Publications by authors named "Christopher Alvarez-Breckenridge"

33 Publications

The Use of Skin Staples as Fiducial Markers to Confirm Intraoperative Spinal Navigation Registration and Accuracy.

Oper Neurosurg (Hagerstown) 2021 May 26. Epub 2021 May 26.

Division of Surgery, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: With the advent of intraoperative computed tomography (CT) for image guidance, numerous examples of accurate navigation being applied to cranial and spinal pathology have come to light. For spinal disorders, the utilization of image guidance for the placement of percutaneous spinal instrumentation, complex osteotomies, and minimally invasive approaches are frequently utilized in trauma, degenerative, and oncological pathologies. The use of intraoperative CT for navigation, however, requires a low target registration error that must be verified throughout the procedure to confirm the accuracy of image guidance.

Objective: To present the use of skin staples as a sterile, economical fiducial marker for minimally invasive spinal procedures requiring intraoperative CT navigation.

Methods: Staples are applied to the skin prior to obtaining the registration CT scan and maintained throughout the remainder of the surgery to facilitate confirmation of image guidance accuracy.

Results: This low-cost, simple, sterile approach provides surface landmarks that allow reliable verification of navigation accuracy during percutaneous spinal procedures using intraoperative CT scan image guidance.

Conclusion: The utilization of staples as a fiducial marker represents an economical and easily adaptable technique for ensuring accuracy of image guidance with intraoperative CT navigation.
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http://dx.doi.org/10.1093/ons/opab132DOI Listing
May 2021

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Nat Med 2021 Jun 3;27(6):985-992. Epub 2021 May 3.

Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA.

Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
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http://dx.doi.org/10.1038/s41591-021-01331-8DOI Listing
June 2021

Surgical Management of Skull Base and Spine Chordomas.

Curr Treat Options Oncol 2021 Mar 20;22(5):40. Epub 2021 Mar 20.

Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 442, Houston, TX, 77030-4009, USA.

Opinion Statement: Management of chordoma along the cranial-spinal axis is a major challenge for both skull base and spinal surgeons. Although chordoma remains a rare tumor, occurring in approximately 1 per 1 million individuals, its treatment poses several challenges. These tumors are generally poorly responsive to radiation and chemotherapy, leading to surgical resection as the mainstay of treatment. Due to anatomic constraints and unique challenges associated with each primary site of disease, gross total resection is often not feasible and is associated with high rates of morbidity. Additionally, chordoma is associated with high rates of recurrence due to the tumor's aggressive biologic features, and postoperative radiation is increasingly incorporated as a treatment option for these patients. Despite these challenges, modern-day surgical techniques in both skull base and spinal surgery have facilitated improved patient outcomes. For example, endoscopic endonasal techniques have become the mainstay in resection of skull base chordomas, improving the ability to achieve gross total resection, while reducing associated morbidity of open transfacial techniques. Resection of spinal chordomas has been facilitated by emerging techniques in preoperative imaging, intraoperative navigation, spinal reconstruction, and radiotherapy. Taken collectively, the treatment of chordoma affecting the skull base and spinal requires a multidisciplinary team of surgeons, radiation oncologists, and medical oncologists who specialize in the treatment of this challenging disease.
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http://dx.doi.org/10.1007/s11864-021-00838-zDOI Listing
March 2021

Initial Approach to the Patient with Multiple Newly Diagnosed Brain Metastases.

Neurosurg Clin N Am 2020 Oct;31(4):505-513

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Brain metastases are the most common intracranial tumor in adults, with increasing incidence owing to prolonged survival times. Roughly half of patients diagnosed with new brain metastases have greater than 1 brain metastasis at the time of diagnosis, raising the question of how to optimize patient care with multiple brain metastases. The authors review studies relevant to the care of patients with brain metastasis, with emphasis on those relevant to the care of patients with multiple brain metastases. They discuss evolving strategies involving multiple modalities and the benefit of surgical management in patients with a large symptomatic brain metastasis.
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http://dx.doi.org/10.1016/j.nec.2020.05.002DOI Listing
October 2020

Predicting tumor-specific survival in patients with spinal metastatic renal cell carcinoma: which scoring system is most accurate?

