J Gregory Cairncross

The University of Calgary, Calgary, Alberta, Canada

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Publications (187)1313.09 Total impact

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    ABSTRACT: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
    The Lancet Oncology 03/2009; 10(5):459-66. DOI:10.1016/S1470-2045(09)70025-7 · 24.73 Impact Factor
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    ABSTRACT: In glioblastoma (GBM), promoter methylation of the DNA repair gene MGMT is associated with benefit from chemotherapy. Because MGMT promoter methylation status can not be determined in all cases, a surrogate for the methylation status would be a useful clinical tool. Correlation between methylation status and magnetic resonance imaging features has been reported suggesting that non-invasive MGMT promoter methylation status detection is possible. In this work, a retrospective analysis of T2, FLAIR and T1-post contrast MR images in patients with newly diagnosed GBM is performed using L1-regularized neural networks. Tumor texture, assessed quantitatively was utilized for predicting the MGMT promoter methylation status of a GBM in 59 patients. The texture features were extracted using a space-frequency texture analysis based on the S-transform and utilized by a neural network to predict the methylation status of a GBM. Blinded classification of MGMT promoter methylation status reached an average accuracy of 87.7%, indicating that the proposed technique is accurate enough for clinical use.
  • Cancer/Radiothérapie 11/2008; 12(6):709-709. DOI:10.1016/j.canrad.2008.08.264 · 1.11 Impact Factor
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    ABSTRACT: Elderly patients have glioblastomas (GBM) that are aggressive and poorly responsive to treatment. They are also prone to the side effects of treatment of GBM. To shed light on the treatment of elderly patients with GBM, we reviewed the treatment toxicities and survival of patients 65 years of age or older who were treated with chemoradiotherapy, which is the new standard of care for GBM in younger patients. Thirty-nine patients at a single cancer center in Canada met the eligibility criteria for this retrospective study. Nineteen patients were treated initially with TMZ and radiotherapy and 20 others were treated with radiotherapy alone (only two had TMZ subsequently). Eight patients in the chemoradiotherapy group (42%) experienced Grade III or IV toxicity versus none in the radiotherapy group. The median overall survival in the chemoradiotherapy group was 8.5 months (range, 2.0-24.7 months) versus 5.2 months (range, 1.5-14.2 months) in the radiotherapy group, an apparent benefit which may have been due to an imbalance in age at diagnosis, extent of resection and performance status. In this series of GBM cases, methylation of the MGMT gene promoter was not associated with longer survival, either overall, or within the chemoradiotherapy treated subset. Elderly patients with GBM treated with chemoradiotherapy can be expected to experience significant toxicity. Large randomized trials will be necessary to determine whether chemoradiotherapy prolongs the survival of elderly patients and whether MGMT promoter status predicts benefit from temozolomide in this subset of patients.
    Journal of Neuro-Oncology 09/2008; 89(1):97-103. DOI:10.1007/s11060-008-9593-6 · 2.79 Impact Factor
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    ABSTRACT: Background Anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA) are currently treated with a combination of surgery, radiotherapy and chemotherapy. Myeloablative therapy with autologous peripheral blood progenitor cell rescue (APBPCR) is one strategy to exploit the chemosensitivity of these tumors while deferring cranial radiation in an effort to avoid radiation-related neurotoxicity. Methods Twenty patients (16 AO, 4 AOA) with a median age of 46 years (range, 19–60) and KPS of 90 (range, 70–100) were treated with 4 cycles of procarbazine, Lomustine (CCNU) and vincristine (I-PCV) every six weeks. Responding patients were eligible for myeloablative therapy with busulfan and thiotepa followed by APBPCR. 1p and 19q chromosomes were analyzed prospectively but patients were enrolled without regard to deletion status. Results Fifteen patients (75%) had a response to I-PCV and 14 underwent transplant. Median disease-free and overall survival of the transplanted patients has not been reached but is at least 36 months. No patients required dose reduction or termination of I-PCV due to toxicity. Hepatic veno-occlusive disease (VOD) was a complication of transplant in three patients and resulted in one death. Patients with and without deletions of 1p and 19q had durable responses. Conclusions This regimen conferred durable responses in more than one-half of patients, allowing deferral of radiotherapy for three years or longer. The major limitation of this approach is the acute toxicity associated with both the induction and consolidation regimens; temozolomide has replaced I-PCV for the current trial and the incidence and severity of VOD is being followed closely.
    Journal of Neuro-Oncology 08/2008; 89(2):187-193. DOI:10.1007/s11060-008-9603-8 · 2.79 Impact Factor
  • Warren P Mason, J Gregory Cairncross
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    ABSTRACT: For nearly a century, glial neoplasms have been classified by microscopic features alone with treatment prescribed based on histology using a "one-size-fits-all" formula. However, recent advances in our understanding of the molecular events underlying gliomagenesis are beginning to change the way we think about the diagnostic classification of gliomas. Indeed, several recurring molecular derangements are now being viewed as cornerstones of a new diagnostic framework because these alterations appear to be superior to traditional microscopic classification schemes as guideposts for treatment selection and prognosis. Moreover, molecular analysis of tumor tissue is identifying aberrant growth signaling pathways in glioma which can now be blocked selectively by a new generation of targeted therapies, including small molecule inhibitors and monoclonal antibodies. Time will tell whether these new agents can be successfully introduced into the clinical arena. In the meantime, the molecular characteristics of gliomas are being used to select patients for both randomized trials and phase II studies.
    Neurology 08/2008; 71(5):365-73. DOI:10.1212/01.wnl.0000319721.98502.1b · 8.30 Impact Factor
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    ABSTRACT: Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response. This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
    Journal of Clinical Oncology 07/2008; 26(18):3015-24. DOI:10.1200/JCO.2007.15.7164 · 17.88 Impact Factor
