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A 30-year-old man presented with weeks of progressive headaches, imbalance, and aphasia. Brain MRI revealed an enhancing left frontal mass (figure 1, A and B). Chest imaging revealed mediastinal and hilar adenopathy (figure 1, C and D). Metastatic cancer was initially suspected, but pulmonary lymph node aspiration revealed sarcoidosis (figure 2A). Subsequent brain biopsy revealed glioblastoma (figure 2B). The authors thank Dr. Maria Cobos Sillero, fellow in the Department of Neuropathology at the Massachusetts General Hospital, for her assistance in obtaining pathologic photographs.

Around the world, there are marked differences in neurology training, including training duration and degree of specialization. In the United States, adult neurology residency is composed of 1 year of internal medicine training (preliminary year) and 3 years of neurology-specific training. Child neurology, which is not the focus of this article, is 2 years of pediatrics and 3 years of neurology training. The route to adult neurology residency training in the United States is standardized and is similar to most other US specialties. Whereas US medical graduates often receive stepwise guidance from their medical school regarding application for residency training, international graduates often enter this complex process with little or no such assistance. Despite this discrepancy, about 10%–15% of residency positions in the United States are filled by international medical graduates.1,2 In adult neurology specifically, 35% of matched positions were filled by international graduates in 2013, 75% of whom were not US citizens.1 In an effort to provide a preliminary understanding of the application process and related terminology (table 1) and thereby encourage international residency applicants, we describe the steps necessary to apply for neurology residency in the United States. The authors thank Dr. Shilpa Chitnis (UT Southwestern Medical Center, Dallas, TX) for review of the manuscript and comments.

Anti-angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti-glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma.

2010Background: Inhibition of vascular endothelial growth factor (VEGF) may enhance immunotherapies and decrease cerebral edema among GBM patients (pts). This multicenter, randomized phase 2 study determined safety and anti-tumor activity of pembrolizumab (P), a PD-1 blocking monoclonal antibody (Mab) with and without bevacizumab (Bev), a humanized anti-VEGF Mab among rGBM pts. Herein, we report the safety lead-in of this study. Methods: Pts in dose level 1 received P 200 mg Q3W and Bev 10 mg/kg Q2W. Dose de-escalation levels -1 and -2 increased the P interval to 4 and 6 weeks, respectively if dose level 1 exceeded maximum tolerated dose (MTD) based on standard 3+3 criteria. Eligible pts were ≥ 18 years, had 1or 2 recurrences, no prior anti-VEGF treatment, and KPS ≥ 70. The primary endpoint was MTD/recommended phase 2 dose (RP2D) determination based on dose limiting toxicity (DLT) during cycle 1. MRI scans were obtained after each 6-week cycle. Results: 6 pts were treated (4 male, 2 female) at1st (n = 2) ...

We read with interest the case report of unrecognized cobalamin deficiency, nitrous oxide, and reversible subacute combined degeneration by Jordan et al.1 We congratulate the authors for recognition, clinical diagnosis, and appropriate management of the patient. We note that …

Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients. [Cancer Res 2007;67(20):9630–6]

Despite the immunogenicity of glioblastoma multiforme (GBM), immune-mediated eradication of these tumors remains deficient. Regulatory T cells (Tregs) in the blood and within the tumor microenvironment of GBM patients are known to contribute to their dismal immune responses. Here, we determined which chemokine secreted by gliomas can preferentially induce Treg recruitment and migration. In the malignant human glioma cell lines D-54, U-87, U-251, and LN-229, the chemokines CCL22 and CCL2 were detected by intracellular cytokine analysis. Furthermore, tumor cells from eight patients with GBM had a similar chemokine expression profile. However, only CCL2 was detected by enzyme-linked immunosorbent assay, indicating that CCL2 may be the principal chemokine for Treg migration in GBM patients. Interestingly, the Tregs from GBM patients had significantly higher expression levels of the CCL2 receptor CCR4 than did Tregs from healthy controls. Glioma supernatants and the recombinant human chemokines CCL2 and CCL22 induced Treg migration and were blocked by antibodies to the chemokine receptors. Production of CCL2 by glioma cells could also be mitigated by the chemotherapeutic agents temozolomide and carmustine [3-bis (2-chloroethyl)-1-nitrosourea]. Our results indicate that gliomas augment immunosuppression by selective chemokine-mediated recruitment of Tregs into the tumor microenvironment and that modulating this interaction with chemotherapy could facilitate the development of novel immunotherapeutics to malignant gliomas.

