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Objective: Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors' knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA-induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity., Methods: This single-arm, multicenter, prospective study included adults aged 18-80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3-5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables., Results: Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume., Conclusions: PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

Background: Traumatic brain injury (TBI) is going to be the third-leading cause of death worldwide, according to the WHO. Two European surveys suggested that adherence to brain trauma guidelines is poor. No study has compared compliance between low- (LMICs) and high-income (UHICs) countries. Hence, this study aimed to investigate differences in the management of severe TBI patients, comparing low- and high-income, and adherence to the BTF guidelines., Methods: A web-based survey was spread through the Global Neuro Foundation, different neurosurgical societies, and social media., Results: A total of 803 neurosurgeons participated: 70.4 from UHICs and 29.6% from LMICs. Hypertonic was administered as an early measure by the 73% and 65% of the responders in LMICs and UHICs, respectively (P=0.016). An invasive intracranial pressure monitoring was recommended by the 66% and 58% of the neurosurgeons in LMICs and UHICs, respectively (P<0.001). Antiseizure drugs (P<0.001) were given most frequently in LMICs as, against recommendations, steroids (87% vs. 61% and 86% vs. 81%, respectively). In the LMICs both the evacuation of the contusion and decompressive craniectomy were performed earlier than in UHICs (30% vs. 17% with P<0.001 and 44% vs. 28% with P=0.006, respectively). In the LMICs, the head CT control was performed mostly between 12 and 24 hours from the first imaging (38% vs. 23%, P<0.001)., Conclusions: The current Guidelines on TBI do not always fit to both the resources and circumstances in different countries. Future research and clinical practice guidelines should reflect the greater relevance of TBI in low resource settings.

Background: Previous research in neurosurgery has examined academic productivity for U.S. medical graduates and residents. However, associations between scholarly output and international medical education, residency training, and fellowship training are scarcely documented., Methods: We identified 1671 U.S. academic neurosurgeons in 2020 using publicly available data along with their countries of medical school, residency, and fellowship training. Using Scopus, h-index, number of publications, and number of times publications were cited were compiled. Demographic, subspeciality, and academic productivity variables were compared between training locations using univariate analysis and multivariable linear regression., Results: Of the current neurosurgery faculty workforce, 16% completed at least 1 component of their training abroad. Canada was the most represented international country in the cohort. Academic productivity for neurosurgeons with international medical school and/or international residency did not significantly differ from that of neurosurgeons trained in the United States. Neurosurgeons with ≥1 U.S. fellowships or ≥1 international fellowships did not have higher academic productivity than neurosurgeons without a fellowship. However, dual fellowship training in both domestic and international programs was associated with higher mean h-index (β = 6.00, 95% confidence interval 1.01 to 10.98, P = 0.02), higher citations (β = 2092.0, 95% confidence interval 460.1 to 3724.0, P = 0.01), and a trend toward higher publications (β = 36.82, 95% confidence interval -0.21 to 73.85, P = 0.051)., Conclusions: Neurosurgeon scholarly output was not significantly affected by international training in medical school or residency. Dual fellowship training in both a domestic and an international program was associated with higher academic productivity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Neurosurgery is a highly competitive residency field with a match rate lower than that of other specialties. The aim of this study was to analyze trends associated with the residency match process from the applicants' and program directors' perspectives., Methods: Between 2010 and 2020, the National Residency Matching Program (NRMP) Applicant and Program Director Surveys, the NRMP Charting Outcomes reports, and the Accreditation Council for Graduate Medical Education (ACGME) Data Resource Books were analyzed to identify the number of applicants interviewed and ranked in US programs, the applicants' ranking preferences, the program directors' preferential factors in offering interviews, and rank list order. Applicants were divided between US senior medical students and independent applicants. Each cohort was dichotomized for matched and unmatched applicants., Results: Over the study period, 2935 applicants applied to neurosurgery residency, including 2135 US senior medical students and 800 independent applicants, with an overall match rate of 65%. Overall, matched applicants had a significantly higher number of publications (p < 0.05). Among US senior medical student applicants, the application-to-interview ratio more than doubled over the study period, yet the number of interview invitations received, interviews accepted, and programs ranked remained unchanged. In the US senior medical student cohort, the number of submitted applications, interview invitations, accepted interviews, and programs ranked did not significantly differ between matched and unmatched applicants. In both cohorts, applicants shifted ranking factors from a more academic focus in early years to more well-being in later years. Letters of recommendation and board scores were key factors for program directors while screening applicants for interviews and ranking., Conclusions: Neurosurgery residency continues to be a highly competitive field in medicine, with match rates of 65%. Recently, applicants have placed greater importance on ranking programs that value residents' well-being, as opposed to strictly academic factors. A data-driven understanding of factors important to applicants and program directors during the match process has the potential to improve resident candidate recruitment and overall resident-program fit, thereby improving well-being during residency, reducing the attrition rate, and overall enhancing the diversity of the neurosurgery resident workforce.

