Publications by authors named "Robert A Fenstermaker"

57 Publications

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab065. Epub 2021 May 7.

KIYATEC, Inc., Greenville, South Carolina, USA.

Background: Clinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment.

Methods: A modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up.

Results: Absent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders ( = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes.

Conclusion: This study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.
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http://dx.doi.org/10.1093/noajnl/vdab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207705PMC
May 2021

Primary Leiomyosarcoma of the Calvarium with Intracranial Extension: a Case Report.

Indian J Surg Oncol 2020 Sep 1;11(Suppl 2):165-169. Epub 2020 Jul 1.

Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY USA.

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http://dx.doi.org/10.1007/s13193-020-01129-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732912PMC
September 2020

Lateral Temporal Approach for Image-Guided Stereotactic Biopsy of Pineal Region Tumors.

World Neurosurg 2021 03 9;147:144-149. Epub 2020 Dec 9.

Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA.

Background: Biopsy of pineal region neoplasms is frequently accomplished by way of endoscopic transventricular access or using an image-guided, computer-assisted stereotactic approach.

Methods: We evaluated a nonorthogonal lateral temporal approach for stereotactic biopsy of pineal region tumors as a variation of previously described stereotactic methods. Magnetic resonance imaging-guided frameless stereotaxy was used to plan and perform biopsies of pineal region tumors using a nonorthogonal trajectory extending from the superior or middle temporal gyri through the temporal stem, anterior to the atrium of the lateral ventricle, and posterior to the corticospinal tract.

Results: All patients had an uncomplicated postoperative course and remained at neurologic baseline. No parenchymal or ventricular hemorrhage was present on postoperative scans. A tissue diagnosis was obtained in all patients.

Conclusions: This method appears to be a safe alternative to stereotactic biopsy using other trajectories and provides adequate tissue for definitive diagnosis.
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http://dx.doi.org/10.1016/j.wneu.2020.11.128DOI Listing
March 2021

The Presence of Survivin on B Cells from Myasthenia Gravis Patients and the Potential of an Antibody to a Modified Survivin Peptide to Alleviate Weakness in an Animal Model.

J Immunol 2020 10 24;205(7):1743-1751. Epub 2020 Aug 24.

Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037

Myasthenia gravis (MG) is an autoimmune disease in which Abs target neuromuscular junction proteins, in particular the acetylcholine receptor. We previously identified the antiapoptotic protein survivin in the autoreactive B cells and plasma cells of MG patients. To further define the role of survivin in MG, we have assessed PBMCs from 29 patients with MG and 15 controls. We confirmed the increased expression of survivin in CD20 lymphocytes from MG patients compared with controls. Furthermore, the CD20 population of cells from MG patients contained a higher percentage of extracellular survivin compared with controls. The analysis of CD4 cells showed an increased percentage of intracellular survivin in MG patients compared with controls, whereas the extracellular survivin CD4 percentage was unaffected. In an experimental mouse model of MG, we assessed the therapeutic potential of an Ab raised to a modified survivin peptide but cross-reactive to survivin. Ab treatment reduced disease severity, lowered acetylcholine receptor-specific Abs, and decreased CD19 survivin splenocytes. The ability to target survivin through Ab recognition of autoreactive cells offers the potential for a highly specific therapeutic agent for MG.
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http://dx.doi.org/10.4049/jimmunol.2000482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504892PMC
October 2020

Black Bone Disease of the Skull.

World Neurosurg 2020 Feb 27;134:548. Epub 2019 Nov 27.

Roswell Park Comprehensive Cancer Center, State University of New York, Buffalo, New York, USA. Electronic address:

We present an image of a patient's skull characterized by dark, irregular discoloration. This was discovered incidentally in a 66-year-old man who underwent craniotomy for resection of a glioblastoma. This image demonstrates cranial black bone disease. This is an abnormal bone pigmentation associated with long-term tetracycline use, as occurred in this patient.
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http://dx.doi.org/10.1016/j.wneu.2019.11.114DOI Listing
February 2020

Disparities among racial/ethnic groups of patients diagnosed with ependymoma: analyses from the Surveillance, Epidemiology and End Results (SEER) registry.

