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Background IDH mutations are thought to represent an early oncogenic event in glioma evolution, found with high penetrance across tumor cells, however in rare cases IDH mutation may exist only in a small subset of the total tumor cells (subclonal IDH-mutation). Methods We present two institutional cases with subclonal IDH1 R132H mutation. In addition, two large publicly-available cohorts of IDH-mutant astrocytomas were mined for cases harboring subclonal IDH mutations (defined as tumor cell fraction (TCF) with IDH mutation ≤0.67) and the clinical and molecular features of these subclonal cases were compared to clonal IDH-mutant astrocytomas. Results Immunohistochemistry (IHC) performed on two institutional WHO grade 4 IDH-mutant astrocytomas revealed only a minority of tumor cells in each case with IDH1 R132H mutant protein, and next-generation sequencing (NGS) revealed remarkably low IDH1 variant allele frequencies compared to other pathogenic mutations, including TP53 and/or ATRX. DNA methylation classified the first tumor as high-grade IDH-mutant astrocytoma with high confidence (0.98 score). In the publicly-available datasets, subclonal IDH mutation was present in 3.9% of IDH-mutant astrocytomas (18/466 tumors). Compared to clonal IDH-mutant astrocytomas (n=156), subclonal cases demonstrated worse overall survival in grades 3 (p=0.0106) and 4 (p=0.0184). Conclusions While rare, subclonal IDH1 mutations are present in a subset of IDH-mutant astrocytomas of all grades, which may lead to a mismatch between IHC results and genetic/epigenetic classification. These findings suggest a possible prognostic role of IDH mutation subclonality, and highlight the potential clinical utility of quantitative IDH1 mutation evaluation by IHC and NGS.

Object Maximal safe tumor resection is part of the standard of care for patients with newly diagnosed glioblastoma. The role of reoperation in the care of patients with recurrent glioblastoma is less clear, and less than a quarter of patients undergo a second surgery. Previous studies have identified preoperative variables associated with the improved survival of patients following reoperation, and guidelines for the selection of patients for reoperation have been devised and validated. In this study, the authors analyzed the relative survival benefit of maximal safe tumor removal in a series of patients with recurrent glioblastoma who all underwent reoperation. Methods In this longitudinal study, the clinical and radiological data of 97 consecutive patients who underwent reoperation for recurrent glioblastoma were prospectively collected. Multiple regression analyses and Kaplan-Meier plotting were performed to identify pre- and postoperative clinical and radiological variables associated with increased survival following reoperation. Results The median postoperative survival of all patients following reoperation was 12.4 months (95% confidence interval [CI] 9.0–15.6 months). Multiple Cox regression analysis revealed that patients with large (> 3 cm3) residual tumors following reoperation had significantly decreased survival relative to those with residual tumors that were small (> 0–3 cm3; hazard ratio [HR] = 3.10, 95% CI 1.69–5.70; p < 0.001) or radiologically absent (0 cm3; HR = 5.82, 95% CI 2.98–11.37; p < 0.001). Large residual tumors had faster rates of subsequent regrowth than small (odds ratio [OR] = 4.22, 95% CI 1.19–14.97; p = 0.026) or radiologically absent (OR = 11.00, 95% CI 2.79–43.43; p = 0.001) residual tumors, and a faster regrowth rate was significantly associated with decreased survival (HR = 4.01, 95% CI 2.26–7.14; p < 0.001). Conclusions The overall survival of patients with recurrent glioblastoma who underwent reoperations increased with decreasing postoperative residual tumor volumes. For patients meeting prognostic criteria for reoperation, the surgical goal should be to minimize residual tumor volume to maximize overall survival. Clinical trial registration no.: NCT00060541 (ClinicalTrials.gov).

