Paula de Robles

An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging

In glioblastoma (GBM), promoter methylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT) is associated with benefit from chemotherapy. Correlations between MGMT promoter methylation and visually assessed imaging features on magnetic resonance (MR) have been reported suggesting that noninvasive detection of MGMT methylation status might be possible. Our study assessed whether MGMT methylation status in GBM could be predicted using MR imaging. We conducted a retrospective analysis of MR images in patients with newly diagnosed GBM. Tumor texture was assessed by two methods. First, we analyzed texture by expert consensus describing the tumor borders, presence or absence of cysts, pattern of enhancement, and appearance of tumor signal in T2-weighted images. Then, we applied space-frequency texture analysis based on the S-transform. Tumor location within the brain was determined using automatized image registration and segmentation techniques. Their association with MGMT methylation was analyzed. We confirmed that ring enhancement assessed visually is significantly associated with unmethylated MGMT promoter status (P=0.006). Texture features on T2-weighted images assessed by the space-frequency analysis were significantly different between methylated and unmethylated cases (P<0.05). However, blinded classification of MGMT promoter methylation status reached an accuracy of only 71%. There were no significant differences in the locations of methylated and unmethylated GBM tumors. Our results provide further evidence that individual MR features are associated with MGMT methylation but better algorithms for predicting methylation status are needed. The relevance of this study lies on the application of novel techniques for the analysis of anatomical MR images of patients with GBM allowing the evaluation of subtleties not seen by an observer and facilitating the standardization of the methods, decreasing the potential for interobserver bias.

Population-Based Study of Pseudoprogression after Chemoradiotherapy in GBM

INTRODUCTION Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients with glioblastoma multiforme (GBM). Case reports have identified GBM patients who experienced transient radiological deterioration after concurrent chemoradiotherapy which stabilized or resolved after additional cycles of adjuvant TMZ, a phenomenon known as radiographic pseudoprogression. Little is known about the natural history of radiographic pseudoprogression. METHODS We retrospectively evaluated the incidence of radiographic pseudoprogression in a population-based cohort of GBM patients and determined its relationship with outcome and MGMT promoter methylation status. RESULTS Out of 43 evaluable patients, 25 (58%) exhibited radiographic progression on the first MRI after concurrent treatment. Twenty of these went on to receive adjuvant TMZ, and subsequent investigation demonstrated radiographic pseudoprogression in 10 cases (50%). Median survival (MS) was better in patients with pseudoprogression (MS 14.5 months) compared to those with true radiologic progression (MS 9.1 months, p=0.025). The MS of patients with pseudoprogression was similar to those who stabilized/responded during concurrent treatment (p=0.31). Neither the extent of the initial resection nor dexamethasone dosing was associated with pseudoprogression. CONCLUSIONS These data suggest that physicians should continue adjuvant TMZ in GBM patients when early MRI scans show evidence of progression following concurrent chemoradiotherapy, as up to 50% of these patients will experience radiologic stability or improvement in subsequent treatment cycles.

Methylation status of MGMT gene promoter in meningiomas

Meningiomas are usually cured by surgical resection. However, approximately 10% are characterized by more aggressive clinical behavior and higher risk of recurrence. Typically, recurrent meningiomas require further surgical resection followed, in some cases, by radiotherapy. To date, no chemotherapeutic agent has proven to be effective in either preventing or treating recurrence. The alkylating chemotherapeutic agent, Temozolomide (TMZ) has shown to increase overall survival in patients with glioblastoma (GBM) but its effectiveness for other types of brain tumor is less known. The clinical benefit of TMZ seems to be limited to those GBM tumors with promoter methylation of the MGMT gene. In this study, we assessed if a biologic rationale exists to support the use of TMZ as a treatment for meningiomas by assessing the MGMT promoter methylation status in these tumors using methylation specific PCR. We investigated the MGMT promoter methylation status in 36 tumors (32 newly diagnosed; 4 recurrent). Histologically, the majority were grade I. Patients were primarily female (64%) with a mean age of 52. None of the meningiomas in our series showed MGMT gene promoter methylation. Based on these data, we conclude that there is no biological rational to suggest that TMZ might have significant anti-meningioma activity.

A feasibility study to assess the integration of a pharmacist into neurooncology clinic

Objective. A multidisciplinary approach is increasingly used in NeuroOncology clinics. Although this model has several advantages, patients report feeling overwhelmed by the complexity of their treatment protocol and staff feel rushed because each provider must evaluate the patient within the limited clinic hours. We hypothesized that the presence of a pharmacist in clinic could address these concerns by (1) reviewing all treatment protocols and side-effect management with patients, (2) being available to address questions outside of clinic and (3) answering staff related medication questions. Methods. The pharmacist met with consenting patients at the initial clinic visit and followed up by telephone two additional times. The pharmacist was available to answer questions outside of clinic hours. Surveys were developed and given to patient and staff to evaluate their experience. Results. Over 4 months, 13 patients were enrolled. The pharmacist interacted with each patient an average of 9 times with 55% of interactions occurring outside scheduled visits and two-thirds of pharmacist interventions directly involving patient care. A total of 85% of patients and staff responded to the evaluation survey and 90% of respondents indicated that the pharmacist should remain part of the NeuroOncology team. Patients reported less stress related to their treatment and clinical staff experienced improved clinical efficiency directly as a result of the presence of the pharmacist. Conclusion. Based on these results, a clinical pharmacist should become a permanent member of the outpatient NeuroOncology clinic. J Oncol Pharm Practice (2009) 15: 79—85.