Objective: To provide the status of women neurosurgeons (WNS) in academic faculty and/or leadership positions in neurosurgery in the United States., Methods: Neurosurgery academic programs were defined as having an Accreditation Council for Graduate Medical Education (ACGME) neurosurgery residency program (NSRP). Using a Google search, gender, academic rank, postgraduate degrees, academic and clinical titles, and subspecialty were recorded for each neurosurgery faculty. Officer gender was recorded for the top 7 neurosurgery U.S. organizations, 7 subspecialty sections, and 50 state neurosurgical societies., Results: WNS were faculty at 77% (89/115) of ACGME NSRPs and constituted 10% of the workforce (186/1773). WNS residents were in 92% of ACGME NSRPs and constituted 19% of the workforce (293/1515). Two NSRPs (8%) had neither WNS faculty nor WNS residents. Of NSRPs without WNS faculty, 52% (13/25) had a faculty size >10. WNS accounted for 3% of NSRP chair positions. Academic rank of WNS faculty was lower than academic rank of men neurosurgeons faculty (P < 0.05). WNS faculty had a higher number of postgraduate degrees (P < 0.05). Pediatrics was the most common subspecialty (30%) among WNS. Over time, WNS held 1% of the leadership positions within the top 7 U.S. neurosurgery organizations and 7% within the 7 subspecialty sections. Over the past 20 years, 28% (14/50) of U.S. state neurosurgical societies had WNS serve as president., Conclusions: In 2020, the gender gap for U.S. WNS faculty and residents still exists. By providing informed benchmarks, our study might help neurosurgery organizations, medical school leadership, hiring committees, editors, and conference speakers to plan their next steps., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Section on Tumors was formed in December of 1984 as the first professional organization devoted to the study and treatment of brain tumors. One year earlier, the Journal of Neuro-Oncology had been established and went on to be sponsored by the Joint Section on Tumors. To celebrate the 35th anniversary of the founding of the Section, we are thrilled to bring you this special issue of Journal of Neuro-Oncology in which current leaders of the Joint Section on Tumors highlight their work and the work of others that have led to significant recent advances in the management of tumors of the central nervous system.

In the past 2 decades, a deeper understanding of the cancer molecular signature has resulted in longer longevity of cancer patients, hence a greater population, who potentially can develop metastatic disease. Spine metastases (SM) occur in up to 70% of cancer patients. Familiarizing ourselves with the key aspects of initial symptom-directed management is important to provide SM patients with the best patient-specific options. We will review key components of initial symptoms assessment such as pain, neurological symptoms, and spine stability. Radiographic evaluation of SM and its role in management will be reviewed. Nonsurgical treatment options are also presented and discussed, including percutaneous procedures, radiation, radiosurgery, and spine stereotactic body radiotherapy. The efforts of a multidisciplinary team will continue to ensure the best patient care as the landscape of cancer is constantly changing., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Target Population: These recommendations apply to adults with newly diagnosed or suspected glioblastoma., Question: What is the effect of extent of surgical resection on patient outcome in the initial management of adult patients with suspected newly diagnosed glioblastoma?, Recommendation: Level II: Maximal cytoreductive surgery is recommended in adult patients with suspected newly diagnosed supratentorial glioblastoma with gross total resection defined as removal of contrast enhancing tumor. Level III: Biopsy, subtotal resection, or gross total resection is suggested depending on medical comorbidities, functional status, and location of tumor if maximal resection may cause significant neurologic deficit., Question: What is the role of cytoreductive surgery in adults with newly diagnosed bi-frontal "butterfly" glioblastoma?, Recommendation: Level III: Resection of newly diagnosed bi-frontal "butterfly" glioblastoma is suggested to improve overall survival over biopsy alone., Question: What is the goal of cytoreductive surgery in elderly adult patients with newly diagnosed glioblastoma?, Recommendation: Level III: Elderly patients (> 65 years) show survival benefit with gross total resection and it is suggested they undergo cytoreductive surgery., Question: What is the role of advanced intraoperative guidance techniques in cytoreductive surgery in adults with newly diagnosed glioblastoma?, Recommendation: Level III: The use of intraoperative guidance adjuncts such as intraoperative MRI (iMRI) or 5-aminolevulinic acid (5-ALA) are suggested to maximize extent of resection in newly diagnosed glioblastoma. There is insufficient evidence to make a suggestion on the use of fluorescein, indocyanine green, or intraoperative ultrasound.

[This corrects the article DOI: 10.1186/s41016-020-00194-1.]., (© The Author(s) 2020.)

Objective: Despite recently heightened advocacy efforts relating to pregnancy and family leave policies in multiple surgical specialties, no studies to date have described female neurosurgeons' experiences with childbearing. The AANS/CNS Section of Women in Neurosurgery created the Women and Pregnancy Task Force to ascertain female neurosurgeons' experiences with and attitudes toward pregnancy and the role of family leave policies., Methods: A voluntary online 28-question survey examined the pregnancy experiences of female neurosurgeons and perceived barriers to childbearing. The survey was developed and electronically distributed to all members of the American Association of Neurological Surgeons and Congress of Neurological Surgeons who self-identified as female in February 2016. Responses from female resident physicians, fellows, and current or retired practicing neurosurgeons were analyzed., Results: A total of 126 women (20.3%) responded to the survey; 57 participants (49%) already had children, and 39 (33%) planned to do so. Participants overwhelmingly had or planned to have children during the early practice and senior residency years. The most frequent obstacles experienced or anticipated included insufficient time to care for newborns (47% of women with children, 92% of women planning to have children), discrimination by coworkers (31% and 77%, respectively), and inadequate time for completion of board requirements (18% and 51%, respectively). There was substantial variability in family leave policies, and a minority of participants (35%) endorsed the presence of any formal policy at their institution. Respondents described myriad unique challenges associated with pregnancy and family leave., Conclusions: Pregnancy and family leave pose significant challenges to the recruitment, retention, and advancement of women in neurosurgery. It is thus imperative to promote clear family leave policies for trainees and practitioners, address discrimination surrounding these topics, and encourage forethought and flexibility to tackle obstacles inherent in pregnancy and the early stages of child rearing.