J Neurosurg Spine 2020 Jun 5:1-11. Epub 2020 Jun 5.

Departments of1Neurosurgery.

Objective: Although several prognostic scores for spinal metastatic disease have been developed in the past 2 decades, the applicability and validity of these models to specific cancer types are not yet clear. Most of the data used for model formation are from small population sets and have not been updated or externally validated to assess their performance. Developing predictive models is clinically relevant as prognostic assessment is crucial to optimal decision-making, particularly the decision for or against spine surgery. In this study, the authors investigated the performance of various spinal metastatic disease risk models in predicting prognosis for spine surgery to treat metastatic renal cell carcinoma (RCC).

Methods: Data of patients who underwent surgery for RCC metastatic to the spine at 2 tertiary centers between 2010 and 2019 were retrospectively retrieved. The authors determined the prognostic value associated with the following scoring systems: the Tomita score, original and revised Tokuhashi scores, original and modified Bauer scores, Katagiri score, the Skeletal Oncology Research Group (SORG) classic algorithm and nomogram, and the New England Spinal Metastasis Score (NESMS). Regression analysis of patient variables in association with 1-year survival after surgery was assessed using Cox proportional hazard models. Calibration and time-dependent discrimination analysis were tested to quantify the accuracy of each scoring system at 3 months, 6 months, and 1 year.

Results: A total of 86 metastatic RCC patients were included (median age 64 years [range 29-84 years]; 63 males [73.26%]). The 1-year survival rate was 72%. The 1-year survival group had a good performance status (Karnofsky Performance Scale [KPS] score 80%-100%) and an albumin level > 3.5 g/dL (p < 0.05). Multivariable-adjusted Cox regression analysis showed that poor performance status (KPS score < 70%), neurological deficit (Frankel grade A-D), and hypoalbuminemia (< 3.5 g/dL) were associated with a higher risk of death before 1 year (p < 0.05). The SORG nomogram, SORG classic, original Tokuhashi, and original Bauer demonstrated fair performance (0.7 < area under the curve < 0.8). The NESMS differentiates survival among the prognostic categories with the highest accuracy (area under the curve > 0.8).

Conclusions: The present study shows that the most cited and commonly used scoring systems have a fair performance predicting survival for patients undergoing spine surgery for metastatic RCC. The NESMS had the best performance at predicting 1-year survival after surgery.
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http://dx.doi.org/10.3171/2020.4.SPINE20173DOI Listing
June 2020

Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

Nat Med 2020 08 2;26(8):1280-1284. Epub 2020 Jun 2.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.
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http://dx.doi.org/10.1038/s41591-020-0918-0DOI Listing
August 2020

Does Obesity Correlate with Postoperative Complications After Elective Posterior Cervical Spine Fusion?

World Neurosurg 2020 09 17;141:e231-e238. Epub 2020 May 17.

Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:

Background: With the increasing prevalence of obesity, there is a need to understand the impact of body mass index (BMI) on spine surgery outcomes. Previous literature has reported the influence of obesity in thoracolumbar surgery; however, the impact of obesity on postoperative complications after posterior cervical fusion (PCF) is unknown.

Methods: Consecutive patients who underwent cervical laminectomy and multi-level instrumented fusion for degenerative spinal conditions at an academic tertiary care hospital between 2012 and 2019 were evaluated. Patients were categorized into groups with a BMI ≥30.0 kg/m. The modified Japanese Orthopedic Association (mJOA) score, Nurick grading, complications, and postoperative radiographic factors were analyzed. Correlations between postoperative outcomes and obesity were calculated at baseline and 1 year.

Results: A total of 275 patients were included, with 80 obese (29.1%) and 195 nonobese (70.9%) patients. At baseline, obesity was associated with worse myelopathy (mJOA score: 10.2 vs. 13.1, P = 0.04 and Nurick grading: 3.2 vs. 1.1, P = 0.05) and abnormal cervical radiographic alignment (C2-7 sagittal vertical axis: 43.9 vs. 38.1 mm, P = 0.04). The intraoperative estimated blood loss was higher among obese patients (561.1 vs. 391.2 mL, P < 0.001). There was no significant difference in absolute scores for neurologic outcomes and radiographic alignment at 12 months after surgery. However, obese patients had significantly more complications than nonobese patients in terms of mechanical failure (6.3% vs. 0.5%, P = 0.05) and wound infection (8.7% vs. 0.0%, P = 0.04).

