Jaclyn J. Renfrow

NFKBIA Deletion in Glioblastomas

BACKGROUND Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. METHODS We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. RESULTS NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. CONCLUSIONS Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

A phase 2 trial of single‐agent bevacizumab given in an every‐3‐week schedule for patients with recurrent high‐grade gliomas

The authors evaluated a 3‐week schedule of bevacizumab in patients with recurrent high‐grade glioma (HGG).

Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas

CONTEXT Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood. OBJECTIVES To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas. DESIGN, SETTING, AND PATIENTS Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells. MAIN OUTCOME MEASURES Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis. RESULTS Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion). CONCLUSION Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.

Molecular Subtyping of Brain Metastases and Implications for Therapy

Opinion statementMolecular subtyping of tumors and treatment with specifically targeted therapy is a rapidly developing trend in oncology. Genetic and protein biomarkers impact biological behavior, patient prognosis, and inform treatment options. Select examples include EGFR mutations in primary non-small cell lung cancers, Her2 overexpression in breast cancer, and BRAF mutations in melanoma. Systemic benefit is emphasized in targeted therapies; yet lung cancer, breast cancer, and melanoma comprise the most common diagnoses in patients with brain metastases making the effectiveness of targeted therapies in the treatment and/or prevention of brain metastases relevant.Emerging evidence suggests efficacy for targeted therapy in the setting of brain metastases. Randomized, phase III clinical trials indicate targeted HER2 treatment with lapatinib and capecitabine in brain metastases from breast cancer increases the time to progression and decreases the frequency of CNS involvement at progression. Phase II trials and retrospective reviews for gefitinib and erlotinib demonstrate these agents may have a role in both the chemoprevention of brain metastases and, in combination with WBRT, treatment for non-small cell lung cancer (NSCLC) brain metastases. Dabrafenib and other BRAF inhibitors have demonstrated improved survival in patients with brain metastases from melanoma in a recent phase II clinical trial. Further data that support the use of these agents are the subject of several active clinical trials. Challenges and future directions for targeted therapies in brain metastases include both better characterization and drug design with respect to central nervous system distribution. Limited published data demonstrate suboptimal CNS distribution of currently available targeted chemotherapeutic agents. Increasing systemic dosing, alternate delivery methods, and new compounds with improved CNS distribution are being pursued. Additionally, eventual resistance to targeted therapies poses a challenge; however, research is showing resistance mutations are conserved and relatively predictable creating opportunities for second-line therapies with additional targeted drugs. Newer targeted therapies represent an additional chemotherapeutic option for the treatment and/or prevention of brain metastases in patients with an appropriate molecular profile.

Tracking Career Paths of Women in Neurosurgery

BACKGROUND Women represent a growing cohort of US neurosurgeons. OBJECTIVE To describe postresidency fellowship, practice environment, and updated academic rank among female neurosurgeons. METHODS Databases from the American Association of Neurological Surgeons (AANS) and the American Board of Neurological Surgery (ABNS) from 1964 to 2013 were reviewed for female neurosurgery residency graduates. Data on postresidency fellowships, practice environment (private vs academic), academic rank, board certification, and AANS/CNS (Congress of Neurological Surgeons) Joint Section on Women in Neurosurgery (WINS) membership were collected in 2016. Academic rank was verified from program websites and electronic correspondence. Faculty members were asked to report directorships and tenure. The AANS/CNS Joint Section on Women in Neurosurgery verified WINS membership. RESULTS A total of 379 female neurosurgery residency graduates were identified in this 50-yr span. Of these, 70% became ABNS certified, and 2.1% left neurosurgery. Twenty-seven percent of women (n = 103) pursued fellowships, with pediatric neurosurgery (33%) the most common. Regarding practice environment, 26% entered academic medicine (n = 91), with 42 at the rank of assistant professor, 33 at the rank of associate professor, and 16 reaching the rank of full professor. CONCLUSION Upon completion of training, 27% of women pursue fellowships. The distribution of women in private vs academic practice environments is proportionate to male neurosurgeons; however, the number women in academic leadership positions remains exceedingly low, with disproportionate representation in higher academic ranks. Women in national organized neurosurgery are increasing. Tracking the career paths of women in neurosurgery is a necessary step to identifying current achievements and opportunities for future progress.