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    ABSTRACT: Intergroup Radiation Therapy Oncology Group Trial 9402 study, a phase III trial of chemotherapy plus radiotherapy (PCV-plus-RT) vs. radiotherapy alone for pure and mixed anaplastic oligodendroglioma confirmed the prognostic significance of 1p 19q deletion and showed that only progression-free survival (PFS) was prolonged in PCV-plus-RT-treated patients and only in association with 1p 19q deletion. We reviewed tumor histopathology, separating 115 tumors deemed to be classic for oligodendroglioma (CFO) from 132 lacking classic features of oligodendroglioma (NCFO) and evaluated the relationship of histopathology and 1p 19q status to treatment and outcome. The study disclosed: (i) overall survival (OS) of patients with CFO was significantly longer than for patients with NCFO (P < 0.0001) and was not affected by necrosis. Median OS for CFO patients with and without necrosis was 6.6 and 6.3 years (OS log-rank P = not significant), respectively, in contrast to NCFO showing 1.9 and 3.3 years respectively (OS log-rank P = 0.014). (ii) Classic oligodendroglial morphology was highly associated with 1p 19q deletion, present in 80% of CFO and only in 13% of NCFO. (iii) On multivariate analysis, both classic oligodendroglial morphology and 1p 19q deletion remained significantly associated with PFS and OS. (iv) Patients with CFO treated with PCV-plus-RT showed a trend toward increased survival compared with CFO treated with RT (P = 0.08). Median OS was not reached in the PCV-plus-RT group and was 6.3 years in RT group. These findings suggest that classic oligodendroglial morphology combined with 1p 19q deletion may in the future be predictive of chemotherapeutic response and survival.
    Brain Pathology 07/2008; 18(3):360-9. DOI:10.1111/j.1750-3639.2008.00129.x · 4.35 Impact Factor
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    ABSTRACT: A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.
    The Lancet Oncology 02/2008; 9(1):29-38. DOI:10.1016/S1470-2045(07)70384-4 · 24.73 Impact Factor
  • Roger Stupp, J. Gregory Cairncross
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    ABSTRACT: Despite optimal surgery and adjuvant radiotherapy, malignant gliomas almost always recur. One cause of failure is explained by the diffusely infiltrating pattern of growth displayed by most gliomas, with malignant cells disseminated far beyond the initial bulky tumor. Although most relapses occur at or near the initial site of tumor, either along the resection margin or at the edge of the radiation field, distant recurrences or seeding of the cerebrospinal fluid (CSF) occurs in long-surviving patients. Malignant gliomas are not a localized disease but instead affect the whole brain and may display wide dissemination even at early stages. Thus, therapeutic strategies aiming only at bulky local disease are doomed to fail. The successful treatments of the future will need to eradicate microscopic disease in many sites within the brain and do so without neurotoxic effects. Here, we summarize progress in the medical treatment of malignant glioma.
    12/2007: pages 223-231;
  • Rebecca A Betensky, David N Louis, J Gregory Cairncross
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    ABSTRACT: Subjects in tumour studies are often misclassified with respect to histologic features that are not routinely recorded in diagnostic reports and that display heterogeneity within tumours. Pathologic analysis of the tumours may miss the feature of interest if the pathologist was not alerted to detail the microscopic feature of interest or if it is not present in the selected specimens. In this setting, only the subjects for whom the outcome is not found are potentially misclassified. Analyses of associations between the observed, potentially misclassified, outcome and a second outcome are invalid if the probability of misclassification depends on the second outcome. Three natural tests of association based on the observed data depend on different numbers of nuisance parameters. Most promising is a test based on the ratio of proportions of the observed feature. We illustrate this test using a study of the association of imaging parameters with genetic features in subjects with oligodendroglioma, a common brain tumour. In this study, calcification, a feature related to the imaging parameters, was potentially misclassified as not present.
    Statistics in Medicine 11/2007; 26(26):4808-16. DOI:10.1002/sim.2895 · 2.04 Impact Factor
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    ABSTRACT: This systematic review examines the role of chemotherapy following surgery and external beam radiotherapy for adults with newly diagnosed malignant glioma. MEDLINE, EMBASE, and the Cochrane Library databases were searched to August 2006 to identify relevant randomized controlled trials (RCTs) and meta-analyses. Proceedings from the 1997 to 2006 annual meetings of the American Society of Clinical Oncology were also searched. Two RCTs reported a survival advantage in favour of radiotherapy with concomitant and adjuvant temozolomide compared with radiotherapy alone in patients with anaplastic astrocytoma or glioblastoma. Twenty-six RCTs and two meta-analyses detected either no advantage or a small survival advantage in favour of adjuvant chemotherapy. Concomitant temozolomide during radiotherapy and post-radiation adjuvant temozolomide is recommended for all patients ages 18-70 with newly diagnosed glioblastoma multiforme who are fit for radical therapy (ECOG 0-1). Temozolomide may be considered in other situations (i.e., ECOG 2, biopsy only, age > 70, intermediate grade glioma), but there is no high-level evidence to support this decision. Moreover, there are few data on long-term toxicities or quality of life with temozolomide. Adjuvant chemotherapy may be an option for younger patients with anaplastic (grade 3) astrocytoma and patients with pure or mixed oligodendroglioma. However, there is no evidence of a survival advantage from adjuvant chemotherapy in these patients, and treatment-related adverse effects and their impact upon quality of life are poorly studied. The combination of procarbazine, lomustine, and vincristine (PCV) is not recommended for patients with anaplastic oligodendroglioma and oligoastrocytoma.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11/2007; 34(4):402-10. · 1.60 Impact Factor
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    ABSTRACT: Anaplastic oligodendroglioma is a malignant brain tumor uniquely sensitive to treatment with both chemotherapy and radiotherapy. There are few prospective clinical trials for newly diagnosed patients and multiple approaches to the treatment of these patients. This study explored the recommended treatment offered by experts in neuro-oncology. A Web-based survey was developed and distributed to 800 members of the Society of Neuro-Oncology (SNO) who had an e-mail address listed with SNO. Questions addressed use of molecular genetic information and treatment recommendations. A total of 99 clinical SNO members (20%) responded. The majority reported practicing at an academic center in the United States. Two-thirds of respondents see more than five patients with newly diagnosed anaplastic oligodendroglioma annually. Molecular genetic testing was requested for more than 75% of patients, and the results significantly influenced treatment recommendations (p = 0.000003). Regardless of molecular genetic status, the most commonly recommended treatment was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%). The current survey demonstrates that although neuro-oncologists have embraced the use of molecular genetic studies in newly diagnosed anaplastic oligodendroglioma, treatment recommendations vary widely and are often independent of the molecular data.
    Neuro-Oncology 08/2007; 9(3):314-8. DOI:10.1215/15228517-2007-002 · 5.29 Impact Factor
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    ABSTRACT: This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.
    British Journal of Cancer 08/2007; 97(3):302-7. DOI:10.1038/sj.bjc.6603876 · 4.82 Impact Factor
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    ABSTRACT: To evaluate the hypothesis that adults with partially resected (PR<50% resection) supratentorial low-grade glioma (LGG) benefit from higher doses of radiation. Patients receiving post-operative radiation for WHO grade I-II LGG at the University of Western Ontario between 1979 and 2001 were studied. Patient characteristics evaluated included: age, gender, symptom duration>30 days, seizures at presentation, Karnofsky performance status (KPS)<70, astrocytoma pathology (AS), and radiation dose. A Cox proportional hazard regression model was constructed to test the influence of radiation dose. One hundred and seven patients were analyzed. Patients who had PR were not significantly different from those with STR (subtotal/total resection) in terms of patient characteristics. Median survival (MST) of PR patients who received<or=50 Gy was 16.5 months while those who received>50 Gy had a MST of 109.2 months. The interaction of radiation dose and extent of resection was tested after controlling for other patient factors by Cox regression model. The interaction was highly significant for both OS and PFS (P=0.013 and P=0.003, respectively). This model remained significant after excluding six patients receiving doses<42 Gy (OS, P=0.024, and PFS, P=0.001). The outcome for patients with LGG is dependent on extent of tumor resection and radiation dose. Patients with PR should be considered for higher radiation dose schedules (>50 Gy). Future trials on therapeutic strategies for LGG should consider stratification of patients by extent of tumor resection. Our data suggests that one dose does not fit all.
    Journal of Neuro-Oncology 04/2007; 82(2):165-70. DOI:10.1007/s11060-006-9141-1 · 2.79 Impact Factor
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    Michael D Blough, Magdalena C Zlatescu, J Gregory Cairncross
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    ABSTRACT: Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter (i.e., gene silencing) occurs in 40% to 50% of patients with glioblastoma and predicts benefit from temozolomide chemotherapy; when unmethylated, MGMT repairs DNA damage induced by temozolomide, contributing to chemoresistance. In this study, we tested the hypothesis that MGMT is regulated by p53 in astrocytic cells, the precursors of which may give rise to glioblastoma. p53 is of interest because, in addition to often being mutated in glioblastoma, inactivation sensitizes some astrocytoma cell lines to temozolomide. MGMT expression was examined in neonatal murine astrocytes and SF767 human astrocytic glioma cells following p53 inactivation by knockout (murine only) or RNAi methods. MGMT mRNA and protein were detected in murine wild-type p53 astrocytes. However, in knockout murine astrocytes and wild-type cells in which p53 was inhibited by RNAi, MGMT expression was reduced by >90%. This effect of p53 on MGMT expression was unrelated to MGMT promoter methylation-in both wild-type and p53-null astrocytes, the MGMT promoter was unmethylated. In wild-type astrocytes, the p53 protein localized to a regulatory region of the MGMT promoter. In SF767 human astrocytic glioma cells, transient knockdown of p53 led to the down-regulation of MGMT gene expression. In murine astrocytes and SF767 cells, p53 regulates MGMT expression without affecting promoter methylation; in astrocytes, this effect may be due to direct binding of p53 to the MGMT promoter. These results imply that the best use of temozolomide requires a thorough understanding of MGMT regulation.
    Cancer Research 02/2007; 67(2):580-4. DOI:10.1158/0008-5472.CAN-06-2782 · 9.28 Impact Factor
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    ABSTRACT: Texture analysis is an important tool for quantitative assessment of medical signals and images. In particular, texture characteristics can help classify and segment specific types of pathology. Often, texture features are extracted from co-occurrence measures of small neighborhoods of pixels. However, methods based on co-occurrence statistics have been largely unsuccessful at differentiating between benign and malignant tissues. We present a texture analysis approach for magnetic resonance images based on local spectral analysis using the S-transform. Our technique produces a texture curve for each pixel in an image that contains spatial frequencies up to the Nyquist frequency. We have successfully used this approach to examine texture characteristics of oligodendroglioma brain tumors. Using our approach, we are able to classify chemosensitive and chemoresistant tumors with high sensitivity and specificity. Texture analysis of magnetic resonance images based on the S-transform may allow improved diagnosis and monitoring of neurological pathology.
    01/2007: pages 311-321; The Fields Institute Communications Series.
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    ABSTRACT: To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas. Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m2 carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men). Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%). Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.
    Journal of Neuro-Oncology 08/2006; 78(3):311-6. DOI:10.1007/s11060-005-9104-y · 2.79 Impact Factor
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    ABSTRACT: We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18-67) and a median KPS of 100 (range, 70-100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44-142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.
    Neuro-Oncology 05/2006; 8(2):183-8. DOI:10.1215/15228517-2005-009 · 5.29 Impact Factor
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    ABSTRACT: Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.
    The Oncologist 03/2006; 11(2):165-80. DOI:10.1634/theoncologist.11-2-165 · 4.54 Impact Factor

