Costas G. Hadjipanayis

Tumor initiating cells in malignant gliomas: biology and implications for therapy

A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas.

Glioblastoma cancer stem-like cells: implications for pathogenesis and treatment.

AbstractGlioblastoma remains one of the deadliest forms of cancer. Infiltrating cancer cells in the surrounding brain prevent complete resection, and tumor cell resistance to chemoradiation results in the poor prognosis of the glioblastoma (GBM) patient. Much research has been devoted over the years to the pathogenesis and treatment of GBM. The tumor stem cell hypothesis, which was initially described in hematopoietic cell malignancies, may explain the resistance of these tumors to conventional therapies. In this model, a certain subset of tumor cells, with characteristics similar to normal stem cells, is capable of producing the variety of cell types, which constitute the bulk of a tumor. As these tumor cells have properties distinct from those constituting the bulk of the tumor, a different approach may be required to eradicate these residual cells within the brain. Here we outline the history behind the theory of GBM cancer stem-like cells, as they are now referred to. We will also discuss the implications of their existence on commonly held beliefs about GBM pathogenesis and how they might influence future treatment strategies.

Glioblastoma with Oligodendroglioma Component (GBM‐O): Molecular Genetic and Clinical Characteristics

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM‐O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM‐Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation‐specific polymerase chain reaction (PCR). GBM‐Os accounted for 11.9% of all GBMs. GBM‐Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM‐Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM‐O appeared to be associated with a younger age at presentation. Among patients with GBM‐O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM‐O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics.

Model-based simulation for early neurosurgical learners

BACKGROUND Restrictions on duty hours and shift length by the Accreditation Council for Graduate Medical Education and public pressure to reduce complications and to improve outcomes in the clinical educational environment have enhanced interest in the use of procedural and surgical simulation to train neurosurgical residents. OBJECTIVE To introduce simple, available, and, when possible, inexpensive model-based simulation for early learners into the initial stages of neurosurgical residency training. METHODS Simulation for early-stage trainees in neurological surgery has taken advantage of model-based systems. The Society of Neurological Surgeons postgraduate year 1 courses have served as one paradigm for designing and using model-based simulators for procedural and surgical skill training as part of a purpose-designed overall curriculum. Ongoing surveys of resident and faculty course participants have supported iterative improvements in simulator models and curriculum from year to year. RESULTS Simulation for basic neurosurgical and intensive care procedures has been undertaken through the use of available materials, surgical technology, and modifications of related existing model simulators. Simulation of common, standard surgical procedures for early learners may be broken into individual surgical skills and maneuvers to prepare trainees for safe practice of these component skills during live procedures under direct supervision appropriate to their training stage. CONCLUSION Model-based simulation is particularly effective for early surgical learners as part of a coordinated curriculum. Almost 600 residents have used model-based simulation during the first 3 years of the Society of Neurological Surgeons boot camp courses, with ongoing modification and improvement of individual simulation models.BACKGROUND:Restrictions on duty hours and shift length by the Accreditation Council for Graduate Medical Education and public pressure to reduce complications and to improve outcomes in the clinical educational environment have enhanced interest in the use of procedural and surgical simulation to tr

Open biopsy in patients with acute progressive neurologic decline and absence of mass lesion

Objective: Patients with acute to subacute neurologic decline undergo a battery of imaging and laboratory tests to determine a diagnosis and treatment plan. Often, after an extensive evaluation, a brain biopsy is recommended as yet another tool to assist in determining the diagnosis. The goal of this retrospective cohort analysis is to measure the sensitivity of open brain biopsy in this patient population, compare these results with the preoperative presumed diagnosis, and evaluate if the biopsy result significantly alters treatment. Methods: The authors reviewed the medical records of 135 consecutive patients who underwent open brain biopsies for acute to subacute progressive neurologic decline between January 1999 and September 2008 at a single institution. All patients with mass lesions, with HIV/AIDS, and who were younger than 20 years of age were excluded from the study. Fifty-one patients met these criteria and all preoperative tests, imaging, and treatment plans were examined and compared with postbiopsy interventions to determine the impact of the biopsy on patient outcome. Results: The sensitivity of open brain biopsy at our institution was 35%. The most common preoperative presumed diagnosis was vasculitis and the most common postoperative finding was Creutzfeldt-Jakob disease, followed by amyloid angiopathy. Postbiopsy hemorrhage was a complication in 4% of patients. Treatment plans changed as a direct result of the biopsy in 8% of patients, and in only 4% did the biopsy findings make a difference in disease course. Conclusion: In patients with progressive neurologic decline without a radiographic mass lesion or immunodeficiency, open brain biopsy often fails to provide a diagnosis and even more rarely does it significantly alter treatment.

Inhibition of DNA Repair by a Herpes Simplex Virus Vector Enhances the Radiosensitivity of Human Glioblastoma Cells

Expression of the herpes simplex virus (HSV) protein, ICP0, from the viral genome, rendered two radioresistant human glioblastoma multiforme cell lines more sensitive to the effects of ionizing radiation. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic survival assays, U87-MG and T98 cell survival was more greatly decreased as a function of ionizing radiation dose when ICP0 was preexpressed in cells compared with when ICP0 was not expressed. Consistent with previous results, we found that the catalytic subunit of DNA-dependent protein kinase was degraded as a function of ICP0 in both cell types. This most likely resulted in the inhibition of DNA repair as inferred by the persistence of gammaH2AX foci or DNA double-strand breaks. Enhanced apoptosis was also found to occur following irradiation of U87-MG cells preinfected with the ICP0-producing HSV-1 mutant, d106. Our results suggest that expression of ICP0 in human glioblastoma multiforme cells inhibits the repair of DNA double-strand breaks after ionizing radiation treatment, decreasing the survival of these cells in part by induction of apoptosis.