Relapsing intracranial plasma cell granuloma: A case report

Plasma cell granuloma is a pathological entity reported in nearly every organ system; however, intracranial cases remain rare. In the current case report, we present a case of intracranial plasma cell granuloma with the longest known follow-up period in the literature. Medical follow-up over 14 years, detailing four recurrences following the patient’s initial presentation and management, is presented. The patient’s treatment course consisted of three craniotomies, 3,600-cGy fractionated radiation and two courses of glucocorticoid therapy. In addition to disease surveillance using clinical examination and imaging, this case represents the first description of the clinical utility of analyzing changes in an inflammatory blood marker, the erythrocyte sedimentation rate, which coincided with recurrence and response to therapy.

Gene–protein correlation in single cells

We present a novel methodology combining traditional fluorescent in situ hybridization with an in situ protein detection technology called proximity ligation assay. This method has potential to perform a detailed analysis of the relationship between gene status and corresponding protein expression in cells and tissues. We demonstrate that the fluorescent in situ gene protein assay methodology is capable of resolving gene and protein patterns simultaneously on a cell-by-cell basis.

Evaluation of a Traumatic Vertebral Artery Occlusion

BACKGROUND Penetrating neck injury occurs in 5%-10% of all trauma cases and carries a significant burden of morbidity and mortality (15%). We describe the evaluation and management of a 25-year-old man shot in the neck with occlusion of the left vertebral artery from its origin to C6. This is a case report in which medical data were analyzed retrospectively with institutional review board approval. CASE DESCRIPTION Neurologic examination revealed paresthesias and dysesthesias in a left C8 dermatomal distribution. Computed tomography angiography of the neck demonstrated no opacification of the left vertebral artery from its origin to C6. Magnetic resonance imaging of the cervical spine revealed an acute infarct in the left cerebellum. A cerebral angiogram highlighted hemodynamic compromise, and the patient was felt to be at significant risk of further cerebral infarction. Augmenting flow to the posterior circulation would mitigate that risk. The patient was taken to the operating room for a transposition of the vertebral artery to the common carotid artery. CONCLUSIONS The patient presented with silent cerebellar infarction due to a vertebral artery injury and impending vertebrobasilar insufficiency. This case demonstrates clinical evaluation of the posterior circulation and treatment with a bypass technique through mobilization of the vertebral artery from the boney vertebral foramen with anastomosis to the common carotid.

Combined interventional and surgical treatment of tandem middle cerebral artery embolus and internal carotid artery occlusion: case report

Tandem internal carotid artery (ICA) origin occlusion and middle cerebral artery (MCA) thromboembolism is a life-threatening condition with poor neurological outcome. The authors report on a patient presenting with acute ischemic stroke from a tandem ICA and MCA occlusion with penumbra. Emergency MCA mechanical thrombectomy was performed through percutaneous cervical ICA access due to the inability to cross the cervical carotid occlusion. Emergency carotid endarterectomy to reperfuse the poorly collateralized hemisphere and repair the ICA access site was performed 2 hours after completion of tissue plasminogen activator (tPA) infusion. This case illustrates the shortest reported interval between tPA infusion and open surgical intervention for carotid revascularization, as well as the role of direct carotid artery access for mechanical thrombectomy. The authors also describe the use of a temporizing femoral artery-to-ICA shunt to maintain cerebral perfusion in the setting of ICA occlusion.

Fungal Contamination of Methylprednisolone Causing Recurrent Lumbosacral Intradural Abscess

Fungal meningitis transmitted through injections of methylprednisolone contaminated with Exserohilum rostratum affected 753 persons and caused 61 deaths in the United States in 2012. We report a case of infection recurrence after 24-months with the unique manifestation of an intradural fungal abscess. Fungal disease should remain on the differential diagnosis list for previously exposed patients.