Publication Stats

18k Citations
1,313.09 Total Impact Points

Institutions

  • 2004–2015
    • The University of Calgary
      • • Department of Clinical Neurosciences
      • • Faculty of Medicine
      Calgary, Alberta, Canada
  • 1992–2014
    • University of Toronto
      • • Department of Medicine
      • • Department of Surgery
      Toronto, Ontario, Canada
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 2008
    • Brain Canada
      Montréal, Quebec, Canada
  • 2004–2008
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
  • 2007
    • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 2004–2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1989–2006
    • Memorial Sloan-Kettering Cancer Center
      • Department of Neurology
      New York City, NY, United States
  • 1998–2002
    • Massachusetts General Hospital
      • Molecular Neurobiology Laboratory
      Boston, MA, United States
    • Salk Institute
      • Molecular Neurobiology Laboratory
      La Jolla, CA, United States
  • 1987–2002
    • The University of Western Ontario
      • • Department of Clinical Neurological Sciences
      • • Department of Oncology
      • • Department of Microbiology and Immunology
      London, Ontario, Canada
  • 2001
    • Université de Sherbrooke
      Sherbrooke, Quebec, Canada
  • 2000
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • American Academy of Neurology
      Saint Paul, Minnesota, United States
  • 1999
    • University of California, San Francisco
      San Francisco, California, United States
  • 1997
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1994
    • Renfrew Victoria Hospital
      Renfrew, Ontario, Canada
  • 1985
    • Cancer Treatment Centre
      Anaheim, California, United States