Bone marrow-derived human mesenchymal stem cells (hMSCs) are capable of localizing to gliomas after systemic delivery and can be used in glioma therapy. However, the mechanism underlying the tropism of hMSCs for gliomas remains unclear. In vitro studies suggest that platelet-derived growth factor BB (PDGF-BB) may mediate this tropism. However, a causal role of PDGF-BB has not been demonstrated in vivo. Therefore, we tested the hypothesis that PDGF-BB mediates the attraction of hMSCs to gliomas in vitro and in vivo.U87 or LN229 glioma cells were transfected with plasmids encoding human PDGF-B. Stable transfected clones that secreted large amounts of PDFG-BB and clones that produced low levels of PDGF were chosen. In vitro migration of hMSCs toward PDGF-B or conditioned media from high- and low-secreting PDGF-B tumor cells was assessed using Matrigel invasion assays. For in vivo localization studies, hMSCs were tracked by bioluminescence imaging (BLI) after transduction with an adenovirus containing luciferase cDNA. In other studies, hMSCs were labeled with green fluorescent protein (gfp) and analyzed for intratumoral localization by immunohistochemistry.In vitro invasion assays showed that significantly more hMSCs migrated toward glioma cells engineered to secrete high levels of PDGF-BB compared with low-secreting gliomas. Anti-PDGF-BB-neutralizing antibody abrogated this increase in migration. Pretreatment of hMSCs with inhibitory antibodies against PDGF receptor-beta also reduced hMSC migration. To demonstrate that PDGF-BB mediates the localization of hMSCs in vivo, hMSCs-Ad-Luc were injected into the carotid artery of mice harboring orthotopic 7-day-old U87-PDGF-BB-high secreting or U87-PDGF-BB-low secreting xenografts and analyzed by BLI. Statistically significant increases in hMSCs were seen within PDGF-BB-high xenografts compared with PDGF-BB-low xenografts. To control for PDGF-BB-induced differences in tumor size and vascularity, gfp-labeled hMSCs were injected into the carotid arteries of animals harboring 4-day old PDGF-BB-high secreting xenografts or 7-day old PDGF-BB-low secreting xenografts. At these times tumors had similar size and vessel density. Statistically significant more hMSCs localized to PDGF-BB-high secreting xenografts compared with PDGF-BB-low secreting xenografts. Pretreatment of hMSCs with anti-PDGFR-beta-inhibitory antibodies decreased the localization of hMSCs in this intracranial model.PDGF-BB increases the attraction of hMSCs for gliomas in vitro and in vivo, and this tropism is mediated via PDGF-beta receptors on hMSCs. These findings can be exploited for advancing hMSC treatment.

✓ This 42-year-old man presented with an intradural extramedullary mass in his lower cervical spine. On imaging studies the lesion mimicked the appearance of a meningioma. At surgery, the mass was found to be an intradural extra-arachnoid tumor. An intraoperative pathological examination determined the lesion to be a Hodgkin lymphoma. The procedure was limited to biopsy sampling and the patient was treated further with adriamycin, bleomycin, vincristine, and dacarbazine chemotherapy, after which remission was demonstrated both clinically and on images. Analysis of a frozen section obtained during the procedure aided in the diagnosis of the tumor, thus preventing further resection and the potential neurological complications associated with more radical resection. To the authors’ knowledge this is the first reported case of a presumed primary intradural extraarachnoid Hodgkin lymphoma.

Background Section of a tight filum terminale is a minimally invasive procedure compared with cord untethering procedures used for more complex spinal abnormalities. Anecdotal evidence suggests, however, that the risk of symptomatic retethering resulting from scarring might be higher than previously thought. Objective To determine the frequency of symptomatic retethering after section of a tight filum terminale and to explore possible risk factors. Methods We reviewed databases at 2 pediatric neurosurgery centers for all patients who had surgery for a suspected tight filum terminale between January 1982 and June 2009. Results We identified 152 patients. The median length of follow-up was 78 months. Thirteen patients (8.6%) went on to retether symptomatically at a median time of 23.4 months after the initial procedure. Eight had early retethering (within 2 years) and 5 had late retethering (after 7 years). Compared with late retetherers, early retetherers were older at initial surgery (median, 9.4 vs 0.9 years of age), had a higher level of the conus (median, L1/L2 vs L3/L4), had more arachnoiditis after initial surgery, and required more repeat untethering procedures. Late retetherers were younger at initial surgery than those who did not retether (median, 0.9 vs 4.5 years of age). Conclusion Symptomatic retethering is not uncommon after a simple filum snip, and long-term follow-up is warranted. Two distinct patterns of retethering were observed. Arachnoiditis caused by infection or a cerebrospinal fluid fistula may predispose to early retethering, whereas early surgery for prevention of tethered cord symptoms may predispose to late retethering.