Globally, the discipline of neurosurgery has evolved remarkably fast. Despite being one of the latest medical specialties, which appeared only around hundred years ago, it has witnessed innovations in the aspects of diagnostics methods, macro and micro surgical techniques, and treatment modalities. Unfortunately, this development is not evenly distributed between developed and developing countries. The same is the case with neurosurgical education and training, which developed from only traditional apprentice programs in the past to more structured, competence-based programs with various teaching methods being utilized, in recent times. A similar gap can be observed between developed and developing counties when it comes to neurosurgical education. Fortunately, most of the scholars working in this field do understand the coherent relationship between neurosurgical education and neurosurgical practice. In context to this understanding, a symposium was organized during the World Federation of Neurological Surgeons (WFNS) Special World Congress Beijing 2019. This symposium was the brain child of Prof. Yoko Kato-one of the eminent leaders in neurosurgery and an inspiration for female neurosurgeons. Invited speakers from different continents presented the stages of development of neurosurgical education in their respective countries. This paper summarizes the outcome of these presentations, with particular emphasis on and the challenges faced by developing countries in terms of neurosurgical education and strategies to cope with these challenges., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Objective: Sub-Saharan Africa (SSA) represents 17% of the world's land, 14% of the population, and 1% of the gross domestic product. Previous reports have indicated that 81/500 African neurosurgeons (16.2%) worked in SSA-i.e., 1 neurosurgeon per 6 million inhabitants. Over the past decades, efforts have been made to improve neurosurgery availability in SSA. In this study, the authors provide an update by means of the polling of neurosurgeons who trained in North Africa and went back to practice in SSA., Methods: Neurosurgeons who had full training at the World Federation of Neurosurgical Societies (WFNS) Rabat Training Center (RTC) over the past 16 years were polled with an 18-question survey focused on demographics, practice/case types, and operating room equipment availability., Results: Data collected from all 21 (100%) WFNS RTC graduates showed that all neurosurgeons returned to work to SSA in 12 different countries, 90% working in low-income and 10% in lower-middle-income countries, defined by the World Bank as a Gross National Income per capita of ≤ US$995 and US$996-$3895, respectively. The cumulative population in the geographical areas in which they practice is 267 million, with a total of 102 neurosurgeons reported, resulting in 1 neurosurgeon per 2.62 million inhabitants. Upon return to SSA, WFNS RTC graduates were employed in public/private hospitals (62%), military hospitals (14.3%), academic centers (14.3%), and private practice (9.5%). The majority reported an even split between spine and cranial and between trauma and elective; 71% performed between 50 and more than 100 neurosurgical procedures/year. Equipment available varied across the cohort. A CT scanner was available to 86%, MRI to 38%, surgical microscope to 33%, endoscope to 19.1%, and neuronavigation to 0%. Three (14.3%) neurosurgeons had access to none of the above., Conclusions: Neurosurgery availability in SSA has significantly improved over the past decade thanks to the dedication of senior African neurosurgeons, organizations, and volunteers who believed in forming the new neurosurgery generation in the same continent where they practice. Challenges include limited resources and the need to continue expanding efforts in local neurosurgery training and continuing medical education. Focus on affordable and low-maintenance technology is needed.

Objective: Postgraduate training in medicine has been under scrutiny in the last 10 years, with a focus on improving residents' education. The aim of this study was to quantify trends in neurosurgery residency (NSR) training and education over the last 10 years., Methods: The authors assessed Accreditation Council for Graduate Medical Education (ACGME), National Resident Matching Program, and American Board of Neurological Surgeons records and searched PubMed to collate 2009-2019 data. Analyzed trends included residents' demographic data, programs' characteristics, graduation and attrition rates, match data, resident case logs, and qualitative educational curriculum changes., Results: Significant increases in residents' demographic data (p < 0.05) included the number of female residents (from 12.7% to 17.6%) and the absolute number of residents (from 1112 to 1462). Age (mean 28.8 years), ethnicity, and number of residents per program (mean 13 residents per program) were unchanged. There were 16 new ACGME NSR programs, with currently 115 programs nationwide. The number of applicants per year (324 applicants per year) and the matching rate (mean 64%) remained stable. The mean attrition rate of 2.6% (range 2%-4%) was higher than the mean 2.1% ACGME attrition rate, a rate that decreased from 3% in 2009 to 1.6% in 2019. Education curriculum changes aimed at the standardization of training across the US included residents' boot camp (2009), the Milestones project (2012), and mandatory 7-year training initiated in 2013. An increase in endovascular, functional, trauma, and spine resident caseload was noted. The number of yearly publications about US NSR education has significantly increased (p < 0.05)., Conclusions: NSR education has received greater attention over the last decade in the US. Standardization of training has been implemented. A steady number of students remain interested in neurosurgery, with an increased number of women entering the field. Attention to wellness, in addition to high-quality education, should be further assessed as a factor to improve the overall NSR training and retention rate.

