Sunnybrook Health Sciences Centre

About: Sunnybrook Health Sciences Centre is a healthcare organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Population & Medicine. The organization has 7689 authors who have published 15236 publications receiving 523019 citations. The organization is also known as: Sunnybrook.

Anticancer Therapies Combining Antiangiogenic and Tumor Cell Cytotoxic Effects Reduce the Tumor Stem-Like Cell Fraction in Glioma Xenograft Tumors

Abstract: Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

Abstract: Summary Background The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. Methods For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. Findings Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6–36·8) in the chemotherapy-alone group and 32·0 months (27·5–36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72–1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5–85·0) with chemotherapy alone and 83·7% (81·4–86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64–1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [ vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [ vs three [ Interpretation Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival. Funding F Hoffmann-La Roche.

Quality of life in the five years after intensive care: a cohort study

Abstract: Data on quality of life beyond 2 years after intensive care discharge are limited and we aimed to explore this area further. Our objective was to quantify quality of life and health utilities in the 5 years after intensive care discharge. A prospective longitudinal cohort study in a University Hospital in the UK. Quality of life was assessed from the period before ICU admission until 5 years and quality adjusted life years calculated. 300 level 3 intensive care patients of median age 60.5 years and median length of stay 6.7 days, were recruited. Physical quality of life fell to 3 months (P = 0.003), rose back to pre-morbid levels at 12 months then fell again from 2.5 to 5 years after intensive care (P = 0.002). Mean physical scores were below the population norm at all time points but the mean mental scores after 6 months were similar to those population norms. The utility value measured using the EuroQOL-5D quality of life assessment tool (EQ-5D) at 5 years was 0.677. During the five years after intensive care unit, the cumulative quality adjusted life years were significantly lower than that expected for the general population (P < 0.001). Intensive care unit admission is associated with a high mortality, a poor physical quality of life and a low quality adjusted life years gained compared to the general population for 5 years after discharge. In this group, critical illness associated with ICU admission should be treated as a life time diagnosis with associated excess mortality, morbidity and the requirement for ongoing health care support.

Brief cognitive screening instruments: an update

Abstract: Objective To review the recent literature on cognitive screening with a focus on brief screening methods in primary care as well as geriatric services. Design The Medline search engine was utilized using the keyword search terms ‘cognitive screening’, ‘cognitive assessment’, and ‘dementia screening’ limiting articles to those published in English since 1998. Results 679 abstracts were retrieved. Articles focusing on attitudes toward cognitive screening, current screening practices, promising new instruments and more recent updates contributing significant information on established instruments were retrieved and incorporated into this review. Reference lists were reviewed for relevant contributing articles. Instruments recommended from previous reviews of cognitive screening and those identified in surveys as most frequently used in primary care and geriatric settings were emphasized in this review. Conclusions Dementia remains under-diagnosed in the elderly population. Despite significant limitations, the Mini Mental State Exam remains the most frequently used cognitive screening instrument. Its best value in the community and primary care appears to be for the purpose of ruling out a diagnosis of dementia. Instruments such as the Mini-Cog, Memory Impairment Screen (MIS), and the General Practitioner Assessment of Cognition (GPCOG) have consistently been recognized for utility in primary care. The clock drawing test (CDT) and newer instruments such as the Montreal Cognitive Assessment (MoCA) and the Rowland Universal Dementia Assessment Scale (RUDAS) are gaining credibility due to improvements in sensitivity, addressing frontal/executive functioning, and decreasing susceptibility to cultural and educational biases. Copyright © 2009 John Wiley & Sons, Ltd.

Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial.

Abstract: ContextIn the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI)ObjectiveTo determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 yearDesign, Setting, and ParticipantsFollow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002InterventionsPatients were randomly assigned to receive intravenously bivalirudin (075 mg/kg bolus, 175 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) Both groups received daily aspirin and a thienopyridine for at least 30 days after PCIMain Outcome MeasuresIncidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollmentResultsAt 6 months, death occurred in 14% of patients in the heparin plus Gp IIb/IIIa group and in 10% of patients in the bivalirudin group (hazard ratio [HR], 070; 95% confidence interval [CI], 043-114; P = 15) Myocardial infarction occurred in 74% and 82% of patients, respectively (HR, 112; 95% CI, 093-134; P = 24), and repeat revascularization was required in 114% and 121% of patients, respectively (HR, 106; 95% CI, 091-123; P = 45) By 1 year, death occurred in 246% of patients treated with heparin plus Gp IIb/IIIa blockade and in 189% of patients treated with bivalirudin (HR, 078; 95% CI, 055-111; P = 16) Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patientsConclusionLong-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI