberg, G. K. 2006; 3 (3): 237-245

  Abstract

  In the normal adult brain, blood vessel formation is tightly down-regulated. However, pathologic processes such as brain tumors can increase the proportion of endothelial cells involved in angiogenesis. When this process is initiated, a complex series of timed events result in new vessel formation. In this review, we will describe the process of angiogenesis in the central nervous system. We will discuss the roles of Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF), Angiopoietins, Platelet Derived Growth Factor (PDGF), and integrins in angiogenesis. We will also look into their significance in disease processes such as neoplasms, arteriovenous malformations (AVM), and Moyamoya disease.

  View details for Web of Science ID 000240424200008

  View details for PubMedID 16918387

• Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer CLINICAL CANCER RESEARCH Simons, J. W., Carducci, M. A., Mikhak, B., Lim, M., Biedrzycki, B., Borellini, F., Clift, S. M., Hege, K. M., Ando, D. G., Piantadosi, S., Mulligan, R., Nelson, W. G. 2006; 12 (11): 3394–3401

  Abstract

  To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer.A single-institution phase I/II trial was done in hormone therapy-naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 x 10(8) GM-CSF gene-transduced, irradiated, cancer cells (6 x 10(7) LNCaP cells and 6 x 10(7) PC-3 cells) for 8 weeks.Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred.This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

  View details for DOI 10.1158/1078-0432.CCR-06-0145

  View details for Web of Science ID 000238169800024

  View details for PubMedID 16740763

• Stereotactic radiosurgery using CT cisternography and non-isocentric planning for the treatment of trigeminal neuralgia. Computer aided surgery Lim, M., Cotrutz, C., Romanelli, P., Schaal, D., Gibbs, I., Chang, S. D., Adler, J. R. 2006; 11 (1): 11-20

  Abstract

  Frame-based radiosurgical rhizotomy has been shown in clinical studies to be effective for managing trigeminal neuralgia (TN). To date, however, only a small pilot study has been published for the frameless, image-guided CyberKnife system. We present our preliminary experience with 29 trigeminal neuralgia patients treated with the frameless CyberKnife using X-ray image-guided targeting, a novel CT method for target definition, and non-isocentric planning.All 29 patients failed previous medical therapy and 14 had undergone prior surgical procedures. CT iohexal cisternography was used to identify the 6- to 8-mm segment of nerve to be lesioned. The marginal dose ranged from 60 to 70 Gy (median 66.4 Gy) as defined at an average 79th percentile. The corresponding Dmax varied from 71.4 to 86.4 Gy (median 77.91 Gy).After a median 10-month follow-up, 26 of 29 (90%) patients rated their pain control as excellent and 3 (10%) reported no improvement. Median time to improvement was 6 days. No or only minor progression in numbness was reported by 22 of 29 (76%) patients, 4 of 29 (14%) patients reported worsening, and 3 of 29 (10%) reported the onset of severe ipsilateral facial numbness. Two patients whose target volume inadvertently included the semi-lunar ganglion developed painful dysethesias in the distribution of their numbness.Although the optimal dose and length of nerve to be lesioned are still being refined, this preliminary experience suggests that image-guided robotic radiosurgery can effectively lesion the trigeminal nerve. Further follow-up is needed to determine whether our method has advantages over the more commonly used procedure for radiosurgical trigeminal rhizotomy.

  View details for PubMedID 16531338

• 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

• CyberKnife radiosurgery for extremity schwannomas: Technical note and case report STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Lim, M., Adler, J. R. 2006; 84 (2-3): 60-63

  Abstract

  Peripheral nerve sheath tumors are uncommon. Although surgical resection remains the treatment of choice for most symptomatic lesions, the potential for intraoperative injury to the nerve is not insignificant. This concern is of particular relevance in those patients with a genetic proclivity to develop multiple peripheral nerve sheath tumors. Here we report four symptomatic peripheral extremity schwannomas all in 1 patient who was treated with CyberKnife radiosurgery. The radiosurgical Dmax in each case was between 24.4 and 25.32 Gy. At 1-year follow-up, patient symptoms had been ameliorated, no tumor had increased in size and there was no compromise in neurological function. Although this experience is still very preliminary, it represents the first published description of a peripheral nerve sheath tumor being treated with stereotactic radiosurgery.

