Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and ‘adult-type’ diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n=22), diffuse oligodendroglial tumors (d-OTs; n=20), diffuse astrocytomas (DAs; n=17), angiocentric gliomas (n=15), and gangliogliomas (n=17). Most LGNTs (84%) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82% of DNETs and 40% of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87%), and MYB fusion genes were the most common genetic alteration in DAs (41%). A BRAF:p.V600E mutation was present in 35% of gangliogliomas and 18% of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78% of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Between April 1981 and May 1984, 61 patients with advanced diffuse large-cell lymphoma completed treatment with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), an innovative pilot chemotherapy program emphasizing weekly treatment, antibiotic prophylaxis, daily corticosteroid treatments, and brief duration (12 weeks). Fifty-one patients (84%) achieved a complete response and 10 patients (16%) had a partial response. Over a median follow-up after treatment of 23 months, the actuarial overall survival for the entire group has been 76%; for complete responders the relapse-free survival has been 90%. Toxicity was modest with one treatment-related death and seven episodes of serious infection. The most frequent toxicity was mucositis. Thus, MACOP-B is an effective treatment for large-cell lymphoma that can be delivered in 12 weeks with an acceptable incidence of toxicity. This regimen can achieve results similar and possibly superior to those of other presently used regimens of longer duration.

Object Bibliometrics is defined as the study of statistical and mathematical methods used to quantitatively analyze scientific literature. The application of bibliometrics in neurosurgery is in its infancy. The authors calculate a number of publication productivity measures for almost all academic neurosurgeons and departments within the US. Methods The h-index, g-index, m-quotient, and contemporary h-index (hc-index) were calculated for 1225 academic neurosurgeons in 99 (of 101) programs listed by the Accreditation Council for Graduate Medical Education in January 2013. Three currently available citation databases were used: Google Scholar, Scopus, and Web of Science. Bibliometric profiles were created for each surgeon. Comparisons based on academic rank (that is, chairperson, professor, associate, assistant, and instructor), sex, and subspecialties were performed. Departments were ranked based on the summation of individual faculty h-indices. Calculations were carried out from January to February 2013. Results The median h-index, g-index, hc-index, and m-quotient were 11, 20, 8, and 0.62, respectively. All indices demonstrated a positive relationship with increasing academic rank (p < 0.001). The median h-index was 11 for males (n = 1144) and 8 for females (n = 81). The h-index, g-index and hc-index significantly varied by sex (p < 0.001). However, when corrected for academic rank, this difference was no longer significant. There was no difference in the m-quotient by sex. Neurosurgeons with subspecialties in functional/epilepsy, peripheral nerve, radiosurgery, neuro-oncology/skull base, and vascular have the highest median h-indices; general, pediatric, and spine neurosurgeons have the lowest median h-indices. By summing the manually calculated Scopus h-indices of all individuals within a department, the top 5 programs for publication productivity are University of California, San Francisco; Barrow Neurological Institute; Johns Hopkins University; University of Pittsburgh; and University of California, Los Angeles. Conclusions This study represents the most detailed publication analysis of academic neurosurgeons and their programs to date. The results for the metrics presented should be viewed as benchmarks for comparison purposes. It is our hope that organized neurosurgery will adopt and continue to refine bibliometric profiling of individuals and departments.

OBJECT The object of this study was to identify and quantify predictors of burnout and career satisfaction among US neurosurgeons. METHODS All US members (3247) of the American Association of Neurological Surgeons (AANS) were invited to participate in a survey between September and December 2012. Responses were evaluated through univariate analysis. Factors independently associated with burnout and career satisfaction were determined using multivariable logistic regression. Subgroup analysis of academic and nonacademic neurosurgeons was performed as well. RESULTS The survey response rate was 24% (783 members). The majority of respondents were male, 40–60 years old, in a stable relationship, with children, working in a group or university practice, and trained in a subspecialty. More than 80% of respondents reported being at least somewhat satisfied with their career, and 70% would choose a career in neurosurgery again; however, only 26% of neurosurgeons believed their professional lives would improve in the future, and 52% believed it would worsen. The overall burnout rate was 56.7%. Factors independently associated with both burnout and career satisfaction included achieving a balance between work and life outside the hospital (burnout OR 0.45, satisfaction OR 10.0) and anxiety over future earnings and/or health care reform (burnout OR 1.96, satisfaction OR 0.32). While the burnout rate for nonacademic neurosurgeons (62.9%) was higher than that for academic neurosurgeons (47.7%), academicians who had practiced for over 20 years were less likely to be satisfied with their careers. CONCLUSIONS The rates of burnout and career satisfaction were both high in this survey study of US neurosurgeons. The negative effects of burnout on the lives of surgeons, patients, and their families require further study and probably necessitate the development of interventional programs at local, regional, and even national levels.