Conclusions: Our results corroborate that PCF surgery provides significant improvement in neurologic and radiographic outcomes at 12 months after surgery for degenerative cervical spinal disorders. Obesity is a factor to consider in the pre-operative risk assessment.
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http://dx.doi.org/10.1016/j.wneu.2020.05.083DOI Listing
September 2020

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.

Nat Genet 2020 04 23;52(4):371-377. Epub 2020 Mar 23.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Comprehensive Cancer Center Vienna, Vienna, Austria.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
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http://dx.doi.org/10.1038/s41588-020-0592-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136154PMC
April 2020

Predictive Analytics in Spine Oncology Research: First Steps, Limitations, and Future Directions.

Neurospine 2019 Dec 31;16(4):669-677. Epub 2019 Dec 31.

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The potential of big data analytics to improve the quality of care for patients with spine tumors is significant. At this moment, the application of big data analytics to oncology and spine surgery is at a nascent stage. As such, efforts are underway to advance data-driven oncologic care, improve patient outcomes, and guide clinical decision making. This is both relevant and critical in the practice of spine oncology as clinical decision making is often made in isolation looking at select variables deemed relevant by the physician. With rapidly evolving therapeutics in surgery, radiation, interventional radiology, and oncology, there is a need to better develop decision-making algorithms utilizing the vast data available for each patient. The challenges and limitations inherent to big data analyses are presented with an eye towards future directions.
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http://dx.doi.org/10.14245/ns.1938402.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944986PMC
December 2019

In Reply: Congress of Neurological Surgeons Systematic Review and Evidence-Based Practice Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors.

Neurosurgery 2019 09;85(3):E618

Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts.

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http://dx.doi.org/10.1093/neuros/nyz235DOI Listing
September 2019

Upfront Surgical Resection of Melanoma Brain Metastases Provides a Bridge Toward Immunotherapy-Mediated Systemic Control.

Oncologist 2019 05 22;24(5):671-679. Epub 2019 Feb 22.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA

Background: Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy.

Material And Methods: An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS.

Results: The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞;  = .12). On multivariate analysis, immunotherapy-naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naïve brain metastases treated with surgery followed by immunotherapy.

Conclusion: In treatment-naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve melanoma brain metastases is warranted.

Implications For Practice: In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy-naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naïve melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.
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http://dx.doi.org/10.1634/theoncologist.2018-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516108PMC
May 2019

The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in -Mutant Breast Cancer Brain Metastases.

Clin Cancer Res 2019 06 22;25(11):3374-3383. Epub 2019 Feb 22.

Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models. The efficacy of GDC-0084 was evaluated in -mutant and wild-type breast cancer cell lines and the isogenic pairs of wild-type and mutant (H1047R/+) MCF10A cells . studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. , the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.

Results: , GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in -mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in wild-type cell lines . , treatment with GDC-0084 markedly inhibited the growth of -mutant, with accompanying signaling changes, and not wild-type brain tumors.

Conclusions: The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685218PMC
June 2019

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors.

Neurosurgery 2019 03;84(3):E152-E155

Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia.

Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below.  SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)?

Recommendations: Level 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. Level 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits.  SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities?

Recommendations: Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT.  SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection?

Recommendations: Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS.  SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence?

Recommendation: Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases.

Question B: Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence?

Recommendation: Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2.
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http://dx.doi.org/10.1093/neuros/nyy542DOI Listing
March 2019

SMO mutant olfactory groove meningiomas-the next in line for targeted therapy.

Neuro Oncol 2017 03;19(3):305-306

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1093/neuonc/now302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464315PMC
March 2017

Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor.

NPJ Precis Oncol 2017 20;1(1). Epub 2017 Mar 20.

2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.

Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the gene family in a subset of our cohort. One-patient with exon 13 fused to exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient's targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.
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http://dx.doi.org/10.1038/s41698-017-0009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871889PMC
March 2017

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy.

Clin Cancer Res 2017 Apr 9;23(7):1809-1819. Epub 2016 Nov 9.

Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.

Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies and macrophages derived from mice were used. RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus in or wild-type non-tumor-bearing mice revealed the safety of this approach. We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380537PMC
April 2017

Are BiTEs the "missing link" in cancer therapy?

Oncoimmunology 2015 Jun 30;4(6):e1008339. Epub 2015 Apr 30.

Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; Department of Pathology; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA ; Department of Biomedical Engineering; Duke University ; Durham, NC, USA.

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.
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http://dx.doi.org/10.1080/2162402X.2015.1008339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485829PMC
June 2015

Ventriculoperitoneal shunt placement for POEMS syndrome.

J Clin Neurosci 2015 Oct 12;22(10):1672-4. Epub 2015 Jun 12.

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street Wang 021, Boston, MA 02114, USA.

We report a 41-year-old woman with a history of an uncomplicated spinal hemangioma resection, who developed acute onset sensory-motor polyneuropathy following influenza vaccine administration. With extensive workup she was diagnosed with POEMS syndrome with progressive headaches, visual loss with papilledema, and repeated elevated lumbar puncture opening pressures despite treatment with acetazolamide and immunosuppressive therapy. Her symptoms dramatically improved following ventriculoperitoneal shunt placement. POEMS syndrome is a paraneoplastic disorder involving a constellation of clinical symptoms including polyneuropathy, organomegaly, endocrinopathy, monoclonal protein elevation, and skin changes. The progression of the disease involves a number of neurovascular sequelae, including symmetric sensory-motor polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy, cerebrovascular accidents, and papilledema associated with increased intracranial pressure. Despite the association of POEMS with papilledema, treatment for this finding typically includes acetazolamide and therapeutic large volume lumbar punctures. To our knowledge, this is the first report of cerebrospinal fluid shunting for the symptomatic management of hydrocephalus associated with POEMS syndrome.
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http://dx.doi.org/10.1016/j.jocn.2015.03.042DOI Listing
October 2015

TGF-β signaling and its targeting for glioma treatment.

Am J Cancer Res 2015 15;5(3):945-55. Epub 2015 Feb 15.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University Columbus, Ohio 43210, USA ; The Ohio State University Comprehensive Cancer Center Columbus, Ohio 43210, USA.

Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine, secreted by a variety of cells including immune cells, tumor cells, and stromal cells. TGF-β signaling is dysregulated in cancer patients, and this aberrant signaling at least in part contributes to initiation and progression of many cancers including glioma. The dysregulated signaling components provide molecular targets for the treatment of glioma. In this article, we review TGF-β signaling and its targeting in glioma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449428PMC
June 2015

Potentiating oncolytic viral therapy through an understanding of the initial immune responses to oncolytic viral infection.

Curr Opin Virol 2015 Aug 4;13:25-32. Epub 2015 Apr 4.

Department of Neurosurgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

Despite the challenge of implementing oncolytic viral therapy into mainstream clinical use, the obstacles of early clinical trials have outlined numerous areas requiring additional investigation. In particular, the role of innate and adaptive immunity has received significant attention in this context. It is increasingly clear that a one-sided approach of either immune suppression or robust immune cell activation is not the answer for clinical success. Rather, recent studies are increasingly demonstrating the delicate balance between both anti-viral immune suppression and immune mediated tumor killing. In this review we focus on aspects of innate immune cell activation following oncolytic viral infection and how this response has the potential of bridging to the broader goal of viral mediated immunotherapy.
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http://dx.doi.org/10.1016/j.coviro.2015.03.015DOI Listing
August 2015

Uncovering a novel mechanism whereby NK cells interfere with glioblastoma virotherapy.

Oncoimmunology 2013 Apr;2(4):e23658

Medical Scientist Training Program; The Ohio State University Medical Center; Columbus, OH USA ; Dardinger Laboratory for Neuro-Oncology and Neurosciences; Department of Neurological Surgery; The Ohio State University Medical Center; Columbus, OH USA.

Despite initial promising results, the success of clinical trials testing oncolytic viruses in glioblastoma patients has been limited. Innate immunity appears to be one among several barriers against successful viral oncolysis. Recent findings suggest a mechanism by which natural killer cells limit the efficacy of oncolytic viruses via natural cytotoxicity receptors.
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http://dx.doi.org/10.4161/onci.23658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654589PMC
April 2013

Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations.