J Neurooncol 2019 Aug 17;144(1):43-51. Epub 2019 Jun 17.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14203, USA.

Purpose: The aim of this study was to identify racial/ethnic disparities with regard to survival among patients with ependymoma.

Methods: Data from the Surveillance, Epidemiology and End Results (SEER) registry between the years of 1973-2015 which included 4821 patients diagnosed with ependymoma were analyzed. Multivariable cox proportional hazard ratios were performed to examine overall survival across racial/ethnic groups of patients with ependymoma, mortality risks across specified age groups, and mortality during specified time intervals, all with corresponding 95% confidence intervals.

Results: Non-Hispanic black patients (n = 421) have higher risk of overall mortality when compared to non-Hispanic white patients (n = 3255) with ependymoma (HR 1.48, CI 1.17-1.87). Risk of mortality was highest when comparing non-Hispanic black children under the age of 3 to non-Hispanic white children of the same age group (HR 3.05, CI 1.55-5.99). Mortality risk has increased among pediatric non-Hispanic black patients compared to pediatric non-Hispanic white patients between the years of 2006-2015, from previous rates between the years 1973-2005 (HR 1.95, CI 1.15-3.33 and HR 2.35, CI 1.24-4.44). Hispanic patients under 3 years had an increased risk of mortality compared to non-Hispanic white patients of this age group (HR 2.49, CI 1.37-4.53). Asian/Pacific Islander patients (n = 282) had no significant difference in outcomes when compared to non-Hispanic white patients.

Conclusions: Our findings showed higher risk of mortality among non-Hispanic black patients compared to non-Hispanic white patients with ependymoma, with highest risk among pediatric patients. These results demonstrate significant need for research in survival outcomes for this disease.
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http://dx.doi.org/10.1007/s11060-019-03214-yDOI Listing
August 2019

KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma.

J Neurooncol 2018 Dec 20;140(3):519-527. Epub 2018 Sep 20.

Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Purpose: A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood-brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.

Methods: KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.

Results: In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.

Conclusions: The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.
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http://dx.doi.org/10.1007/s11060-018-2992-4DOI Listing
December 2018

Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth .

Clin Cancer Res 2018 06 14;24(11):2642-2652. Epub 2018 Mar 14.

Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes. We have reported that active, specific vaccination with a long peptide survivin immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen. Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to survivin that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well. In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984688PMC
June 2018

Circulating CD9+/GFAP+/survivin+ exosomes in malignant glioma patients following survivin vaccination.

Oncotarget 2017 Dec 10;8(70):114722-114735. Epub 2017 Oct 10.

Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, 14263 USA.

Glioma cells release exosomes in culture and into the extracellular matrix . These nanobodies transport an array of biomolecules and are capable of mediating cell-cell communication. Circulating exosomes in cancer patients may be indicative of disease status and response to therapy. The inhibitor of apoptosis protein (IAP) survivin (SVN) promotes cancer cell proliferation, local immune suppression and resistance to chemotherapy and it is a potential cancer biomarker. We used imaging flow cytometry to perform quantitative measurements of circulating SVN+ exosomes in the serum of malignant glioma patients undergoing investigational treatment with an anti-survivin vaccine (SurVaxM). Serum from glioma patients contained abundant CD9+ exosomes with both SVN and glial fibrillary acidic protein (GFAP) on their surface. Survivin and GFAP were evaluated both independently and together as possible tumor markers on CD9+ exosomes. Patients with longer time to tumor progression generally exhibited a decrease in circulating CD9+/SVN+ and CD9+/GFAP+/SVN+ exosomes immediately following survivin vaccination; whereas, those with early tumor progression had an increase in exosomes, despite anti-survivin immunotherapy. Serum from non-cancer healthy control individuals had very few detectable CD9+/GFAP+/SVN+ exosomes, although CD9+/GFAP+ exosomes were detectable in small numbers. This study demonstrates that patients with malignant gliomas have CD9+/GFAP+/SVN+ and CD9+/SVN+ exosomes that are released into the circulation and that early reductions in their numbers following anti-survivin immunotherapy might be associated with longer progression-free survival.
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http://dx.doi.org/10.18632/oncotarget.21773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777727PMC
December 2017