Neuroendocrine dysfunction includes suspected hyper- and hypofunction of the pituitary gland. Causative lesions may include primary masses of the pituitary such as pituitary microadenomas and macroadenomas, as well as extrinsic masses, typically centered in the suprasellar cistern. Clinical syndromes related to hormonal dysfunction can be caused by excessive hormonal secretion or by inhibited secretion due to mass effect upon elements of the hypothalamic-pituitary axis. Additionally, complications such as hemorrhage may be seen in the setting of an underlying mass and can result in hormonal dysfunction. MRI with high-resolution protocols is the best first-line test to evaluate the sella turcica and parasellar region. CT provides complementary information regarding bony anatomy, and may be appropriate as a first-line test in certain instances, but it provides less detail and lesion characterization when compared to MRI. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: Machine learning (ML) is an application of artificial intelligence (AI) that gives computer systems the ability to learn data, without being explicitly programmed. Currently, ML has been successfully used for optical character recognition, spam filtering, and face recognition. The aim of the present study was to review the current applications of ML in the field of neuro-oncology., Methods: We conducted a systematic literature review using the PubMed and Cochrane databases using a keyword search for January 30, 2000 to March 31, 2018. The data were clustered for neuro-oncology scope of ML into 3 categories: patient outcome predictors, imaging analysis, and gene expression., Results: Data from 5346 patients in 29 studies were used to develop ML-based algorithms (MLBAs) in neuro-oncology. MLBAs were used to predict the outcomes for 2483 patients, with a sensitivity range of 78%-98% and specificity range of 76%-95%. In all studies, the MLBAs had greater accuracy than the conventional ones. MLBAs for image analysis showed accuracy in diagnosing low-grade versus high-grade gliomas, ranging from 80% to 93% and 90% for diagnosing high-grade glioma versus lymphoma. Seven studies used MLBAs to analyze gene expression in neuro-oncology., Conclusions: MLBAs in neuro-oncology have been shown to predict patients' outcomes more accurately than conventional parameters in a retrospective analysis. If their high diagnostic accuracy in imaging analysis and detection of somatic mutations are corroborated in prospective studies, the use of tissue diagnosis or liquid biopsy might be curtailed. Finally, MLBAs are promising to help guide targeted therapy, can lead to personalized medicine, and open areas of study in the cancer cellular signaling system, not otherwise known., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to evaluate the efficacy of stereotactic radiosurgery (SRS) for spinal metastases from hepatocellular carcinoma (HCC) compared with other radioresistant histologies (renal cell carcinoma [RCC], melanoma, and sarcoma) in terms of local control (LC) and pain control., Methods and Materials: We performed a retrospective review of patients treated with SRS to the spine for metastatic HCC, RCC, melanoma, and sarcoma between January 2007 and May 2014. Radiographic assessments of LC, overall survival, and patient-reported pain control were analyzed as univariable analyses and with various patient- and treatment-related parameters as multivariable analyses (MVA)., Results: Of the 96 patients treated with SRS, 41 patients had radioresistant histologies, including 18 HCC, 1 mixed HCC and cholangiocarcinoma, 15 RCC, 6 melanoma, and 1 leiomyosarcoma. Extraosseous disease was present in 63% of patients (74% in HCC; 55% in non-HCC; P = not significant). Spinal cord compression was present in 29% of patients (32% in HCC; 27% in non-HCC; P = not significant), and 24% of patients had decompressive surgery before SRS (26% in HCC; 23% in non-HCC; P = not significant). With a median follow-up time of 8.7 months, the actuarial 3-, 6-, and 12-month LC rates were 71%, 61%, 41%, respectively, for HCC, and 94%, 94%, and 85%, respectively, for non-HCC. The median time to local failure was 3 months for HCC and 11 months for non-HCC. On MVA, there was a strong trend toward inferior LC with HCC (P = .059). Of the 28 patients with pretreatment pain, pain relief was achieved in 93% of patients, but the 2 patients who did not experience pain relief both had HCC. The actuarial 3-, 6-, and 12-month pain control rates were 68%, 51%, 17%, respectively, for HCC, and 100%, 89%, and 89%, respectively, for non-HCC (P = .023), and remained significant on MVA (P = .034)., Conclusions: Compared with other radioresistant histologies, HCC has inferior LC and pain relief after SRS. Whether HCC may benefit from further dose escalation or combined treatment with new therapies is an area of future research., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objective: Spinal surgery is taught and practiced within 2 different surgical disciplines: neurological surgery and orthopedic surgery. We have provided a unified analysis of spine-focused faculty at U.S. residency programs., Methods: A total of 278 Accreditation Council for Graduate Medical Education training programs were assessed to identify 923 full-time faculty members with a spinal surgery designation, defined by spine fellowship training or surgeon case volume >75% spine surgeries. Faculty were assessed with respect to parent discipline, years of fellowship training, academic rank, gender, and academic productivity (h-index)., Results: The spine-teaching workforce contains 55% orthopedic surgeons and 45% neurosurgeons with wide gender asymmetry overall and at all faculty ranks. Of the female spine surgeons, those with neurosurgical training (64.44%) nearly doubled the number with orthopedic training (35.56%). Academic productivity increased with academic rank similarly for both genders and subspecialties. Orthopedic spine surgeons had a greater mean fellowship number compared with the neurological spine surgeons. Fellowship time of completion (intraresidency/infolded vs. postresidency) did not significantly affect the h-indexes. Addition of fellowship conferred academic productivity benefit for orthopedic surgeons only., Conclusions: Neurological and orthopedic spine surgery showed similar patterns for the spread of faculty across academic ranks and trends in academic productivity. Marked gender disparity was seen in both neurosurgical and orthopedic surgery, with fewer female spine surgeons seen at every academic rank. Orthopedic spine surgeons had a greater mean fellowship number than did their neurosurgical counterparts, and a lack of fellowship correlated with lower academic productivity in orthopedic, but not neurological, spine surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This article presents guidelines for imaging utilization in patients presenting with hearing loss or vertigo, symptoms that sometimes occur concurrently due to proximity of receptors and neural pathways responsible for hearing and balance. These guidelines take into account the superiority of CT in providing bony details and better soft-tissue resolution offered by MRI. It should be noted that a dedicated temporal bone CT rather than a head CT best achieves delineation of disease in many of these patients. Similarly, optimal assessment often requires a dedicated high-resolution protocol designed to assess temporal bone and internal auditory canals even though such a study will be requested and billed as a brain MRI. Angiographic techniques are helpful in some patients, especially in the setting of vertigo. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2018 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: Apparent increases in the size of cerebral metastases after stereotactic radiosurgery (SRS) can be caused by pseudoprogression or true disease progression, which poses a diagnostic challenge at conventional MRI. The purpose of this study was to assess whether interval change in DWI and perfusion MRI parameters can differentiate pseudoprogression from progressive disease after treatment with SRS., Materials and Methods: Patients with apparent growth of cerebral metastases after SRS treatment who underwent pre- and post-SRS DWI, dynamic susceptibility contrast (DSC)-MRI, and perfusion dynamic contrast-enhanced (DCE)-MRI were retrospectively evaluated. Final assignment of pseudoprogression or progressive disease was determined at 6-month follow-up imaging using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Mean values of apparent diffusion coefficient (ADC), DCE-MRI-derived volume transfer constant (K trans ), and DSC-MRI-derived relative cerebral blood volume (CBV) from pre- and post-SRS MRI scans were compared between groups using univariate and regression analysis. Fisher exact test was used to compare interval change of imaging biomarkers., Results: Of 102 cerebral metastases evaluated, 32 lesions in 29 patients met our inclusion criteria. The mean duration of follow-up was 7.2 months (range, 6-14 months). Twenty-two lesions were determined as pseudoprogression, and 10 lesions were determined as progressive disease using the Response Assessment in Neuro-Oncology Brain Metastases criteria at 6-month follow-up MRI. The interval change pattern of our imaging parameters matched the expected patterns of treatment response for ADC (23/32 lesions; 72%; p = 0.055; odds ratio, 5.1), K trans (24/32 lesions; 75%; p = 0.006; odds ratio, 19.2), and relative CBV (27/32 lesions; 84%; p = 0.001; odds ratio, 25.3)., Conclusion: Pseudoprogression can be distinguished from disease progression in cerebral metastases treated with SRS via an interval decrease in relative CBV and K trans values.