  View details for DOI 10.1159/000094033

  View details for Web of Science ID 000239562300002

  View details for PubMedID 16790987

• Visual field preservation after curative multi-modality treatment of occipital lobe artemovenous malformations NEUROSURGERY Sinclair, J., Marks, M. P., Levy, R. P., Adler, J. R., Chang, S. D., Lopez, J. R., Do, H. M., Bell-Stephens, T. E., Lim, M., Steinberg, G. K. 2005; 57 (4): 655-666

  Abstract

  Occipital lobe arteriovenous malformations (AVMs) provide challenging management decisions because of their proximity to the visual cortex and optic radiations. Preservation of visual function throughout treatment is the mainstay of therapeutic planning. We reviewed visual field (VF) outcomes of all patients who received curative treatment for occipital AVMs at Stanford University to evaluate the efficacy of different treatment strategies.We conducted a retrospective review of 55 patients with occipital AVMs treated at Stanford University between 1984 and 2003. Clinical presentation, AVM morphology, and treatment modality were correlated with VF function before and after therapeutic intervention.Of 55 patients, 48 (87.3%) underwent multimodality AVM treatment (7 patients < 3 yr from radiosurgery were excluded from final analysis). One patient died from intracerebral hemorrhage 11 months post-radiosurgery, and five patients deferred further treatment. Forty-two patients (87.5%) were cured, with no residual AVM on final angiography. Curative therapeutic modalities used included embolization alone (2 patients), microsurgery alone (6 patients), microsurgery with radiosurgery (1 patient), microsurgery with embolization (23 patients), radiosurgery with embolization (4 patients), and embolization with radiosurgery and microsurgery (6 patients). Mean follow-up was 5.8 years including treatment. VF follow-up was available in all 42 patients. Twenty-eight (66.7%) patients experienced no change in VFs, six (14.3%) patients with previously abnormal VFs improved, and eight (19.0%) patients showed worsening of VFs (although none developed a new homonymous VF deficit). Duration of treatment was related to VF outcome in patients who presented without a history of AVM-related hemorrhage.Occipital AVMs can be safely cured using multimodality strategies with minimal risk to visual function despite the proximity of these lesions to the visual cortex and associated pathways.

  View details for DOI 10.1227/01.NEU.0000175547.05291.85

  View details for PubMedID 16239877

• alpha(v)beta(3) integrin in central nervous system tumors HUMAN PATHOLOGY Lim, M., Guccione, S., Haddix, T., Sims, L., Cheshier, S., Chu, P., Vogel, H., Harsh, G. 2005; 36 (6): 665-669

  Abstract

  alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

  View details for DOI 10.1016/j.humpath.2005.03.014

  View details for PubMedID 16021573

• CyberKnife radiosurgery for idiopathic trigeminal neuralgia. Neurosurgical focus Lim, M., Villavicencio, A. T., Burneikiene, S., Chang, S. D., Romanelli, P., McNeely, L., McIntyre, M., Thramann, J. J., Adler, J. R. 2005; 18 (5): E9-?