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

J Natl Compr Canc Netw 2017 11;15(11):1331-1345

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.
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http://dx.doi.org/10.6004/jnccn.2017.0166DOI Listing
November 2017

Impact of the Number of Metastatic Tumors Treated by Stereotactic Radiosurgery on the Dose to Normal Brain: Implications for Brain Protection.

Stereotact Funct Neurosurg 2017 11;95(5):352-358. Epub 2017 Oct 11.

Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Purpose/objectives: The purpose of this study was to evaluate the effect of the number of brain lesions for which stereotactic radiosurgery (SRS) was performed on the dose volume relationships in normal brain.

Materials And Methods: Brain tissue was segmented using the patient's pre-SRS MRI. For each plan, the following data points were recorded: total brain volume, number of lesions treated, volume of brain receiving 8 Gy (V8), V10, V12, and V15.

Results: A total of 225 Gamma Knife® treatments were included in this retrospective analysis. The number of lesions treated ranged from 1 to 29. The isodose for prescription ranged from 40 to 95% (mean 55%). The mean prescription dose to tumor edge was 18 Gy. The mean coverage, selectivity, conformity, and gradient index were 97.5%, 0.63, 0.56, and 3.5, respectively. The mean V12 was 9.5 cm3 (ranging from 0.5 to 59.29). There was no correlation between the number of lesions and brain V8, V12, V10, or V15. There was a direct and statistically significant relationship between the brain volume treated (V8, V10, V12, and V15) and total volume of tumors treated (p < 0.001). In our study, the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3.

Conclusions: The number of metastatic brain lesions treated bears no significant relationship to total brain tissue volume treated when using SRS. The fact that the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3 is useful for establishing guidelines. Although standard practice has favored using whole brain radiation therapy in patients with more than 4 lesions, a significant amount of normal brain tissue may be spared by treating these patients with SRS. SRS should be carefully considered in patients with multiple brain lesions, with the emphasis on total brain volume involved rather than the number of lesions to be treated.
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http://dx.doi.org/10.1159/000480666DOI Listing
August 2018

Novel vaccines for glioblastoma: clinical update and perspective.

Immunotherapy 2016 11;8(11):1293-1308

Department of Neurosurgery, State University of New York at Buffalo, Jacobs School of Medicine & Biomedical Sciences, Buffalo, NY 14260, USA.

Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment.
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http://dx.doi.org/10.2217/imt-2016-0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619015PMC
November 2016

Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma.

Cancer Immunol Immunother 2016 11 30;65(11):1339-1352. Epub 2016 Aug 30.

Department of Biostatistics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. The current clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM (500 μg) in Montanide ISA 51 with sargramostim (100 μg) at 2-week intervals. SurVaxM was well tolerated with mostly grade one adverse events (AE) and no serious adverse events (SAE) attributable to the study drug. Six patients experienced local injection site reactions; three patients reported fatigue (grades 1 and 2), and 2 patients experienced myalgia (grade 1). Six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than 6 months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.
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http://dx.doi.org/10.1007/s00262-016-1890-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069322PMC
November 2016

Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

Acta Neurochir (Wien) 2016 07 16;158(7):1363-6. Epub 2016 May 16.

Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Albany, NY, USA.

Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment.
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http://dx.doi.org/10.1007/s00701-016-2832-2DOI Listing
July 2016

Life-Threatening Mannitol-Induced Hyperkalemia in Neurosurgical Patients.

World Neurosurg 2016 Jul 13;91:672.e5-9. Epub 2016 Apr 13.

Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA; Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, USA. Electronic address:

Background: Mannitol is the most commonly used intraoperative hypertonic solution in patients undergoing craniotomy. However, its use has been reported to be associated with hyperkalemia, which can occasionally be life threatening.