Background: For the first time in Southeast Asia, a Fundamentals of Neurosurgery Boot Camp was held at the University of Medicine 1 in Yangon, Myanmar, February 24-26, 2017. The aim of this course was to teach and train fundamental skills to neurosurgery residents., Methods: The Myanmar Neurosurgical Society, Foundation for International Education in Neurosurgery, Society for Neurological Surgeons, The University of Medicine 1 in Yangon, Myanmar, and the Henry Ford Department of Neurosurgery developed a 2-day resident training course. Day 1 activities consisted of lectures by faculty, small group case discussions, and industry-supported demonstrations of surgical techniques. Day 2 activities consisted of hands-on skill stations for common neurosurgical procedures with each station supervised by attending faculty. Written evaluations were distributed before the meeting, immediately after the meeting, and 6 months after the meeting., Results: Boot camp attendees included 40 residents and 24 neurosurgical faculty from Myanmar, Cambodia, Nepal, Singapore, South Korea, Thailand, and Vietnam. There were 35 evaluations completed before the boot camp, 34 completed immediately after boot camp, and 20 completed 6 months after boot camp. Knowledge of participants improved from 62.75% before boot camp to 71.50% 6 months after boot camp (P = 0.046)., Conclusions: Boot camps provide fundamental didactic and technical exposure to trainees in developed and developing countries and help standardize training in basic neurosurgical competencies, while exposing local faculty to important teaching methods. This model provides a sustainable solution to educational needs and demonstrates to local neurosurgeons how they can take ownership of the educational process., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Question: What are the indications for stereotactic radiosurgery (SRS) treatment vs observation for patients with intracanalicular vestibular schwannomas without evidence of radiographic progression?, Recommendation: Level 3: If tinnitus is not observed at presentation, it is recommended that intracanalicular vestibular schwannomas and small tumors (<2 cm) without tinnitus be observed as observation does not have a negative impact on tumor growth or hearing preservation compared to treatment., Question: Is there a difference in outcome based on radiosurgery equipment used: Gamma Knife (Elekta, Stockholm, Sweden) vs linear accelerator-based radiosurgery vs proton beam?, Recommendation: There are no studies that compare 2 or all 3 modalities. Thus, recommendations on outcome based on modality cannot be made., Question: Is there a difference in outcome based on the dose delivered?, Recommendation: Level 3: As there is no difference in radiographic control using different doses, it is recommended that for single fraction SRS doses, <13 Gy be used to facilitate hearing preservation and minimize new onset or worsening of preexisting cranial nerve deficits., Question: Is there a difference in outcome based on the number of fractions?, Recommendation: As there is no difference in radiographic control and clinical outcome using single or multiple fractions, no recommendations can be given., Question: What is the best time sequence for follow-up images after SRS?, Recommendation: Level 3: Follow-up imaging should be obtained at intervals after SRS based on clinical indications, a patient's personal circumstances, or institutional protocols. Long-term follow-up with serial magnetic resonance imagings to evaluate for recurrence is recommended. No recommendations can be given regarding the interval of these studies., Question: Is there a role for retreatment?, Recommendation: Level 3: When there has been progression of tumor after SRS, SRS can be safely and effectively performed as a retreatment., Question: What is the risk of radiation-induced malignant transformation of vestibular schwannomas treated with SRS?, Recommendation: Level 3: Patients should be informed that there is minimal risk of malignant transformation of vestibular schwannomas after SRS., Question: What are the indications for SRS in patients with neurofibromatosis type 2?, Recommendation: Level 3: Radiosurgery is a treatment option for patients with neurofibromatosis type 2 whose vestibular schwannomas are enlarging and/or causing hearing loss.  The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter&#95;7., (Copyright © 2017 by the Congress of Neurological Surgeons)

Ependymomas of the posterior fossa in adults are relatively rare, represent less than 1% of adult intracranial gliomas. Most of the cases are WHO grade II. Due to their rarity, there are no randomized studies regarding the best management of these tumors. It seems that surgical resection has a major role in their management. Unlike the scenario in children, these tumors can be cured by gross total resection without adjuvant therapy in the majority of cases. Hence, knowing the different surgical approaches, with their pros and cons, is important in order to offer the patient the best treatment. In this paper, we review the current literature on surgery for ependymomas of the posterior fossa in adults, and the advantages and risks of the principal surgical approaches, namely the telo-velar and the transvermian, are discussed.