Cancer Res 2013 Jun;73(11):3441-50

Department of Neurological Surgery, Dardinger Neuro-oncology Center, Solid Tumor Program at the James Comprehensive Cancer Center, Center for Biostatistics, Departments of Pathology, Veterinary Biosciences, and Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.

To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1(loxP/+); Trp53(-/+) genetic mouse model of glioma (Mut3 mice). Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but, by 7 weeks, there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas than control Mut3 mice perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV versus controls. MCMV infection increased phosphorylated STAT3 (p-STAT3) levels in neural stem cells (NSC) harvested from Mut3 mice subventricular zone, and, in vivo, there was increased p-STAT3 in NSCs in MCMV-infected compared with control mice. Of relevance, human CMV (HCMV) also increased p-STAT3 and proliferation of patient-derived glioblastoma neurospheres, whereas a STAT3 inhibitor reversed this effect in vitro and in vivo. These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136413PMC
June 2013

MicroRNAs activate natural killer cells through Toll-like receptor signaling.

Blood 2013 Jun 11;121(23):4663-71. Epub 2013 Apr 11.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

MicroRNAs (miRNAs) bind to complementary sequences of target mRNAs, resulting in translational repression or target degradation and thus gene silencing. miRNAs are abundant in circulating blood, yet it is not known whether, as a class of regulatory molecules, they interact with human natural killer (NK) cells. Here we found that the treatment of human NK cells with several mature miRNAs in the presence of a low concentration of interleukin-12 induced CD69 expression, interferon-γ production, and degranulation marker CD107a expression. In vivo, infusion of several miRNAs alone in murine peripheral blood also resulted in comparable NK-cell activation, but not T-cell activation. Furthermore, miRNA administration significantly protected mice from tumor development in an NK cell-dependent manner. Mechanistically, we found that miRNA stimulation led to downstream activation of nuclear factor κB (NF-κB), an effect that was blunted by a block in Toll-like receptor 1(TLR1) signaling and attenuated in lymphoma patients. Knockdown of TLR1 resulted in less activation by miRNAs. Collectively, we show that miRNAs have a capacity to selectively activate innate immune effector cells that is, at least in part, via the TLR1-NF-κB signaling pathway. This may be important in the normal host defense against infection and/or malignant transformation.
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http://dx.doi.org/10.1182/blood-2012-07-441360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674667PMC
June 2013

NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors.

Nat Med 2012 Dec 25;18(12):1827-34. Epub 2012 Nov 25.

Medical Scientist Training Program, Ohio State University Medical Center, Columbus, Ohio, USA.

The role of the immune response to oncolytic Herpes simplex viral (oHSV) therapy for glioblastoma is controversial because it might enhance or inhibit efficacy. We found that within hours of oHSV infection of glioblastomas in mice, activated natural killer (NK) cells are recruited to the site of infection. This response substantially diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK cells preferentially lysed oHSV-infected human glioblastoma cell lines. This enhanced killing depended on the NK cell natural cytotoxicity receptors (NCRs) NKp30 and NKp46, whose ligands are upregulated in oHSV-infected glioblastoma cells. We found that HSV titers and oHSV efficacy are increased in Ncr1(-/-) mice and a Ncr1(-/-) NK cell adoptive transfer model of glioma, respectively. These results demonstrate that glioblastoma virotherapy is limited partially by an antiviral NK cell response involving specific NCRs, uncovering new potential targets to enhance cancer virotherapy.
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http://dx.doi.org/10.1038/nm.3013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668784PMC
December 2012

Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV.

Clin Cancer Res 2012 Sep 2;18(18):4931-41. Epub 2012 Jul 2.

Dardinger Laboratory for Neuro-oncology and Neurosciences, Northwestern University, Evanston, Illinois, USA.

Purpose: Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus-derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV.

Experimental Design: Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated.

Results: Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery.

Conclusion: This study shows that combining ATN-224 with oHSV significantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-0697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784008PMC
September 2012

The histone deacetylase inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells by inhibition of STAT5/T-BET signaling and generation of gamma interferon.

J Virol 2012 Apr 8;86(8):4566-77. Epub 2012 Feb 8.