Case Description And Literature Review: In this report, we discuss the case of a patient who had intraoperative cardiac arrest secondary to mannitol-induced hyperkalemia during a craniotomy for tumor resection. In addition, we provide a comprehensive review of the literature concerning similar cases previously reported, as well as a discussion of the pathophysiology of mannitol-induced hyperkalemia. Review of the literature suggests that patients prone to this phenomenon are young and healthy individuals with normal preoperative and postoperative cardiopulmonary and renal functions. The literature also suggests that the total dose of mannitol, as well as its rate of infusion, may play a role in the development of this phenomenon.

Conclusions: Knowledge of the existence of mannitol-induced hyperkalemia is paramount for the neurosurgeon and the anesthesiologist, because early treatment with insulin and calcium can quickly restore normal cardiac rhythm and prevent intraoperative death.
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http://dx.doi.org/10.1016/j.wneu.2016.04.021DOI Listing
July 2016

Papillary tumor of the pineal region with extended clinical and radiologic follow-up.

Surg Neurol Int 2015 7;6(Suppl 18):S451-4. Epub 2015 Oct 7.

Department of Neurosurgery, Roswell Park Cancer Institute, University at Buffalo, State University of New York, Buffalo, NY, USA ; Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.

Background: Papillary tumor of the pineal region (PTPR) is a rare neoplasm with only anecdotal data to guide the treatment. Results of treatment with surgery, radiation therapy, and chemotherapy have been reported to have varying degrees of success. Here we report a patient with a PTPR, who underwent subtotal resection, gamma knife stereotactic radiosurgery, and adjuvant temozolomide chemotherapy.

Case Description: During 9 years of clinical and radiographic follow-up, the patient has had regression of residual tumor and remains asymptomatic.

Conclusion: When gross total resection of a PTPR is not possible, treatment with gamma knife stereotactic radiosurgery and temozolomide chemotherapy may provide long-term tumor control.
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http://dx.doi.org/10.4103/2152-7806.166782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604644PMC
November 2015

Central Nervous System Cancers, Version 1.2015.

J Natl Compr Canc Netw 2015 Oct;13(10):1191-202

From University of Alabama at Birmingham Comprehensive Cancer Center; City of Hope Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Yale Cancer Center/Smilow Cancer Hospital; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; The University of Texas MD Anderson Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of Washington/Seattle Cancer Care Alliance; Roswell Park Cancer Institute; Duke Cancer Institute; UC San Diego Moores Cancer Center; University of Michigan Comprehensive Cancer Center; Memorial Sloan Kettering Cancer Center; St. Jude Children's Research Hospital/University of Tennessee Health Science Center; Massachusetts General Hospital Cancer Center; American Brain Tumor Association; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Stanford Cancer Institute; Fred & Pamela Buffet Cancer Center; Huntsman Cancer Institute at the University of Utah; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Moffitt Cancer Center; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.
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http://dx.doi.org/10.6004/jnccn.2015.0148DOI Listing
October 2015

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2014 Nov;12(11):1517-23

From University of Alabama at Birmingham Comprehensive Cancer Center; City of Hope Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; The University of Texas MD Anderson Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of Washington/Seattle Cancer Care Alliance; Memorial Sloan Kettering Cancer Center; Roswell Park Cancer Institute; Duke Cancer Institute; UC San Diego Moores Cancer Center; American Brain Tumor Association; University of Michigan Comprehensive Cancer Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; Massachusetts General Hospital Cancer Center; Vanderbilt-Ingram Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Stanford Comprehensive Cancer Center; Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; Huntsman Cancer Institute at the University of Utah; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Moffitt Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; and National Comprehensive Cancer Network.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.
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http://dx.doi.org/10.6004/jnccn.2014.0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337873PMC
November 2014

Survivin as a potential mediator to support autoreactive cell survival in myasthenia gravis: a human and animal model study.

PLoS One 2014 22;9(7):e102231. Epub 2014 Jul 22.

Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102231PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106794PMC
March 2016

Challenges in the development of a survivin vaccine (SurVaxM) for malignant glioma.

Expert Rev Vaccines 2014 Mar;13(3):377-85

Department of Neurosurgery, Roswell Park Cancer Institute and State University of New York School of Medicine and Biomedical Sciences, Elm and Carlton Streets, Buffalo, NY 14263, USA.

There is growing interest in immunotherapy for malignant gliomas. This interest stems from a number of immunological observations, together with the failure of conventional therapeutic agents to produce broad and clinically meaningful improvements in survival and quality of life. The challenges faced in translating laboratory-based immunological observations to Phase I and II clinical trials for immunotherapy of gliomas are substantial. Nevertheless, as our understanding of the effects of active specific vaccination in glioma patients grows, results support optimism that such methods may eventually prove useful as an adjunctive treatment for these cancers. This paper highlights a number of barriers encountered in the translational development of a survivin-targeted peptide vaccine (SurVaxM) for patients with malignant gliomas.
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http://dx.doi.org/10.1586/14760584.2014.881255DOI Listing
March 2014

Method for securing titanium cerebellar retractors.

Surg Neurol Int 2013 14;4:146. Epub 2013 Nov 14.

Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, NY, USA ; Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; Buffalo, NY, USA.

Background: Traditional stainless steel retractors can interfere with electromagnetic neuronavigation and intraoperative magnetic resonance imaging (ioMRI). In such cases, titanium instruments are frequently used; however, they often shift during the procedure. The authors describe a simple technique, illustrated with intraoperative photographs, for securing titanium cerebellar retractors into place to keep both the retractors and tissues in their desired locations throughout a craniotomy.

Methods: Titanium retractors were used by our institute's neurosurgical service during operations utilizing electromagnetic neuronavigation or ioMRI. Once the retractor was in the desired position, a 2-0 silk suture was placed around a retractor tong and tied outside the skin. Two sutures were placed on either side of the titanium retractor in the same fashion.

Results: Retractors were subsequently noted to remain in their desired position throughout the operative procedure.

Conclusions: The authors describe a technique for securing titanium cerebellar retractors into their desired position during a craniotomy to minimize their movement during the procedure. This simple technique can help to eliminate a potential frequent source of surgeon frustration, and has proven to be quick to perform, safe, and practicable.
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http://dx.doi.org/10.4103/2152-7806.121404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841919PMC
December 2013

Central nervous system cancers.

J Natl Compr Canc Netw 2013 Sep;11(9):1114-51

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.
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http://dx.doi.org/10.6004/jnccn.2013.0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124889PMC
September 2013

Cranial base repair with combined vascularized nasal septal flap and autologous tissue graft following expanded endonasal endoscopic neurosurgery.

J Neurol Surg A Cent Eur Neurosurg 2013 Mar 14;74(2):101-8. Epub 2013 Jan 14.

Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, United States.

Background: The expanded endonasal endoscopic approach provides excellent visualization and access to midline skull base lesions, albeit with a relatively high risk of postoperative cerebrospinal fluid (CSF) leakage. We present our experience with the expanded endonasal endoscopic approach to the skull base in an institution where, previously, a traditional transsphenoidal approach with a surgical microscope had been used.

Patients: We performed a retrospective review to identify patients who underwent expanded endonasal endoscopic surgery and analyzed demographic, pathological, and operative data with particular attention to repair of the skull base defects in 55 procedures performed on 49 patients. We compared the outcomes of 10 primary operations in which we repaired skull base defects using only autologous or allogeneic tissue grafts and 39 primary operations in which we used a vascularized mucoperichondrial nasal septal flap with or without a layered autologous tissue graft.

