Mark G. Hamilton

A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas.

Reovirus is an oncolytic virus with activity in in vivo models of malignant gliomas (MGs). The primary aims were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of intratumoral administration of reovirus in patients with recurrent MGs. Response, survival, and time to progression (TTP) were secondary aims. Patients were adults, had Karnofsky Performance score > or = 60, received prior radiotherapy with or without chemotherapy, and had up to the third recurrence of MG. Reovirus was administered intratumorally stereotactically at 1 x 10(7), 1 x 10(8), or 1 x 10(9) tissue culture infectious dose 50 (TCID50) in a volume of 0.9 ml. Twelve patients were treated at three dose levels (3, 6, and 3 patients, respectively). Seven were men, median Karnofsky Performance score was 80, and median age was 53.5 years. There were no grade III or IV adverse events (AEs) definitely or probably related to treatment. Ten patients had tumor progression, one had stabilization, and one was not evaluable for response. Median survival was 21 weeks (range, 6-234), and one is alive 54 months after treatment. Median TTP was 4.3 weeks (range, 2.6-39). An MTD was not reached. The intratumoral administration of the genetically unmodified reovirus was well tolerated using these doses and schedule, in patients with recurrent MG.

Venous Thromboembolism in Neurosurgery and Neurology Patients

Thromboembolism is a common problem in neurosurgery and neurology patients. Within this diverse population are subpopulations of patients with varying degrees of thromboembolic risk: low, moderate, and high. Patients at substantial risk for deep vein thrombosis and pulmonary embolism include those with spinal cord injury, brain tumor, subarachnoid hemorrhage, head trauma, stroke, and patients undergoing a neurosurgical operation. There are prophylactic strategies that can be applied to these various risk groups that will dramatically reduce the incidence of thromboembolism. The risk of pulmonary embolism or fatal pulmonary embolism typically exceeds the risk of severe or fatal bleeding from adequate prophylaxis, and these techniques should be applied on a routine basis. To adequately care for patients with deep venous thrombosis and pulmonary embolism, the physician requires a thorough understanding of the methods of diagnosis, the pharmacokinetics of heparin and warfarin, and a knowledge of their role in the treatment strategies that have proven efficacy and safety. In addition, an awareness of the low molecular weight heparins and heparinoids is becoming essential. These new agents have a potentially promising role in both the prophylaxis and treatment of patients with neurological disease. The principles concerning the prophylaxis, diagnosis, and clinical management of venous thromboembolic disease in neurosurgery and neurology patients are dealt with in this review.

The p75 neurotrophin receptor is a central regulator of glioma invasion.

The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.

Methylprednisolone for acute spinal cord injury: 5-year practice reversal.

OBJECTIVE To re-evaluate practice patterns for methylprednisolone (MP) administration in patients with acute spinal cord injury (SCI) within the spinal surgery community across Canada five years after the publication of practice recommendations. METHODS Canadian orthopedic and neurological spine surgeons were surveyed at their respective annual meetings about their practice of steroid administration for acute SCI by means of a questionnaire comprised of the same seven questions posed five years ago plus an additional question related to change of view. RESULTS Forty-two surgeons and twenty-one residents directly involved in the acute management of SCI completed the questionnaire. Seventy-six percent of spinal surgeons do not prescribe MP for SCI in sharp contrast to 76% who prescribed it five years ago. Of the 24% who use steroids, the NASCIS II dosing regimen is most commonly followed. One third of physicians continue to administer MP because of fear of litigation. CONCLUSIONS Over a five year period there has been a complete reversal in practice patterns of MP administration for SCI, along with an increased familiarity of the published literature. Attendance at meetings, participation in local group discussions, and peer-reviewed publications appear effective in altering practice preferences arising from peer pressure and even fear of litigation.

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient–derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity against human brain tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate the oncolytic potential of MYXV in immunocompetent racine glioma models. Here, we report that MYXV infects and kills all racine cell glioma lines and that its effects are enhanced by rapamycin. Intratumoral administration of MYXV with rapamycin improved viral replication in the tumor and significantly prolonged host survival. Similarly, coadministration via a method of convection-enhanced delivery (CED) enhanced viral replication and efficacy in vivo. Mechanisms by which rapamycin improved MYXV oncolysis included an inhibition of type I IFN production in vitro and a reduction of intratumoral infiltration of CD68(+) microglia/macrophages and CD163(+) macrophages in vivo. Our findings define a method to improve MYXV efficacy against gliomas by rapamycin coadministration, which acts to promote immune responses engaged by viral delivery.