Glioblastoma in the elderly: An age-old problem

5 years after randomization to coronary angioplasty or coronary artery bypass graft surgery. Circulation 1997;96(9 suppl):II-11– II-15. 20. Petrovitch H, White L, Masaki KH, et al. Influence of myocardial infarction, coronary artery bypass surgery, and stroke on cognitive impairment in late life. Am J Cardiol 1998;81: 1017–1021. 21. Potter GG, Plassman BL, Helms MJ, et al. Age effects of coronary artery bypass graft on cognitive status change among elderly male twins. Neurology 2004;63:2245–2249.

Ethical and legal considerations for Canadian registries.

that will impact the creation and operation of neurological disease registries in Canada. This document is not meant to provide legal or ethical advice. In order to ensure that applicable laws and organizational policies are adhered to in an appropriate manner, it is recommended that legal advisors and relevant organizational representatives be consulted. For registries to succeed, it is critical to proactively consider legal and ethical issues such as consent and privacy. Additional ethical and legal considerations include: the involvement of Aboriginal people and their communities, languages and communication; setting up of biobanks; data management; data ownership; and conducting transparent registry operations. The Belmont Report Ethical Principles and Guidelines for the protection of human subjects of research6 and the Government of Canada Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS-2)7 should be referred to for the ethical principles that need to be considered during the creation of disease registries. In addition, Registries for Evaluating Patient Outcomes: A User’s Guide5 produced by The Agency for Healthcare Research and Quality provides useful information. However, this document presents perspectives and reviews legislation particularly relevant to the United States which differ in some respects from Canadian law and research policies and practice. In preparation of this guideline, we examined relevant Canadian and international literature as well as Canadian policy and legislation. We also consulted with Canadian privacy officers and specialists in research ethics. Finally, topic themes and issues were discussed with patients and families in project focus groups.

Evaluation of neurological patient registries

in the number of national as well as international registries for a variety of neurological conditions, with corresponding increase in the amount of publications arising from these efforts [ref]. The registries were established for determining the natural history of a specific disease, the effectiveness of new treatments, the quality of care and/or other patient-related outcomes. The purpose of this chapter is to provide an approach to registry evaluation and quality assessment. In preparation of this chapter, we reviewed current literature and consensus guidelines on registry evaluations. We also consulted with medical experts and registry/database specialists as part of a national registry meeting to provide feedback and consensus on criteria to be used for evaluation of disease registries in Canada.

Population based analysis ependymoma patients in Alberta from 1975 to 2007.

BACKGROUND Ependymomas are rare tumors of the central nervous system whose management is controversial. This population-based study of adults and children with ependymoma aims to (1) identify clinical and treatment-related factors that impact survival and (2) determine if postoperative radiotherapy (RT) can improve survival of patients with subtotal resection (STR) to levels similar to patients who had gross total resection (GTR). METHODS This retrospective population-based study evaluated 158 patients with ependymoma diagnosed between 1975-2007 in Alberta, Canada. RESULTS Younger patients (<7 years of age) were more likely to be diagnosed with grade III tumors compared with adults in whom grade I tumors were more common (p=0.003). Adults were more likely to have spinally located tumors compared to young children whose tumors were typically found in the brain. Overall, young children with ependymoma were more likely to die than older children or adults (p=0.001). An equivalent number of patients underwent GTR as compared with STR (48% vs 45%, respectively). Overall, older age, spinal tumor location, lower grade, and GTR were associated with improved progression free survival but only GTR was associated with significant improvement in overall survival. Median survival after STR and RT was 82 months compared with 122 months in patients who had GTR (p=0.0022). CONCLUSIONS This is the first Canadian population-based analysis of patients with ependymoma including adults and children. Extent of resection appears to be the most important factor determining overall survival. Importantly, the addition of RT to patients initially treated with STR does not improve survival to levels similar to patients receiving GTR.

Neurological registry quality control and quality assurance

This section of the guideline discusses procedures and best practices around quality control and quality assurance. In developing this section of the guideline we reviewed available literature and best practice; consulted with registry and disease experts; and derived consensus recommendations. Quality, as defined by the International Standards Organization (ISO) in standard ISO 8402:1994, is the “totality of characteristics of an entity that bear on its ability to satisfy stated and implied needs.”194 In the context of registries, this means that registry data characteristics must altogether satisfy the intended and implied needs of the registry purpose. For example, if the purpose of your registry is to study all female adults of child-bearing age with epilepsy; then your registry data must consist only of female adults of child-bearing age who have a diagnosis of epilepsy. It is important to note that quality and registry purpose are inherently related. Registry creators will therefore need to define what quality means for their specific purpose(s). While quality control and quality assurance are related concepts it is important to understand that they are different. Quality assurance (QA) is the process that maintains a desired level of quality.195 QA is a proactive process done in advance of obtaining an outcome. Examples of QA activities might include audits, training, procedure documentation, selection of quality tools etc. Quality control (QC) is the assessment of whether an outcome meets quality expectations.195 QC is a reactive process done once an outcome has been obtained. Examples of QC activities might include testing a product sample to determine if it meets requirements; or conducting a site inspection visit. Useful registries must have good quality data.196,197