  Abstract

  Gamma knife surgery is an accepted treatment option for trigeminal neuralgia (TN). The safety and efficacy of CyberKnife radiosurgery as a treatment option for TN, however, has not been established.Forty-one patients were treated between May 2002 and September 2004 for idiopathic TN at Stanford University and the Rocky Mountain CyberKnife Center. Patients with atypical pain, multiple sclerosis, or previous radiosurgical treatment or a follow-up duration of less than 6 months were excluded. Patients were evaluated for the level of pain control, response rate, time to pain relief, occurrence of hypesthesia, and time to pain recurrence with respect to the length of the nerve treated and the maximum and the minimum dose to the nerve margin. Thirty-eight patients (92.7%) experienced initial pain relief at a median of 7 days after treatment (range, 24 hours-4 months). Pain control was ranked as excellent in 36 patients (87.8%), moderate in two (4.9%), and three (7.3%) reported no change. Six (15.8%) of the 38 patients with initial relief experienced a recurrence of pain at a median of 6 months (range 2-8 months). Long-term response after a mean follow-up time of 11 months was found in 32 (78%) of 41. Twenty-one patients (51.2%) experienced numbness after treatment.CyberKnife radiosurgery for TN has high rates of initial pain control and short latency to pain relief compared with those reported for other radiosurgery systems. The doses used for treatment were safe and effective. Higher prescribed doses were not associated with improvement in pain relief or recurrence rate. The hypesthesia rate was related to the length of the trigeminal nerve treated.

  View details for PubMedID 15913285

• Characterization of the integrin alpha v beta 3 in arteriovenous malformations and cavernous malformations CEREBROVASCULAR DISEASES Lim, M., Haddix, T., Harsh, G. R., Vogel, H., Steinberg, G. K., Guccione, S. 2005; 20 (1): 23-27

  Abstract

  Alpha V beta 3 (alphavbeta3) is an integrin specifically expressed on the endothelial cells of central nervous system (CNS) neoplasms. However, no data exist on the expression of alphavbeta3 in vascular malformations of the CNS. In this study, we investigate the expression of alphavbeta3 in arteriovenous malformations (AVMs) and cavernous malformations (CMs).Frozen samples of AVMs from 12 patients and CMs from 5 patients were obtained intraoperatively. Once the final pathology had been confirmed, immunohistochemistry was performed using an antibody to the integrin alphavbeta3. The alphavbeta3 expression pattern was graded according to the percentage of positively staining vessels.Ten of 12 AVMs demonstrated alphavbeta3 immunopositivity. Six of these 10 AVMs had moderate or strong staining. Most notably, 5 of the 6 moderate or strongly staining AVMs came from patients 22 years of age or younger. Four of these 6 AVMs had previously been embolized. None of the cavernous malformations demonstrated alphavbeta3 immunopositivity.alphavbeta3 may contribute to the formation of AVMs in younger patients. alphavbeta3 may also provide a potential therapeutic target. The lack of alphavbeta3 expression in cavernous malformations, despite their high vascular densities, suggests that the pathophysiology of their formation differs from that of AVMs.

  View details for DOI 10.1159/000086123

  View details for PubMedID 15925879

• Efficacy and safety of stereotactic radiosurgery for glomus jugulare tumors. Neurosurgical focus Lim, M., Gibbs, I. C., Adler, J. R., Chang, S. D. 2004; 17 (2): E11-?

  Abstract

  Since the mid-1990s the use of radiosurgery for glomus jugulare tumors has grown in popularity. Despite its increased use, follow-up periods for radiosurgery are short and the numbers of patients reported are small. To add to the available information, the authors report their experience with the application of linear accelerator (LINAC) or CyberKnife modalities in 13 patients with 16 tumors.All patients were treated with frame-based LINAC or CyberKnife radiosurgery, with doses ranging from 1400 to 2700 cGy. Patients were retrospectively assessed for posttreatment side effects, which included hearing loss, tongue weakness, and vocal hoarseness. The patients' most recent magnetic resonance (MR) images were also assessed for changes in tumor size. The median follow-up duration was 41 months and the mean follow-up period was 60 months. All tumors remained stable or decreased in size on follow-up MR images. All patients had stable neurological symptoms, and one experienced transient ipsilateral tongue weakness and hearing loss, both of which subsequently resolved. One patient experienced transient ipsilateral vocal cord paresis; however, this individual had received previous external-beam radiation therapy.The authors' findings continue to support radiosurgery as an effective and safe method of treatment for glomus jugulare tumors that results in low rates of morbidity.

