There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Identification of human brain tumour initiating cells

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.

https://cancerres.aacrjournals.org/content/canres/63/18/5821.full.pdf

Identification of a Cancer Stem Cell in Human Brain Tumors

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syndrome (intestinal polyposis and brain tumors). 10 However, most familial cases have

Malignant Gliomas in Adults

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Erratum. Emerging Neurosurgery in Africa – WFNS Rabat Reference Center (WFNS-RTC) for Training African Neurosurgeons

The extracellular matrix (ECM) is the naturally occurring substrate upon which cells migrate, proliferate, and differentiate in vivo [1,2]. The ECM functions as a biological adhesive that maintains the normal cytoarchitecture of different tissues and defines the key spatial relationships among dissimilar cell types. A loss of coordination and an alteration in the interactions between mesenchymal cells and epithelial cells separated by an ECM are thought to fundamental steps in the development and progression by an ECM are thought to fundamental steps in the development and progression of cancer. The interested reader can now refer to a number of key review articles in this field [2–4].

The Extracellular Matrix: Cues from the Microcellular Environment Which Can Inhibit or Facilitate Glioma Cell Growth

I am deeply honored to be appointed as the new Editor-in-Chief (EIC) of the Journal of Neurosurgery (JNS). I follow Dr. John Jane Sr., who has served admirably and tirelessly in this role since October 1992, and has implemented numerous transformative changes within the Journal of Neurosurgery Publishing Group (JNSPG) (Fig. 1). As such, the task for me is somewhat daunting; however, I view this task as a tremendous opportunity at a time when the standard operating procedures for publications for associations, such as the American Association of Neurological Surgeons (AANS), are being rewritten, in part, by shifts from print to online publishing. At a time of transition, such as this, it is wise to review salient aspects of the history of the JNS as we prepare to chart a new course for our future. Since its inception in 1944 there have been 6 previous EICs of the JNS (Table 1), all of whom have left indelible marks on the progress and stature of the journal. In addition, we should also remember the insightful and deliberative force of Dr. John F. Fulton, who, in the spring of 1943, in response to a request by Dr. Alfonso Asenjo in Santiago, Chile, worked with the officers of the Harvey Cushing Society (now AANS) to establish the first specialty-specific and international journal devoted to neurosurgery. In the words of Dr. R. Glen Spurling, a major participant in the US military effort during World War II, Dr. Fulton “fathered the JNS.”1 The first issue of the journal was published in January 1944, and the lead article was written by Dr. Gilbert Horrax on the many contributions of Harvey Cushing to the science and practice of neurosurgery throughout his career.4 There were initially 5 members appointed to the Editorial Board. Issues were published bimonthly until 1962, at which time it was necessary to increase the number of issues to 12 per year to accommodate the ever-increasing number of accepted submissions. From its first issue, the JNS has been maintained as an international journal accepting neurosurgical submissions from around the world.1,8 The same holds true to this day, with authors from over 60 countries submitting their best work for peer review in 2012. In this era of bibliometrics, we can indeed be proud of the JNS, which, from 2011 data, has a 5-year Impact Factor (IF) of 3.088, and total citations of 28,800, which is more than any other neurosurgical journal. The proliferation of neurosurgical centers throughout the world and the widespread accessibility of scientific and clinical data have led to an exponential rise in the number of submissions and, consequently, the number of published pages in the JNS over the past 50 years. Whereas in 1963 there were 165 individual papers and 1111 pages of text published in the JNS,1 in 2012 there were 1208 accepted manuscripts from a total of 3604 submissions, and a near 5-fold increase in pages printed at 5106 pages. Obviously, to accommodate such an incredible increase in volume of submissions and Editorial

Leading transition while maintaining tradition

PURPOSE: Pediatric secondary high grade glioma (sHGG), which result from malignant transformation of low grade glioma (PLGG), are a poorly understood group of tumors with devastating outcomes. PATIENTS AND METHODS: We performed a population-based study combined with long-term follow-up of PLGG that transformed to sHGG. Exonic-sequencing and copy number alterations were investigated on a discovery cohort, followed by detailed genetic analysis of all tumors. Clinical and outcome data analysis of a genetically distinct subgroup was performed. RESULTS: sHGG were observed in 28/888 (3.2%) patients treated in Southern Ontario for PLGG with a median latency of 2.74 years (range, 0.18-20.3 years). sHGG were characterized by a high somatic mutation load (23 per genome). Alterations in chromatin modifying genes and major telomere maintenance pathways were observed in 57% and 54% of sHGG respectively. However, specific mutations in IDH1, H3F3A G34 and ATRX were extremely rare. The most recurrent somatic alterations were the oncogenic BRAF V600E mutation and deletion of the tumor suppressor gene CDKN2A, observed in 39% and 57% of sHGG respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced to the patient-matched PLGG counterparts. These early alterations were rarely observed in non-transformed PLGG (p < 0.0001) and primary childhood high grade glioma (p = 0.0023). The BRAF mutant sHGG subgroup was characterized by longer latency periods to transformation than non-BRAF mutant sHGG (median 6.59 versus 1.62 years; p < 0.0001). Furthermore, 5-year overall survival of children with BRAF mutant and wild-type PLGG that transformed were 75% ± 15% and 29% ± 12% respectively (p = 0.024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation provides a window of opportunity for aggressive surgical interventions, targeted therapy against oncogenic BRAF, and extended surveillance to potentially mitigate the devastating transformation event.

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Bi-21braf mutation and cdkn2a deletions define a clinically distinct subgroup of childhood secondary high grade glioma

The authors1 have succinctly described the course of a 15-year-old boy with dysembryoplastic neuroepithelial tumor (DNET) occupying the corpus callosum and pericallosal region. They have successfully kept the patient symptom free and in remission by surgery alone. Most DNETs are situated in the brain parenchyma, with superficial cortical regions being the most common location. Occasionally, DNETs may be quite aggressive and large, and can extend from the cortex to the white matter, and then to the deep nuclei such as the basal ganglia. Very rarely, malignant features may be seen within these tumors. After 3 years, the patient is doing well without neurological issues. Although the imaging features were suggestive of DNET, the location was not. The authors have done well to draw our attention to atypically presenting DNETs, and to underscore the role of surgery in these cases.

James T. Rutka

Papers

Erratum. Emerging Neurosurgery in Africa – WFNS Rabat Reference Center (WFNS-RTC) for Training African Neurosurgeons

The Extracellular Matrix: Cues from the Microcellular Environment Which Can Inhibit or Facilitate Glioma Cell Growth

Leading transition while maintaining tradition

Bi-21braf mutation and cdkn2a deletions define a clinically distinct subgroup of childhood secondary high grade glioma

Dysembryoplastic neuroepithelial tumor