Results: Primary expanded endonasal endoscopic procedures were performed in 49 patients with sellar pathology (33 pituitary adenomas, 4 Rathke's cleft cysts, 1 pituicytoma, 1 pituitary metastasis) and non-sellar pathology (3 meningiomas, 3 clival chordomas, 1 clival mucocele, 1 craniopharyngioma, and 2 esthesioneuroblastomas). Postoperative CSF leakage occurred following 5 of the 49 primary operations (10.2%). This occurred in 2 of 10 primary operations (20.0%) in which the skull base defect was repaired using only autologous and/or allogeneic tissue grafts, necessitating a total of 3 operative CSF leak repairs in those 2 patients. The remaining 3 postoperative CSF leaks occurred in the 39 primary operations (7.7%) in which skull base repair was performed using a mucoperichondrial nasal septal flap, necessitating operative repair in 2 of those patients.

Conclusion: The repair of skull base defects created during expanded endonasal endoscopic surgery is improved by use of a mucoperichondrial nasal septal flap combined with a layered autologous tissue graft. When CSF leakage occurs despite nasal septal flap closure, the site of the leakage may be easier to localize and repair.
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http://dx.doi.org/10.1055/s-0032-1330118DOI Listing
March 2013

Tumoral Bing-Neel Syndrome presenting as a cerebellar mass.

Clin Neurol Neurosurg 2013 Jun 16;115(6):823-6. Epub 2012 Aug 16.

Neuro-Oncology Program, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

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http://dx.doi.org/10.1016/j.clineuro.2012.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572123PMC
June 2013

Intracranial meningiomas in patients with uterine sarcoma treated with long-term megestrol acetate therapy.

World Neurosurg 2011 Nov;76(5):477.e16-20

Department of Neurosurgery, Roswell Park Cancer Institute and School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.

Objective: To report a series of four patients with uterine sarcoma, including one with müllerian adenosarcoma (MA) and three with low-grade endometrial stromal sarcoma (LGESS), who developed intracranial meningiomas while receiving the progesterone agonist megestrol acetate.

Methods: The hospital records, imaging studies, and pathology slides of four patients who were treated for uterine sarcomas and subsequently developed intracranial meningiomas were reviewed.

Results: All patients underwent surgery for their gynecologic cancers and received maintenance therapy with long-term hormonal suppression with megestrol acetate. Each of the four patients later developed neurologic symptoms secondary to intracranial meningiomas. Three patients had more than one meningioma. Histopathologic examination of all excised tumors showed strong immunoreactivity for progesterone receptors (PRs).

Conclusions: Patients with uterine sarcoma subtypes LGESS and MA may be predisposed to develop meningiomas, particularly in the setting of long-term treatment with megestrol acetate. Alternatively, preexisting, clinically silent meningiomas in these patients may have progressed to the point of clinical symptoms in the presence of the progesterone agonist megestrol acetate. Without previous imaging studies showing the presence or absence of meningioma before initiation of megestrol acetate treatment, there is no way to draw definitive conclusions regarding this possibility. Clinical and neuroradiologic surveillance for meningiomas should be strongly considered in patients with these uterine sarcoma subtypes, particularly in patients undergoing long-term suppressive therapy with megestrol acetate.
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http://dx.doi.org/10.1016/j.wneu.2011.03.035DOI Listing
November 2011

Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis.

Cancer Res 2012 Jan 11;72(1):133-43. Epub 2011 Nov 11.

Department of Molecular and Biomedical Pharmacology, and Graduate Center for Toxicology, University of Kentucky College of Medicine and Markey Cancer Center, Lexington, Kentucky 40536, USA.

Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3'-5' exonuclease and nucleoside diphosphate kinase, are novel participants in the cellular response to UV radiation (UVR)-induced DNA damage. NM23-H1 deficiency compromised the kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision repair of (6-4) photoproducts in vitro. Kinase activity of NM23-H1 was critical for rapid repair of both polychromatic UVB/UVA-induced (290-400 nm) and UVC-induced (254 nm) DNA damage, whereas its 3'-5' exonuclease activity was dominant in the suppression of UVR-induced mutagenesis. Consistent with its role in DNA repair, NM23-H1 rapidly translocated to sites of UVR-induced (6-4) photoproduct DNA damage in the nucleus. In addition, transgenic mice hemizygous-null for nm23-m1 and nm23-m2 exhibited UVR-induced melanoma and follicular infundibular cyst formation, and tumor-associated melanocytes displayed invasion into adjacent dermis, consistent with loss of invasion-suppressing activity of NM23 in vivo. Taken together, our data show a critical role for NM23 isoforms in limiting mutagenesis and suppressing UVR-induced melanomagenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-1795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251703PMC
January 2012

Antitumor cytotoxic T-cell response induced by a survivin peptide mimic.