Small extracellular vesicles as tumor biomarkers for glioblastoma.

Small extracellular organelles such as exosomes and microvesicles are currently being studied as a novel way to track tumor progression, pseudoprogression, and treatment monitoring. Their role in intercellular communication shows potential in the treatment of even the most formidable cancers. Glioblastoma (GBM) is the most common malignancy of the brain and has no known cure. A large emphasis has been placed on trying to improve the prognosis of this aggressive primary brain tumor. It has recently been discovered that small extracellular vesicles, mainly exosomes and microvesicles, play a role in the cell signaling process that leads to uncontrollable cell growth indicative of a tumor state. Here we describe the role of exosomes and microvesicles as a tumor biomarker for tracking the progression of different types of cancer, with an emphasis on GBM.

Neuroendoscopic Colloid Cyst Resection: A Case Cohort with Follow-Up and Patient Satisfaction

OBJECTIVE To analyze the safety and efficacy of neuroendoscopic colloid cyst resection and to assess patient satisfaction. METHODS A retrospective analysis of a single surgeons experience with neuroendoscopic resection of colloid cysts was performed. Surgeries performed in 56 patients were reviewed. Surgeries involved an anterolateral neuroendoscopic technique. Patients were followed postoperatively for an average of 14.9 months. Patients were also interviewed regarding their preoperative symptoms, resolution of symptoms postoperatively, and their degree of satisfaction. RESULTS The median operative time was 82 minutes, and the median duration of hospital stay was 5 days. During surgery, the ventricles were explored for residual cyst wall or cyst content, and none were encountered. On immediate postoperative imaging, cyst recurrence was not noted for any patient, and only 1 patient has had evidence of recurrence on long-term follow-up. Various preoperative symptoms were described by patients; depending on the specific symptoms, 70%-100% resolution of symptoms was shown after surgery. Along with clinical follow-up, patients were interviewed regarding their perception of surgery and recovery. Of the patients contacted, 100% reported satisfaction with the surgery, and 91% noted satisfaction with their recovery. Reported complications included memory loss, infection, deep vein thrombosis, and postoperative hematoma. There were 2 perioperative deaths (3.5%) related to surgery. CONCLUSIONS Neuroendoscopic colloid cyst resection can reliably achieve complete lesion removal with short operative times. In addition, there is a high level of reported patient satisfaction. To our knowledge, this is the largest case series of neuroendoscopic colloid cyst resections from a single surgeon.

Incidental sinonasal findings identified during preoperative evaluation for endoscopic transsphenoidal approaches.

Background The endoscopic transsphenoidal approach (eTSA) to lesions of the sellar region is typically performed jointly by neurosurgeons and otolaryngologists. Occasionally, the approach is significantly altered by sinonasal disease, anatomic variants, or previous surgery. However, there are no current guidelines that describe which physical or radiological findings should prompt a change in the plan of care. The purpose of this study was to determine the incidence of sinonasal pathology or anatomic variants noted endoscopically or by imaging that altered preoperative or intraoperative management. Methods A retrospective review was performed of 355 consecutive patients who underwent combined neurosurgery–otolaryngology endoscopic sella approach from August 1, 2007 to April 1, 2011. Our practice in these patients involves preoperative otolaryngology clinical evaluation and MRI review. Intraoperative image guidance is not routinely used in uncomplicated eTSA. Results The most common management alteration was the addition of image guidance based on anatomic variants on MRI, which occurred in 81 patients (35.0%). Eight patients (2.9%) were preoperatively treated with antibiotics and surgery was postponed secondary to acute or chronic purulent rhinosinusitis; two (0.7%) required functional endoscopic sinus surgery for medically refractory disease before eTSA. Five patients (1.8%) required anterior septoplasty intraoperatively for severe nasal septal deviation. Two patients (0.7%) had inverted papilloma and one patient had esthesioneuroblastoma identified preoperatively during rigid nasal endoscopy. Conclusion This is one of the larger reviews of patients undergoing eTSA for sellar lesions and the only study that describes how intraoperative management may be altered by preoperative sinonasal evaluation. We found a significant incidence of sinonasal pathology and anatomic variants that altered routine operative planning; therefore, a thorough sinonasal evaluation is warranted in these cases.

Water-Soluble Spinel Ferrites by a Modified Polyol Process as Contrast Agents in MRI

Magnetic nanoparticles have recently been very attractive for biomedical applications. In this study, we have synthesized ferrite nanoparticles for application as contrast agents in MRI experiments. Fe3O4 and MnFe2O4 spinel ferrites with a mean size of 11–12 nm, were prepared by a modified polyol route in commercially available polyethylene glycol with molecular weight 600 (PEG‐600). The reaction takes place in the presence of water soluble and non‐toxic tri‐block copolymer known as Pluronic® F‐127 (PEO100‐PPO65‐PEO100). The nanoparticles have saturation magnetization values of 52 and 68 emu/g for MnFe2O4 and Fe3O4, respectively. Both the Fe3O4, and MnFe2O4 nanoparticles make stable solutions in water known as ferrofluids. Preliminary data demonstrated the capability of these nanoparticles to induce imaging contrast in T2 weighted MRI experiments, making these materials suitable for biomedical applications such as medical MRI.