  View details for PubMedID 15329026

• The efficacy of linear accelerator stereotactic radiosurgery in treating glomus jugulare tumors TECHNOLOGY IN CANCER RESEARCH & TREATMENT Lim, M., Gibbs, I. C., Adler, J. R., Martin, D. P., Chang, S. D. 2003; 2 (3): 261-265

  Abstract

  Treatment of glomus jugulare tumors with radiosurgery has grown in acceptance since the first reported treatment in 1995, but only a few centers have reported their experiences with limited follow up time. We report our experience with stereotactic radiosurgery in nine patients with ten glomus tumors. All patients were treated either with frame based LINAC or Cyberknife with doses ranging from 1600 cGy to 2500 cGy. Three patients received no previous therapy and one patient received additional external beam radiation for concomitant treatment of carotid body tumors. Patients were then followed for post treatment side effects in addition to change in tumor size by MRI evaluation. The median clinical follow-up time was 26 months (mean 54 months), median radiographic follow-up was 21.5 months (mean 46 months), with a range from 3 to 126 months. The results from our center demonstrated nine of ten tumors to be stable in size by MRI exam, and one tumor which regressed in size. Nine patients had stable neurological symptoms, and one patient experienced transient ipsilateral tongue weakness and hearing loss, both of which subsequently resolved. Our results continue to support radiosurgery as a suitable form of treatment for glomus jugulare tumors as evidenced by results from this four and a half year follow-up.

  View details for Web of Science ID 000183918300008

  View details for PubMedID 12779355

• Reversible posterior leukoencephalopathy occurring during resection of a posterior fossa tumor: Case report and review of the literature NEUROSURGERY Moriarity, J. L., Lim, M., Storm, P. B., Beauchamp, N. J., Olivi, A. 2001; 49 (5): 1237–39

  Abstract

  Our goal was to present a clinically and radiographically documented case of reversible posterior leukoencephalopathy (RPL) that occurred during resection of a posterior fossa tumor. Although RPL has been previously described in multiple nonsurgical settings, we hope that this case description makes RPL more clinically and radiographically recognizable to neurosurgeons.RPL is the clinical syndrome of headaches, altered mental status, seizures, and visual loss, with radiographic findings of reversible parieto-occipital changes on cerebral computed tomographic and magnetic resonance imaging scans. It has been previously reported in the settings of malignant hypertension, renal disease, eclampsia, and immunosuppression. To our knowledge, the patient presented represents the first clinically and radiographically documented case of RPL occurring during resection of a posterior fossa tumor. The patient intraoperatively exhibited wide fluctuations in blood pressure and awoke with clinical and radiographic findings consistent with RPL.Aggressive intraoperative and postoperative management of the patient's blood pressure, supportive intensive care, rehabilitation, and close radiographic follow-up were performed.RPL can occur as a result of intraoperative variations in blood pressure, even among young, previously healthy individuals. With the aforementioned interventions, the patient experienced significant clinical and radiographic recovery.

  View details for DOI 10.1097/00006123-200111000-00040

  View details for Web of Science ID 000171760000047

  View details for PubMedID 11846918

• Overexpression of hypoxia-inducible factor 1 alpha in common human cancers and their metastases CANCER RESEARCH Zhong, H., De Marzo, A. M., Laughner, E., Lim, M., Hilton, D. A., Zagzag, D., Buechler, P., Isaacs, W. B., Semenza, G. L., Simons, J. W. 1999; 59 (22): 5830–35

  Abstract

  Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.

  View details for Web of Science ID 000083853300032

  View details for PubMedID 10582706

• Induction of immunity to prostate cancer antigens: Results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer CANCER RESEARCH Simons, J. W., Mikhak, B., Chang, J. F., DeMarzo, A. M., Carducci, M. A., Lim, M., Weber, C. E., Baccala, A. A., Goemann, M. A., Clift, S. M., Ando, D. G., Levitsky, H. I., Cohen, L. K., Sanda, M. G., Mulligan, R. C., Partin, A. W., Carter, H. B., Piantadosi, S., Marshall, F. F., Nelson, W. G. 1999; 59 (20): 5160–68

  Abstract

  Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.

  View details for Web of Science ID 000083267400021

  View details for PubMedID 10537292