Objective: Differentiation of radiation necrosis (RN) from recurrent tumor (RT) in treated patients with glioblastoma remains a diagnostic challenge. The purpose of this study is to evaluate the diagnostic performance of multiparametric MRI in distinguishing RN from RT in patients with glioblastoma, with the use of a combination of MR perfusion and diffusion parameters., Materials and Methods: Patients with glioblastoma who had a new enhancing mass develop after completing standard treatment were retrospectively evaluated. Apparent diffusion coefficient (ADC), volume transfer constant (K trans ), and relative cerebral blood volume (rCBV) values were calculated from the MR images on which the enhancing lesions first appeared. Repeated measure of analysis, logistic regression, and ROC analysis were performed., Results: Of a total of 70 patients evaluated, 46 (34 with RT and 12 with RN) met our inclusion criteria. Patients with RT had significantly higher mean rCBV (p < 0.001) and K trans (p = 0.006) values and lower ADC values (p = 0.004), compared with patients with RN. The overall diagnostic accuracy was 85.8% for rCBV, 75.5% for K trans , and 71.3% for ADC values. The logistic regression model showed a significant contribution of rCBV (p = 0.024) and K trans (p = 0.040) as independent imaging classifiers for differentiation of RT from RN. Combined use of rCBV and K trans at threshold values of 2.2 and 0.08 min -1 , respectively, improved the overall diagnostic accuracy to 92.8%., Conclusion: In patients with treated glioblastoma, rCBV outperforms ADC and K trans as a single imaging classifier to predict recurrent tumor versus radiation necrosis; however, the combination of rCBV and K trans may be used to improve overall diagnostic accuracy.

Background: The neurosurgical boot camp has been fully incorporated into U.S. postgraduate education. This is the first implementation of the neurosurgical boot in a developing country. To advance neurosurgical education, we developed a similar boot camp program, in collaboration with Bolivian neurosurgeons, to determine its feasibility and effectiveness in an international setting., Methods: In a collective effort, the Bolivian Society for Neurosurgery, Foundation for International Education in Neurological Surgery, Solidarity Bridge, and University of Massachusetts organized and executed the first South American neurosurgical boot camp in Bolivia in 2015. Both U.S. and Bolivian faculty led didactic lectures followed by a practicum day using mannequins and simulators. South American residents and faculty were surveyed after the course to determine levels of enthusiasm and their perceived improvement in fund of knowledge and course effectiveness., Results: Twenty-four neurosurgery residents from 5 South American countries participated. Average survey scores ranged between 4.2 and 4.9 out of 5. Five Bolivian neurosurgeons completed the survey with average scores of 4.5-5. This event allowed for Bolivian leaders in the field to unify around education, resulting in the formation of an institute to continue similar initiatives. Total cost was estimated at $40 000 USD; however, significant faculty, industry, and donor support helped offset this amount., Conclusion: The first South American neurosurgical boot camp had significant value and was well received in Bolivia. This humanitarian model provides a sustainable solution to education needs and should be expanded to other regions as a means for standardizing the core competencies in neurosurgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Systematic review of the literature to evaluate the role of decompressive craniectomy (DC) after severe traumatic brain injury (TBI), comparing the first major randomized clinical trial on this topic (DECRA) with subsequent literature., Methods: A systematic literature search was performed from 2011 to 2015. Citations were selected using the following inclusion criteria: closed severe TBI and DC. Exclusion criteria included most patients ≤18 years old, ≤20 participants, review articles, DC for reasons other than TBI, or surgical procedures other than DC. Primary outcomes included mortality and Glasgow Outcome Scale (GOS) at discharge, 6 months, and 1 year after injury. Assessment of risk of bias of the randomized controlled trials was also performed., Results: Only 12 of 5528 articles satisfied the eligibility criteria; of these studies, 3 were randomized controlled trials. DC in specific populations does not offer GOS or mortality advantages compared with medical treatment; on the other hand, when DC with open dural flap was compared with an alternative means of decompression, e.g., DC with multiple dural stabs, the latter showed significant advantage in mortality and GOS. Nonrandomized studies showed decreased mortality and increased GOS in patients aged ≤50 years when DC was performed <5 hours after TBI and with Glasgow Coma Scale score >5., Conclusions: Our study underscores the importance of continued international prospective data collection for assessing types of surgical interventions in addition to DC and their timing in patients who have severe TBI. In addition, in geographic areas with limited access to advanced medical treatment for severe TBI, DC is of benefit when performed <5 hours after injury in younger patients with Glasgow Coma Scale >5., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Appropriate imaging modalities for the follow-up of malignant or aggressive musculoskeletal tumors include radiography, MRI, CT, (18)F-2-fluoro-2-deoxy-D-glucose PET/CT, (99m)Tc bone scan, and ultrasound. Clinical scenarios reviewed include evaluation for metastatic disease to the lung in low- and high-risk patients, for osseous metastatic disease in asymptomatic and symptomatic patients, for local recurrence of osseous tumors with and without significant hardware present, and for local recurrence of soft tissue tumors. The timing for follow-up of pulmonary metastasis surveillance is also reviewed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment., (Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Vertebral compression fracture (VCF) occurs after stereotactic body radiation therapy (SBRT) for spine metastasis. Recently, single fraction radiosurgery (sfSRS) is used more frequently. The aim of this study is to determine the clinical outcome of VCF after sfSRS. Spinal instability neoplastic score (SINS) criteria were used to retrospectively score 143 consecutive vertebral segments in 79 patients treated with SRS. Follow-up MRI, pain, and neurologic assessments obtained every 3-6 months. Pain also scored at 7, 14, and 30 days after sfSRS. Follow up was 16 ± 18 months ±SD, range 3-78. Long-term radiographic control occurred in 94 % of cases. Pain improvement resulted within 7 days in 100 % of cases with severe pain and sustained long-term in 95 %. VCF occurred in 21 % of segments: 30 % were de novo VCF. The overall 1 year fracture free probability (1yFFP) was 76 %. Pre-existing VCF resulted in higher probability to progress: 1yFFP 90 versus 60 %. Symptoms presented in 6 % of cases with de novo VCF and 39 % with progressive. The former were treated with vertebral augmentation (VA), the latter with open surgery. Surgery/VA prior to SRS did not change risk of progressive VCF. Univariate but not multivariate analysis identified histology (colorectal), pre-existing VCF, and pain (severe) as significant predictors of VCF. In conclusion, sfSRS compares favourably to SBRT for radiographic and pain control with similar VCF risk. Patients with pre-existing VCF have a higher probability to progress, become symptomatic, and require surgery. These results may help discussing risk and benefits with patients undergoing sfSRS for spinal metastasis and developing new treatment algorithms.