Cancer Immunol Immunother 2010 Aug 27;59(8):1211-21. Epub 2010 Apr 27.

Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Survivin is a tumor-associated antigen with significant potential as a cancer vaccine target. We have identified a survivin peptide mimic containing human MHC class I epitopes and a potential class II ligand that induces a potent antitumor response in C57BL/6 mice with GL261 cerebral gliomas. This peptide is able to elicit both CD8+ CTL and T helper cell responses in C57BL/6 mice. The corresponding region of the human survivin molecule represented by peptide SVN53-67 is 100% homologous to the murine protein, but SVN53-67 is weakly immunogenic in man. We evaluated several amino acid substitutions in putative human MHC I anchor positions in SVN53-67 to identify potential peptide mimics that could provide an enhanced antitumor immune response against human glioma and primary central nervous system lymphoma (PCNSL) cells in culture. We evaluated survivin peptides with predicted binding to human HLA-A*0201 antigen using peptide-loaded dendritic cells from PBMC of patients with these malignancies. One alteration (M57) led to binding to HLA-A*0201 with significantly higher affinity. We compared the ability of autologous dendritic cells loaded with SVN53-67 peptide and SVN53-67/M57 in CTL assays against allomatched and autologous, survivin-expressing, human malignant glioma and PCNSL cells. Both SVN53-67 and SVN53-67/M57 produced CTL-mediated killing of malignant target cells; however, SVN53-67/M57 was significantly more effective than SVN53-67. Thus, SVN53-67/M57 may act as a peptide mimic to induce an enhanced antitumor CTL response in tumor patients. The use of SVN53-67/M57 as a cancer vaccine might have application for cancer vaccine therapy.
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http://dx.doi.org/10.1007/s00262-010-0845-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603658PMC
August 2010

Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors.

J Neurooncol 2009 Dec 9;95(3):355-365. Epub 2009 Jul 9.

The Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.

In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98(EGFR). EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.t.) injection or intracerebral (i.c.) convection enhanced delivery (CED) of (125)I-labeled or unlabeled BD-EGF (40 microg (10)B/10 microg EGF) to F98 glioma bearing rats. At 24 h. there was 43% more radioactivity in EGFR(+) tumors following CED compared to i.t. injection, and a doubling of the tumor boron concentration (22.3 microg/g vs. 11.7 microg/g). CED of BD-EGF resulted in a 7.2x increase in the volume of distribution within the infused cerebral hemisphere and a 1.9x increase in tumor uptake of BD-EGF compared with i.t. injection. Based on these favorable biodistribution data, BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following i.c. tumor implantation and 24 h. after CED of BD-EGF. These animals had a MST of 54.1 +/- 4.7 days compared to 43.0 +/- 2.8 days following i.t. injection. Rats that received BD-EGF by CED in combination with i.v. boronophenylalanine (BPA), which has been used in both experimental and clinical studies, had a MST of 86.0 +/- 28.1 days compared to 39.8 +/- 1.6 days for i.v. BPA alone (P < 0.01), 30.9 +/- 1.4 days for irradiated controls and 25.1 +/- 1.0 days for untreated controls (overall P < 0.0001). These data have demonstrated that the efficacy of BNCT was significantly increased (P < 0.006), following i.c CED of BD-EGF compared to i.t injection, and that the survival data were equivalent to those previously reported by us using the boronated anti-human-EGF mAb, C225 (cetuximab).
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http://dx.doi.org/10.1007/s11060-009-9945-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830857PMC
December 2009
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