Efficacy and Safety Evaluation of Human Reovirus Type 3 in Immunocompetent Animals: Racine and Nonhuman Primates

Purpose: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates. Experimental Design: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys. Results: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus’ antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates. Conclusions: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Venous Thromboembolism Prophylaxis in Patients Undergoing Cranial Neurosurgery: A Systematic Review and Meta-analysis

BACKGROUND:Randomized clinical trials (RCTs) have usually supported using heparin prophylaxis against venous thromboembolism (VTE) in patients undergoing cranial neurosurgery. The tradeoff between benefit and bleeding risk, however, has not been adequately characterized. OBJECTIVE:To conduct a systematic review and meta-analysis assessing the extent to which low-dose unfractionated heparin (LDUH) or low-molecular-weight heparin (LMWH) prophylaxis reduces the rate of VTE and increases the rate of intracerebral hemorrhage (ICH) and other bleeding in patients undergoing elective cranial neurosurgery. METHODS:We selected RCTs that evaluated LDUH or LMWH prophylaxis of VTE in patients undergoing elective cranial neurosurgery. A meta-analysis assessing heparins vs no heparin (either with or without mechanical methods) was performed. RESULTS:Eight RCTs were identified. Six RCTs involving 1170 patients evaluated LDUH or LMWH vs a control group. Five of 6 trials found a significant reduction in the risk of symptomatic and asymptomatic VTE with heparin prophylaxis. The pooled risk ratio was 0.58 (95% confidence interval, 0.45-0.75). ICH was more common in those receiving heparin, but not statistically significantly. For every 1000 patients who receive heparin prophylaxis, 91 VTE events will be prevented (approximately 35 of which are proximal deep vein thrombosis or pulmonary embolism and 9 to 18 of which are symptomatic), whereas 7 ICHs and 28 more minor bleeds will occur. CONCLUSION:Heparin prophylaxis for patients undergoing elective cranial neurosurgery reduces the risk of VTE but may also increase bleeding risks with a ratio of serious or symptomatic VTE relative to serious bleeding that is only slightly favorable.

Endoscopic versus microsurgical resection of third ventricle colloid cysts.

OBJECTIVE Endoscopic resection of colloid cysts has been performed as an alternative to microsurgical resection and stereotactic aspiration since 1982. To date, there are limited published studies comparing these procedures. In this study, we present the largest series of endoscopic resections published to date and compare outcomes to a cohort of microsurgical resections performed at the same institution. METHODS A retrospective chart review was conducted for all patients in the Calgary Health Region undergoing resection of a colloid cyst between 1991 and 2004. Comparison was made between patients treated with endoscopic resection versus microsurgical resection. RESULTS Twenty-five endoscopic and nine microsurgical procedures were performed. Complete resection was achieved in 24 of 25 procedures in the Endoscopic group, compared with all 9 procedures in the Microsurgical group. Patients in the Endoscopic group had a reduced operative time (mean 104 minutes versus 217 minutes) and reduced length of stay (3.8 days versus 8.4 days) compared to the Microsurgical group. One patient in the Endoscopic group had a complication (hemiparesis/pulmonary embolus). By contrast, 3 patients in the Microsurgical group had complications (seizure, ventriculitis/bone flap infection, and transient memory deficit). There was one recurrence in each group which both occurred at 5 years follow-up. The mean length of follow-up is 38 months in the Endoscopic group and 33 months in the Microsurgical group. CONCLUSION Endoscopic resection of colloid cysts can be performed with significantly lower risk of complication than microsurgical resection and with equivalent surgical success. Operative time and length of hospital stay are both significantly reduced with endoscopic resection.

Complications of endoscopic third ventriculostomy in previously shunted patients.

OBJECTIVE Endoscopic third ventriculostomy (ETV) is considered to be a safe and effective treatment in selected patients as an initial treatment for obstructive hydrocephalus and at the time of shunt malfunction in previously shunted patients. We compared the outcome and complications of ETV between patients with newly diagnosed hydrocephalus and those with previous shunting procedures. METHODS A retrospective review of patients undergoing ETV from 1996 to 2004 at Albertas Childrens Hospital and Foothills Medical Centre was completed. Patient data included symptoms at clinical presentation, cause of hydrocephalus, age at initial shunt, number of previous shunt revisions, age at ETV, complications, and subsequent shunting procedures performed. RESULTS A total of 131 patients were identified with a minimum follow-up duration of 1 year; 71 (82.5%) of 86 patients who underwent ETV as a primary procedure and 36 (80%) of 45 patients who had ETV at the time of shunt malfunction were shunt-free at the last follow-up evaluation. Patients younger than 1 year old who underwent ETV were more likely to require an additional procedure for control of their hydrocephalus (P < 0.01). Serious complications after ETV occurred more frequently in patients who presented at the time of shunt malfunction (14 of 45 patients, 31%) compared with patients who underwent primary ETV (seven of 86 patients, 8%) (P = 0.02). Previously shunted patients with a history of two or more revisions (P = 0.03) and who experienced a serious complication at the time of ETV (P = 0.01) were more likely to require shunt replacement. CONCLUSION ETV is an effective treatment both in selected patients with newly diagnosed hydrocephalus and in patients with a previous shunting procedure who are presenting with malfunction. Complications of ETV occur more frequently in previously shunted patients than in patients treated for newly diagnosed hydrocephalus, and care must be taken in the selection and treatment of these patients.