The recognition of stem cells (SC) in the adult CNS and in association with gliomas has spawned an entire field of research and intense investigation. A large body of knowledge is being accumulated to gain insight into the pathobiology of gliomas with the intent of finally improving the grave prognosis that continues to beset patients with high grade gliomas (HGG). In this article, we provide a historical overview of the events leading to the discovery of SC and glioma stem cells (GSC). We then focus on the current understanding of GSC with respect to markers, clinical significance, and their targeting. We discuss current data and developments using SC as vehicles to delivery therapeutic agents to HGG. We conclude with a discussion of opportunities for future development and concepts aimed at reducing tumor recurrence and improving survival for patients with HGG.

Most patients presenting with uncomplicated, nontraumatic, primary headache do not require imaging. When history, physical, or neurologic examination elicits "red flags" or critical features of the headache, then further investigation with imaging may be warranted to exclude a secondary cause. Imaging procedures may be diagnostically useful for patients with headaches that are: associated with trauma; new, worse, or abrupt onset; thunderclap; radiating to the neck; due to trigeminal autonomic cephalgia; persistent and positional; and temporal in older individuals. Pregnant patients, immunocompromised individuals, cancer patients, and patients with papilledema or systemic illnesses, including hypercoagulable disorders may benefit from imaging. Unlike most headaches, those associated with cough, exertion, or sexual activity usually require neuroimaging with MRI of the brain with and without contrast to exclude potentially underlying pathology before a primary headache syndrome is diagnosed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment., (Copyright © 2014 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Glioblastoma is the most common, and at the same time, most aggressive type of high-grade glioma (HGG). The prognosis of glioblastoma patients treated with standard therapy including surgery, temozolomide and radiation therapy remains poor. Peroxisome proliferator-activated receptor-α (PPARα) agonists are in widespread clinical use for the treatment of hyperlipidemia. Recent evidence has suggested a potential role in various cancers including glioblastoma. In this study, we characterized the effects of PPARα agonist, fenofibrate, directly on HGG cells and glioma stem cells (GSC). Fenofibrate exhibited dose-dependent p53-independent anti-proliferative effects on HGG starting at 25 μM and pro-apoptotic effects starting at 50 μM, suggesting that the anti-proliferative actions are present only at 25 μM. PPARα was expressed in all HGG cell lines. Inhibition of PPARα with specific inhibitor GW6471 did not affect either proliferation or apoptosis suggesting that these are PPARα-independent effects. Fenofibrate treatment of HGG cells robustly diminished the expression of key signaling pathways, including NF-κB and cyclin D1. Phosphorylation of Akt was also diminished, with no change in total Akt. Effects on apoptotic signaling molecules, Bax and Bcl-xL, had a trend towards pro-apoptotic effects. With respect to GSC, fenofibrate treatment at 25 μM significantly decreased invasion in association with a decrease in CD133 and Oct4 expression. Overall, results support consideration of fenofibrate as an anti-glioma agent and establish its potential as an adjunct treatment strategy for HGG. Translation to the clinical setting could be rapid given its current use as a clinical agent and its low toxicity profile.

Background: Patients undergoing stereotactic headframe placement for radiosurgery report that discomfort associated with the headframe often lasts for the duration of the treatment day (approximately 6 hours). We hypothesize that blockade of scalp nerves prior to headframe placement reduces the incidence of moderate to severe head pain during the entire treatment day. We describe a randomized, double-blind, placebo-controlled study of awake patients having radiosurgery for intracranial pathology that examines whether scalp nerve blockade and local anesthetic infiltration results in superior patient comfort versus infiltration alone., Methods: Twenty seven adult patients undergoing stereotactic radiosurgery were randomized to receive a nerve block with placebo or bupivacaine 0.5% with epinephrine. Supraorbital and greater occipital nerve blocks using blinded syringes were performed by the anesthesiologist in addition to subcutaneous infiltration of pin sites with lidocaine 1% by the surgeon. Pain was reported using 10 cm visual analog scales (VAS) at pre-specified time points during the treatment day. The primary outcome measure was the presence of pain scores classified as "zero to mild pain (VAS <4)" or "moderate to severe pain (VAS > or = 4)"., Results: 27 patients were randomized to placebo (n = 14) and nerve block (n = 13) groups. The proportion of moderate to severe pain measurements were significantly less in the nerve block group than the placebo group (4.9% vs. 24.1%; odds ratio, 0.166; 95% confidence interval 0.029-0.955; p = 0.044). There were no adverse events., Conclusion: Scalp nerve block significantly decreased moderate to severe head pain in radiosurgery patients throughout the treatment day.

The past decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells (GSC) and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. Herein, we present a novel framework for considering GSC targets based on direct and indirect strategies. Direct strategies target GSC molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect strategies target the microenvironment of the GSC, namely the perivascular, hypoxic and immune niches. Progress made on GSC targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting GSC provides an unprecedented opportunity for revolutionary approaches to treat high-grade gliomas that continue to have a poor patient prognosis., (© 2011 Japanese Cancer Association.)

Background: Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Recently, evidence for a viral cause has been postulated, possibly SV40 or more likely cytomegalovirus (CMV). One report indicated that 80% of patients with newly diagnosed glioblastoma multiforme have detectable cytomegalovirus DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus., Patients and Methods: In the current study, we examined peripheral blood of 5 patients with newly diagnosed glioblastoma multiforme. Peripheral blood was collected in anticoagulated tubes from five patients with newly diagnosed glioblastoma multiforme referred for radiation therapy. We used standard methods for detecting CMV by reverse transcriptase-polymerase chain reaction (RT-PCR) and peripheral blood culture., Results: None of our patients had circulating CMV., Conclusion: There are four subtypes of glioblastoma. We hypothesize that circulating CMV might be limited to some, but not all of these subtypes, and that our failure to detect CMV might be attributed to the fact that none of these patients had the appropriate subtype or subtypes.