Medical Scientist Training Program, The Ohio State University Medical Center and The James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

Tumor virotherapy has been and continues to be used in clinical trials. One barrier to effective viral oncolysis, consisting of the interferon (IFN) response induced by viral infection, is inhibited by valproic acid (VPA) and other histone deacetylase inhibitors (HDACi). Innate immune cell recruitment and activation have been shown to be deleterious to the efficacy of oncolytic herpes simplex virus (oHSV) infection, and in this report we demonstrate that VPA limits this deleterious response. VPA, administered prior to oHSV inoculation in an orthotopic glioblastoma mouse model, resulted in a decline in NK and macrophage recruitment into tumor-bearing brains at 6 and 24 h post-oHSV infection. Interestingly, there was a robust rebound of recruitment of these cells at 72 h post-oHSV infection. The observed initial decline in immune cell recruitment was accompanied by a reduction in their activation status. VPA was also found to have a profound immunosuppressive effect on human NK cells in vitro. NK cytotoxicity was abrogated following exposure to VPA, consistent with downmodulation of cytotoxic gene expression of granzyme B and perforin at the mRNA and protein levels. In addition, suppression of gamma IFN (IFN-γ) production by VPA was associated with decreased STAT5 phosphorylation and dampened T-BET expression. Despite VPA-mediated immune suppression, mice were not at significantly increased risk for HSV encephalitis. These findings indicate that one of the avenues by which VPA enhances oHSV efficacy is through initial suppression of immune cell recruitment and inhibition of inflammatory cell pathways within NK cells.
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http://dx.doi.org/10.1128/JVI.05545-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318659PMC
April 2012

Deciphering the Multifaceted Relationship between Oncolytic Viruses and Natural Killer Cells.

Adv Virol 2012 11;2012:702839. Epub 2011 Dec 11.

Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210, USA.

Despite active research in virotherapy, this apparently safe modality has not achieved widespread success. The immune response to viral infection appears to be an essential factor that determines the efficacy of oncolytic viral therapy. The challenge is determining whether the viral-elicited immune response is a hindrance or a tool for viral treatment. NK cells are a key component of innate immunity that mediates antiviral immunity while also coordinating tumor clearance. Various reports have suggested that the NK response to oncolytic viral therapy is a critical factor in premature viral clearance while also mediating downstream antitumor immunity. As a result, particular attention should be given to the NK cell response to various oncolytic viral vectors and how their antiviral properties can be suppressed while maintaining tumor clearance. In this review we discuss the current literature on the NK response to oncolytic viral infection and how future studies clarify this intricate response.
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http://dx.doi.org/10.1155/2012/702839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263705PMC
August 2012

NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human.

J Clin Invest 2011 Apr;121(4):1456-70

Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.

IL-15 may have a role in the development of T cell large granular lymphocyte (T-LGL) or NKT leukemias. However, the mechanisms of action and the identity of the cell subset that undergoes leukemic transformation remain elusive. Here we show that in both mice and humans, NKp46 expression marks a minute population of WT NKT cells with higher activity and potency to become leukemic. Virtually 100% of T-LGL leukemias in IL-15 transgenic mice expressed NKp46, as did a majority of human T-LGL leukemias. The minute NKp46+ NKT population, but not the NKp46⁻ NKT population, was selectively expanded by overexpression of endogenous IL-15. Importantly, IL-15 transgenic NKp46⁻ NKT cells did not become NKp46+ in vivo, suggesting that NKp46+ T-LGL leukemia cells were the malignant counterpart of the minute WT NKp46+ NKT population. Mechanistically, NKp46+ NKT cells possessed higher responsiveness to IL-15 in vitro and in vivo compared with that of their NKp46⁻ NKT counterparts. Furthermore, interruption of IL-15 signaling using a neutralizing antibody could prevent LGL leukemia in IL-15 transgenic mice. Collectively, our data demonstrate that NKp46 identifies a functionally distinct NKT subset in mice and humans that appears to be directly susceptible to leukemic transformation when IL-15 is overexpressed. Thus, IL-15 signaling and NKp46 may be useful targets in the treatment of patients with T-LGL or NKT leukemia.
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http://dx.doi.org/10.1172/JCI43242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069763PMC
April 2011