Barbara Fisher

Bio: Barbara Fisher is an academic researcher from University of Western Ontario. The author has contributed to research in topics: Radiation therapy & Temozolomide. The author has an hindex of 40, co-authored 116 publications receiving 26509 citations. Previous affiliations of Barbara Fisher include London Health Sciences Centre & Mayo Clinic.

Malignant teratoid/rhabdoid tumour: long-term survival.

Abstract: The patient is a previously healthy 19-month-old child who became symptomatic in October 1998 with right hand weakness and cessation of new words with progression of right sided weakness and decreased sensation over the next month. The computed tomography (CT) and magnetic resonance imaging (MRI) scans demonstrated a large, deep, left frontal periventricular enhancing mass with several cystic areas. A left frontoparietal craniotomy was performed and the tumour was grossly resected. The pathological diagnosis was AT/RT. Grossly, the tumour was composed of firm, pink-tan hemorrhagic tissue. Sections showed a densely cellular, infiltrating neoplasm with areas of necrosis (some calcified), fascicular and focal sheets of collagen, and a variable, often prominent reticulin network. There was no endothelial proliferation. Light microscopy with hematoxylin and eosin stain (Figure 1) revealed a varied tumour appearance predominantly composed of larger tumour cells, with randomly dispersed nests of small undifferentiated cells close to the interface of tumour and normal brain tissue. The larger cells had several growth patterns: some were loosely arranged bi- or multi-polar cells forming cords and acinar structures against a faintly basophilic mucinous background, some were elongated cells arranged in coarse follicles or other compact bundles, while others were arranged in sheets or nests with prominent, sometimes glassy eosinophilic and cytoplasmic inclusions and eccentric nuclei (rhabdoid cells). Larger cells had nuclei with vesicular chromatin and prominent nucleoli, and smaller cells had hyperchromatic nuclei. Mitoses were focally numerous with some atypical in form, and cytoplasmic glycogen was inconspicuous. Immunohistochemical studies revealed widespread staining for epithelial membrane antigen (EMA), vimentin (Figure 2), glial fibrillary acid protein (GFAP), groups of cells with membranous patterns of staining for CD99, regional staining for neuron-specific enolase (NSE), scattered staining for transthyretin, and rare staining for actin, cytokeratin, and synaptophysin. The tumour was positive for chromosome 22 monosomy. Electron microscopy showed polygonal cells arranged in ill-defined acini that formed inconspicuous, sometimes entwined short microvillus processes. Variable numbers of intermediate filaments were identified and some cells showed a rudimentary basal lamina. Desmosomes were not seen, and there was no evidence of neural differentiation.

Response to Weltman and Fleury Malheiros, re Lassman et al.