Appropriate imaging modalities for screening, staging, and surveillance of patients with suspected and documented metastatic disease to bone include (99m)Tc bone scanning, MRI, CT, radiography, and 2-[(18)F]fluoro-2-deoxyglucose-PET. Clinical scenarios reviewed include asymptomatic stage 1 breast carcinoma, symptomatic stage 2 breast carcinoma, abnormal bone scan results with breast carcinoma, pathologic fracture with known metastatic breast carcinoma, asymptomatic well-differentiated and poorly differentiated prostate carcinoma, vertebral fracture with history of malignancy, non-small-cell lung carcinoma staging, symptomatic multiple myeloma, osteosarcoma staging and surveillance, and suspected bone metastasis in a pregnant patient. No single imaging modality is consistently best for the assessment of metastatic bone disease across all tumor types and clinical situations. In some cases, no imaging is indicated. The recommendations contained herein are the result of evidence-based consensus by the ACR Appropriateness Criteria((R)) Expert Panel on Musculoskeletal Radiology.

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients' survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.

Background: Intraoperative brain shift may cause inaccuracy of stereotactic image guidance on the basis of preoperatively acquired imaging data. The purpose of our study was to determine whether factors predicting brain shift affect the success of image-guided resection of malignant brain tumors., Methods: We retrospectively studied 54 patients who underwent image-guided resections of histopathologically confirmed malignant brain tumors (9 metastases, 45 high-grade gliomas). Precautions were taken during surgery to minimize brain shift, but intraoperative imaging was not performed. The following factors predictive of intraoperative brain shift were assessed: tumor size, periventricular location, patient age, prior surgery or radiation therapy, patient positioning, use of mannitol, and length of operative time. Postoperative magnetic resonance imaging was obtained in all cases within 48 hours of surgery to assess extent of resection., Results: Perioperative mortality was 0% in our series; perioperative morbidity was 3 of 54 patients (5.5%); 1 patient required reoperation for a hematoma, and 2 had transient neurological deficits. Successful resection was accomplished in 93% of tumors less than 30 cm(3) compared with 63.6% of tumors greater than 30 cm(3) (P = .026, Fisher exact test). This difference was more pronounced for patients with malignant gliomas. However, other factors predictive of intraoperative brain shift were not associated with unsuccessful resection., Conclusions: Intraoperative brain shift does not significantly affect the likelihood of successful resection of malignant brain tumors smaller than 30 cm(3). Larger tumors are less likely to be successfully resected, although factors other than brain shift can contribute to unsuccessful resection.

Arsenic trioxide (As(2)O(3)) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As(2)O(3) on solid tumors are poorly defined. Previously, we reported that As(2)O(3) induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As(2)O(3) treatment. When upregulation of BNIP3 induced by As(2)O(3) was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3 Delta TM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As(2)O(3)-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As(2)O(3)-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As(2)O(3) acts to induce autophagic cell death in malignant glioma cells.

The cyclin-dependent kinase inhibitor p27KIP1 is considered not only a prognostic factor in cancer, but also a promising anti-cancer agent. However, the relationship between p27KIP1 and telomerase, that has potential as tumor-marker, remains to be elucidated. In this study, using the recombinant adenoviral vector expressing p27KIP1 (Adp27KIP1), we investigated whether p27KIP1 affects telomerase activity in malignant glioma U373-MG cells. Overexpression of p27KIP1 suppressed telomerase activity in tumor cells. The down-regulation of telomerase was due to inhibition of the human telomerase reverse transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was partially induced by interfering with binding sites of the hTERT core promoter for transcription factors Myc and Sp1. These findings identify a novel role for p27KIP1 in down-regulation of telomerase activity.

The management of patients with glioblastoma remains challenging with an average survival of 32-56 weeks. We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry criteria for this study included: recurrent malignant glioma after surgical resection and conventional radiation therapy. At the time of recurrence, computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed. GC was administered 24 h after surgery (10 mg/kg/day) for 7 days. Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts. Adenoviral vector shedding, and local or systemic toxicity did not occur in this study. Magnetic resonance imaging showed lack of increased brain edema in the treated patients. Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity. Additionally, PCR for HSV-tk was negative in the brain 3 months after injection. The patients' Karnofsky score was maintained > or = 70 in 8/10 patients (80%) and 5/9 patients (55%) 3 and 6 months respectively, after gene therapy. Ten of 11 patients survived > or = 52 weeks from diagnosis with an average survival of 112.3 weeks. One patient is still alive 248 weeks from diagnosis. These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is currently in progress.

Object: Ionizing radiation is the gold-standard adjuvant treatment for glioblastoma multiforme (GBM), the most aggressive primary brain tumor. The mechanisms underlying neoplastic glial cell growth inhibition after administration of ionizing radiation, however, remain largely unknown. In this report, the authors characterize the response of GBM cells to ionizing radiation and elucidate factors that correlate with the radiosensitivity of these tumors., Methods: Six human GBM cell lines were subjected to increasing doses of radiation. Each demonstrated a dose-dependent suppression of cell proliferation. In the most radiosensitive cell line, the authors demonstrated a transient increase in the expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27, which corresponded with a G1 cell-cycle arrest. In contrast, the most radioresistant cell line demonstrated a decrease in p21 and p27 expression levels, which correlated with a failure to arrest. Apoptosis did not occur in any cell line following irradiation. Instead, autophagic cell changes were observed following administration of radiation, regardless of the relative radiosensitivity of the cell line., Conclusions: These findings elucidate some of the molecular responses of GBMs to irradiation and suggest novel targets for future therapy.