OBJECTIVE Excessive dissatisfaction and stress among physicians can precipitate burnout, which results in diminished productivity, quality of care, and patient satisfaction and treatment adherence. Given the multiplicity of its harms and detriments to workforce retention and in light of the growing physician shortage, burnout has garnered much attention in recent years. Using a national survey, the authors formally evaluated burnout among neurosurgery trainees. METHODS An 86-item questionnaire was disseminated to residents in the American Association of Neurological Surgeons database between June and November 2015. Questions evaluated personal and workplace stressors, mentorship, career satisfaction, and burnout. Burnout was assessed using the previously validated Maslach Burnout Inventory. Factors associated with burnout were determined using univariate and multivariate logistic regression. RESULTS The response rate with completed surveys was 21% (346/1643). The majority of residents were male (78%), 26-35 years old (92%), in a stable relationship (70%), and without children (73%). Respondents were equally distributed across all residency years. Eighty-one percent of residents were satisfied with their career choice, although 41% had at some point given serious thought to quitting. The overall burnout rate was 67%. In the multivariate analysis, notable factors associated with burnout included inadequate operating room exposure (OR 7.57, p = 0.011), hostile faculty (OR 4.07, p = 0.008), and social stressors outside of work (OR 4.52, p = 0.008). Meaningful mentorship was protective against burnout in the multivariate regression models (OR 0.338, p = 0.031). CONCLUSIONS Rates of burnout and career satisfaction are paradoxically high among neurosurgery trainees. While several factors were predictive of burnout, including inadequate operative exposure and social stressors, meaningful mentorship proved to be protective against burnout. The documented negative effects of burnout on patient care and health care economics necessitate further studies for potential solutions to curb its rise.

Object Surgical site infection (SSI) is a serious and costly complication of spinal surgery. There have been several conflicting reports on the use of intrawound vancomycin powder in decreasing SSI in spine surgery. The purpose of this study is to answer the question: “Does intrawound vancomycin powder reduce the rate of SSIs in spine surgery?” Methods A comprehensive search of multiple electronic databases and bibliographies was conducted to identify clinical studies that evaluated the rates of SSI with and without the use of intrawound vancomycin powder in spine surgery. Independent reviewers extracted data and graded the quality of each paper that met inclusion criteria. A random effects meta-analysis was then performed. Results The search identified 9 retrospective cohort studies (Level III evidence) and 1 randomized controlled trial (Level II evidence). There were 2574 cases and 106 infections in the control group (4.1%) and 2518 cases and 33 infections (1.3%) in the treatment group, yielding a pooled absolute risk reduction and relative risk reduction of 2.8% and 68%, respectively. The meta-analysis revealed the use of vancomycin powder to be protective in preventing SSI (relative risk = 0.34, 95% confidence interval 0.17–0.66, p = 0.021). The number needed to treat to prevent 1 SSI was 36. A subgroup analysis found that patients who had implants had a reduced risk of SSI with vancomycin powder (p = 0.023), compared with those who had noninstrumented spinal operations (p = 0.226). Conclusions This meta-analysis suggests that the use of vancomycin powder may be protective against SSI in open spinal surgery; however, the exact population in which it should be used is not clear. This benefit may be most appreciated in higher-risk populations or in facilities with a high baseline rate of infection.