Bone marrow is a complex tissue and is a source of several stem/progenitor cell populations. In addition to hematopoietic stem cells and endothelial progenitors,1–4 the bone marrow is also a source of a less well-characterized stem cell/progenitor population referred to as mesenchymal stem cells (MSCs). This cell population was originally identified in the 1970s by Friedenstein et al,1,5 who placed whole bone marrow in plastic culture dishes and, after removing the nonadherent (hematopoietic) cells, was left with an adherent cell population that had the ability to differentiate into colonies resembling bone or cartilage. Castro-Malaspina et al6 used similar methods to isolate adherent bone marrow cells, which others showed could be induced to differentiate into a variety of mesenchymal elements, including fat, bone, cartilage, and bone marrow stroma.7–10 Most recently, Pittenger and Marshak4 and Pittenger et al9 isolated a bone marrow population, referred to as MSCs, that grew as adherent cells on plastic, could be expanded ex vivo to high passage numbers, and could be differentiated into multiple mature connective tissue cell types, particularly adipocytes, chondrocytes, and osteocytes. Although there is no specific surface marker that defines MSCs, human MSCs are negative for CD45 and CD31 and express CD105, CD73, CD90, CD44, and CD166.11 In the mouse, there is less consensus regarding the defining surface markers,12–14 but several studies indicate that mouse MSCs are negative for CD45, CD11b, and CD31 and positive for stem cell antigen-1 (Sca-1), and CD9.14,15 Physiologically, these cells are thought to give rise to the bone marrow stromal elements that provide the microenvironment and supporting structure necessary for marrow homeostasis.1,4,16–19 For the neurosurgeon, MSCs are of interest because of their potential use in the therapy of a variety of neurological disorders.12 In the field of neuro-oncology, we and others have reported that ex vivo expanded human bone marrow–derived MSCs (BM-MSCs) selectively localize to human gliomas after systemic administration and can be engineered to deliver antiglioma therapies to experimental human glioblastomas such as interferon-β and tumor necrosis factor-α–related apoptosis-inducing ligand.20,21 Exogenous MSCs also localize to areas of stroke,22 traumatic brain injury,23 and intracerebral hemorrhage,24 suggesting a potential role in these pathological processes. MSCs are also of interest because of the potential involvement of endogenous MSCs in normal physiological responses to injury and inflammation and because they may comprise the stroma of solid tumors, the milieu of which is much like a nonhealing wound.25 Recent evidence suggests that endogenous MSCs may be an important component of glioblastoma multiforme, the most common adult malignant brain tumor. Specifically, cells resembling MSCs can be isolated from fresh glioma specimens obtained at surgery.26,27 Like BM-MSCs, these tumor derived-MSCs grow as adherent cells in culture; differentiate into adipocytes, chondrocytes, and osteocytes; and express the requisite MSC surface markers.26,27 These tumor-derived MSCs are thought to contribute to the stroma of human gliomas. Although it is postulated that MSCs may be recruited into areas of inflammation, injury, and tumors from a pool of circulating BM-MSCs originating from the bone marrow, to date there is conflicting evidence supporting the notion that BM-MSCs actually circulate in the bloodstream. However, an alternative source of MSCs may be the local tissues within peripheral organs. Cells similar to MSCs have been reported to be found in tissues other than the bone marrow, including fat, dermis, muscle, liver, pancreas, lung, endometrium, kidney, vessels, and brain.28–36 It is suggested that MSCs may reside throughout the body in most postnatal organs.28,32 Although Rutka et al37 reported in the 1980s that nonglial, mesenchymal cells can be cultured from normal brain tissue, the isolation of cells with the specific characteristics of MSCs from the brain has only begun to be explored, and the existence of brain-derived MSCs (Br-MSCs) and their location within the brain remains unclear. Identifying MSCs in normal brain tissue would provide new insight into the capacity of central nervous system tissues to respond to inflammation and tumor formation. In this context, we sought to determine the extent to which cells with the features of MSCs exist in normal brain tissue and to determine the location of these cells in the brain. Consequently, we isolated and cultured cells from normal mouse brain using the same methods used to isolate BM-MSCs and thereby identified cells that were similar to BM-MSCs in terms of morphology, surface markers, and differentiation pattern, which we called brain-derived MSCs (Br-MSCs). Histological studies suggest that these Br-MSCs reside within the perivascular niche. We propose that these Br-MSCs may represent a pool of local stem cells that maintain normal homeostasis of the perivascular niche and are capable of responding to tissue stresses within the brain.