A 54-year-old white man presented with slowly progressive incoordination and weakness. He had normal motor development until, at 16 years of age, he noted difficulty walking and difficulty reading despite normal visual acuity. By the fourth decade of life, he developed poor coordination and balance, as well as inability to walk. In subsequent years, he developed progressive, painless sensory loss, weakness, and atrophy in his distal arms and legs. His vision problems progressed and he also developed dysarthria without dysphagia. Family history was negative except for an uncle who was described as "clumsy." Results of an oculomotor examination were notable for increased square-wave jerks, persistent bilateral gaze-evoked nystagmus with saccadic pursuit, intact vestibulo-ocular reflex, and saccadic dysmetria. He had a mixed dysarthria with flaccid and ataxic characteristics and severe weakness and atrophy in the distal limb muscles. Sensation was diminished to the midforearms and midthighs in all modalities. Deep tendon reflexes were absent throughout, with no response to plantar stimulation. He had marked appendicular ataxia with mild axial ataxia. Magnetic resonance imaging of the brain revealed severe cerebellar atrophy. Results of an electrodiagnostic study suggested a severe axonal sensorimotor polyneuropathy with active and chronic denervation. The differential diagnosis in a patient with ataxia, neuropathy, and oculomotor features is discussed; a methodical approach to the diagnostic workup is suggested; and the final diagnosis is revealed.

Objective: To determine the impact on resident training and patient safety of a dedicated lumbar puncture (LP) service utilizing mid-level practitioners (MLP). Background LP is a common bedside procedure. An unsuccessful LP may lead to repeated procedures or fluoroscopy guided LP, increasing patient risks associated with radiation exposure. With reduction in resident work hours by the ACGME, many academic institutions are using MLPs to supplement the provision of patient care, including performing LPs. To our knowledge, the impact of the utilization of specialized MLPs on resident training and patient safety specific to LPs has not been studied. Design/Methods: We conducted a retrospective chart review of inpatients undergoing bedside LP by either a neurology resident physician or neurology MLP from July 2009 through August 2011. Results: A total of 97 LPs were reviewed, 40 performed by a MLP and 57 by a resident physician. Successful bedside LP was documented in 70% and 71.9% of cases by the MLP and residents, respectively (p=0.1815). The average number of skin punctures required to obtain CSF was 1.53 by the MLP vs. 1.67 by residents (p=0.252). There was a numerical but non-significant trend toward improvement when comparing success rate and number of puncture attempts of the MLP in the first six months compared to the second six months of clinical practice (70% vs 77%, p=0.252 and 1.57 to 1.47, p=0.659, respectively). There was insufficient recorded data to make similar comparisons for residents. Conclusions: This study demonstrates no difference between a trained neurology MLP and neurology resident physicians in success rates or safety of performing bedside LP. Nor did we find evidence for negative impact on resident training or proficiency. Specifically there was no evidence for decreased LP success rates in the resident group following introduction of a specialized MLP. Disclosure: Dr. Jordan has nothing to disclose. Dr. Greenberg has received personal compensation for activities with DioGenix, Greater Good Foundation, Biogen Idec, Serono, Inc., Sanofi-Aventis Pharmaceuticals, Inc., the Multiple Sclerosis Association of America and Teva Neuroscience as a consultant and/or speaker. Dr. Greenberg holds stock and/or stock options in Diogeix. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Amplimmune, Inc. and the Accelerated Cure Project. Dr. Lee has received personal compensation for activities with Boehringer Ingelheim as a speaker.

Despite the immunogenicity of glioblastoma multiforme (GBM), the most common primary brain neoplasm, immune clearance of these tumors is still insufficient for tumor eradication and control. Elevated frequency of CD4+ CD25+FoxP3+ T regulatory (Treg) cells in peripheral blood or tumor-infiltrating lymphocytes has been observed in patients with various solid tumors including glioblastoma. This presence of high Treg fraction contributes to the dismal immune responses generated within these patients and prompted us to investigate the possible mechanism of Tregs selective recruitment in GBM patients. We hypothesized that the chemokines produced by gliomas induce this preferentially Treg migration. In the human malignant glioma cell lines D-54, U-87, U-251 and LN229, the chemokines CCL22 and CCL2 were preferentially produced compared to CXCL9, CCL3, and CCL4 by using cytokine flow cytometry and confirmed with ELISA. Additionally, gliomas obtained directly from human patients demonstrated a similar chemokine expression profile. Glioma supernatants, recombinant CCL2 and CCL22 could induce the migration of Tregs, which could be blocked by neutralizing antibodies to these chemokines. Flow cytometric investigation of the expressions of the CCL2 and CCL22 chemokine receptors CCR2 and CCR4 on peripheral T cells indicated that GBM patients have more CD4+CD25+ T cells that express CCR2 (26%) and CCR4 (53%) in contrast to the CD4+CD25+ T subset from normal individuals that express CCR2 (17%) and CCR4 (42%). These data indicate that gliomas modulate immunosuppression by the selective recruitment of Tregs into the tumor microenvironment and those therapies that modulate this interaction may be potentially synergistic with tumor immunotherapies.