Abstract: In Reply to Weltman and Fleury Malheiros: We thank Drs. Weltman and Fleury Malheiros for their comments on our recent article.1 We agree that our analyses were performed on a retrospective dataset, and interpretations are thus subject to limitations and potential biases inherent to any retrospective study. For example, as we discussed in the article, neither central review of pathology nor imaging was performed. Multivariate analyses attempted to control for potential confounding variables, but only a randomized prospective study would definitively address this concern. However, we believe that our conclusions (and cross-comparisons) are supported not only by our own observations but also by recent data and treatment trends in neuro-oncology. For example, in our study, treatment group imbalances did not contribute to differences in outcome in the Cox model. Groups were reasonably well balanced for potential confounders, such as performance status. In addition, Weltman and Fleury Malheiros suggest that standard of care for anaplastic oligoendrogliomas includes radiotherapy as part of the initial treatment regimen. We agree that radiotherapy has well-established efficacy and, for many years, was the standard approach. However, treatment options have evolved since the initial studies during the 1960s–1980s cited by Drs. Weltman and Malheiros. It is now well established that oligodendrogliomas, especially those harboring 1p19q co-deletion, respond to chemotherapy. For example, the recently publicized long-term follow-up of RTOG 9402 demonstrated that chemo-radiotherapy doubled median survival relative to radiotherapy alone in 1p19q co-deleted cases (14.7 vs. 7.3 years).2 Moreover, the German NOA-04 trial of newly diagnosed anaplastic gliomas also suggested that primary chemotherapy is equi-efficacious as primary radiotherapy.3 Furthermore, survival with 1p19q codeleted anaplastic oligodendrogliomas is at least several years. Accordingly, radiotherapy-induced dementia as a late toxicity4 is a real concern. Consequently, many neuro-oncologists advocate for chemotherapy alone and defer radiotherapy until disease progression in 1p19q codeleted cases. The same concern is well established in the controversies surrounding late neuro-cognitive toxicity from early radiotherapy in the treatment of low-grade gliomas, primary central nervous system lymphoma, and resected brain metastases. Therefore, the acknowledged limitations of our retrospective design notwithstanding, our results are concordant with these studies suggesting that overall survival was not compromised by deferring radiotherapy.1 Absent a clear survival advantage, deferred radiotherapy in favor of chemotherapy alone is certainly a reasonable initial strategy. We are not alone. For example, 42% of neuro-oncologists surveyed in 2005 recommended deferring radiotherapy in codeleted cases.5 Similarly, 57% of patients in our retrospective dataset who receive a diagnosis of codeleted tumors since 2005 were treated with chemotherapy alone (almost exclusively temozolomide).6 Therefore, as stated in our publication, “subject to the limitations of study design, our data suggest that initial treatment with chemotherapy alone may be a reasonable option for patients with 1p19q codeleted tumors.”1 Regardless of advised therapy, in our clinical experience, many patients refuse radiotherapy because of perceived concerns about neuro-toxicity. Therefore, although ongoing or future prospective studies may show that deferred radiotherapy adversely affects survival, concerns about cognitive injury are important in determining optimal therapy, and survival may not be the only end point of clinical importance. The CATNON or CODEL phase III trials (for non- or codeleted anaplastic gliomas, respectively) may help to assess quality of life outcomes. Clearly, neuro-oncology is a multidisciplinary field, and treatment requires individualization that depends on discussion among both physicians and patients of risks and benefits of various strategies.

Short Communication Pulmonary sequelae after electron spinal irradiation q

Abstract: We measured pulmonary function in 21 patients, after craniospinal irradiation with a posterior spinal electron beam. The median age at treatment was 7.5 years. Nine patients (43%) demonstrated abnormal pulmonary function tests, five with restrictive changes, one with isolated diminished diffusion capacity, and three with obstructive disease. These changes were mild and predominantly asymptomatic. q 2001 Elsevier Science Ireland Ltd. All rights reserved.

Combination C hemotherapy a nd R adiotherapy f or P rimary Central N ervous S ystem L ymphoma: R adiation T herapy Oncology G roup S tudy 9 3-10

Abstract: Purpose: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We prospectively studied the use of combination chemotherapy plus cranial irradiation in newly diagnosed patients with PCNSL. Patients and Methods: We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98 were assessable. Patients first received five cycles of methotrexate 2.5 g/m 2 , vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain radiotherapy (RT) was administered to a total dose of 45 Gy and all patients received high-dose cytarabine after RT. Results: Fifty-eight percent of patients with measurable disease had a complete response to preirradiation chemotherapy and 36% had a partial (> 50%) response, for a 94% response rate. Median progression-free survival was 24.0 months and overall survival was 36.9 months. Age was an important prognostic factor; median survival was 50.4 months in patients younger than 60 and only 21.8 months in those aged 60 or older (P < .001). Fifty-three percent of patients had grade 3 or 4 toxicity during induction chemotherapy, half of which was hematologic. However, 12 patients (15%) experienced severe delayed neurologic toxicity, eight of whom died. Conclusion: This is the first multicenter trial demonstrating improved survival with the combination of chemotherapy plus RT compared with previous reports of RT alone. A high-dose methotrexate-based regimen produced a high response rate before RT was administered. High-dose methotrexate combined with cranial irradiation is an effective therapeutic approach to PCNSL, but neurotoxicity is a delayed risk of this approach. J Clin Oncol 20:4643-4648. © 2002 by American Society of Clinical Oncology.

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Abstract: methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Abstract: BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Abstract: Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

IDH1 and IDH2 Mutations in Gliomas

Abstract: Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...