Object Tumor size is likely to be a major determinant of hearing preservation after surgery for vestibular schwannoma. Findings in some large case series have not supported this concept, possibly due to variation in the technique used for tumor measurement. The authors sought to determine if the length of tumor–cochlear nerve contact was predictive of hearing outcome in adults undergoing resection of a vestibular schwannoma. Methods Patients who underwent a hearing-preserving approach for resection of a vestibular schwannoma at one institution by a neurosurgeon/neurotologist team between 2001 and 2005 were screened. Patients with American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Class A or B hearing preoperatively were included. Magnetic resonance images were reviewed and used to calculate the length of tumor–cochlear nerve contact. Tumors were also measured according to AAO-HNS guidelines. Results Thirty-one patients were included, 8 (26%) of whom had hearing preservation. Univariate analysis revealed that extracanalicular length of tumor–cochlear nerve contact (p = 0.0365), preoperative hearing class (p = 0.028), I–V interpeak latency of the brainstem auditory evoked potential (p = 0.021), and the interaural I–V interpeak latency difference (p = 0.018) were predictive of hearing outcome. Multivariate analysis confirmed the predictive value of extra-canalicular length of contact and preoperative hearing class (p = 0.041 and p = 0.0235, respectively). Conclusions Vestibular schwannomas with greater lengths of tumor–cochlear nerve contact increase a patient's risk for hearing loss after surgery with attempted hearing preservation. Involvement of the internal auditory canal produces a constant risk of hearing loss. Data from the experience of a single surgical team can be used to estimate the probability of good hearing outcome for any given patient with serviceable hearing and a vestibular schwannoma.

To the Editor: A 42-year-old man who was in rehabilitation for intravenous substance abuse presented with a three-month history of seizures and incoordination. Other symptoms included dysarthria, a hesitant pattern of speech, myoclonic jerks, postural tremor, emotional lability, and fluctuating short-term memory. On questioning he admitted that for four years he had been concentrating his methadone preparation, which was diluted with a grape-flavored drink, by heating it in an uncoated aluminum pot. He would then reconstitute the residue for intravenous injection. His serum aluminum level was 6650 nmol per liter (reference interval

Aluminum toxicity first came to attention in the medical literature as a sequela of peritoneal or hemodialysis, where accumulation of aluminum in body tissues results from the use of aluminum-containing dialysate and phosphate binders. The most common clinical presentations of aluminum toxicity include anemia, bone disease, and a syndrome of encephalopathy known as the dialysis encephalopathy sydrome (DES). We present the unique case of a 42-year-old man who developed chronic aluminum toxicity from the intravenous injection of a methadone preparation intended for oral consumption. The methadone solution was concentrated for intravenous injection by heating in aluminum cookware. Experiments performed in our laboratory reproducing this technique, using weakly acidic solutions similar to popular drink mixes, confirmed that significant amounts of elemental aluminum can be leached from aluminum cookware when heated. The patient presented to medical attention with generalized seizures, profound cerebellar dysfunction, myoclonus, and speech apraxia, all of which are characteristic of DES. The peripheral blood film revealed bizarre red cell morphology, with clear features of iron deficiency and prominent coarse basophilic stippling, suggesting impaired iron utilization, which is at least one mechanism of aluminum related hematologic toxicity. A bone marrow biopsy demonstrated extensive osteosclerosis and myelosclerosis, compatible with significant metabolic bone disease. Subsequent investigations revealed a serum aluminum level of 7200 nmol/L, eighteen times the upper limit of normal (400 nmol/L). Chelation therapy with a continuous intravenous infusion of deferoxamine was started, and over a course of ten months the serum aluminum level was reduced to 2390 nmol/L with few side effects. The patient made a significant neurologic recovery and returned to life in the community. This is the first detailed account of the successful use of deferoxamine to chelate aluminum in a patient without dialysis-dependent renal insufficiency. This case also highlights heavy metal exposure as a diagnostic consideration in intravenous substance abusers presenting with multiorgan dysfunction, and the importance of performing a thorough inquiry into injection drug practices when evaluating these patients.