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Toronto, Canada

Sunnybrook Research Institute is the research component of Sunnybrook Health science Centre in Toronto, Ontario. It is one of the largest research centres in Canada, second only to the University Health Network within the Toronto Academic Health science Centre Network. SRI is fully affiliated with the University of Toronto.Conducting over $100 million in research every year, SRI is home to a number of breakthroughs that have transformed health care. The research institute supports the activities of over 200 scientists and clinician-scientists, over 200 research associates, engineers, physicists and technicians and over 300 students and trainees that works in 250,000 square feet of state-of-the-art research space in northeastern Toronto. They work to prevent disease and develop treatments that enhance and extend life. These aims derive from SRI’s core vision: to achieve discovery and its translation into clinic to set best practices. Wikipedia.

Sargent D.J.,Sunnybrook Research Institute | Grothey A.,Mayo Medical School
Nature Reviews Clinical Oncology | Year: 2013

The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. © 2013 Macmillan Publishers Limited.

Wilcox M.E.,University of Toronto | Adhikari N.K.J.,Sunnybrook Research Institute
Critical Care | Year: 2012

Introduction: Telemedicine extends intensivists' reach to critically ill patients cared for by other physicians. Our objective was to evaluate the impact of telemedicine on patients' outcomes.Methods: We searched electronic databases through April 2012, bibliographies of included trials, and indexes and conference proceedings in two journals (2001 to 2012). We selected controlled trials or observational studies of critically ill adults or children, examining the effects of telemedicine on mortality. Two authors independently selected studies and extracted data on outcomes (mortality and length of stay in the intensive care unit (ICU) and hospital) and methodologic quality. We used random-effects meta-analytic models unadjusted for case mix or cluster effects and quantified between-study heterogeneity by using I 2(the percentage of total variability across studies attributable to heterogeneity rather than to chance).Results: Of 865 citations, 11 observational studies met selection criteria. Overall quality was moderate (mean score on Newcastle-Ottawa scale, 5.1/9; range, 3 to 9). Meta-analyses showed that telemedicine, compared with standard care, is associated with lower ICU mortality (risk ratio (RR) 0.79; 95% confidence interval (CI), 0.65 to 0.96; nine studies, n = 23,526; I 2= 70%) and hospital mortality (RR, 0.83; 95% CI, 0.73 to 0.94; nine studies, n = 47,943; I 2= 72%). Interventions with continuous patient-data monitoring, with or without alerts, reduced ICU mortality (RR, 0.78; 95% CI, 0.64 to 0.95; six studies, n = 21,384; I 2= 74%) versus those with remote intensivist consultation only (RR, 0.64; 95% CI, 0.20 to 2.07; three studies, n = 2,142; I 2= 71%), but effects were statistically similar (interaction P = 0.74). Effects were also similar in higher (RR, 0.83; 95% CI, 0.68 to 1.02) versus lower (RR, 0.69; 95% CI, 0.40 to 1.19; interaction, P = 0.53) quality studies. Reductions in ICU and hospital length of stay were statistically significant (weighted mean difference (telemedicine-control), -0.62 days; 95% CI, -1.21 to -0.04 days and -1.26 days; 95% CI, -2.49 to -0.03 days, respectively; I 2> 90% for both).Conclusions: Telemedicine was associated with lower ICU and hospital mortality among critically ill patients, although effects varied among studies and may be overestimated in nonrandomized designs. The optimal telemedicine technology configuration and dose tailored to ICU organization and case mix remain unclear. © 2012 Wilcox et al.; licensee BioMed Central Ltd.

Plate K.H.,Frankfurt University Medical School | Scholz A.,Frankfurt University Medical School | Dumont D.J.,Sunnybrook Research Institute
Acta Neuropathologica | Year: 2012

The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to tumor angiogenesis. Many of these processes have been described in developmental angiogenesis; however, the relative contribution and relevance of these in human brain cancer remain unclear. Preclinical tumor models support a role for sprouting angiogenesis, vascular co-option and myeloid cell-derived angiogenesis in glioma vascularization, whereas a role for the other four mechanisms remains controversial and rather enigmatic. The anti-angiogenesis drug Avastin (Bevacizumab), which targets VEGF, has become one of the most popular cancer drugs in the world. Anti-angiogenic therapy may lead to vascular normalization and as such facilitate conventional cytotoxic chemotherapy. However, preclinical and clinical studies suggest that anti-VEGF therapy using bevacizumab may also lead to a pro-migratory phenotype in therapy resistant glioblastomas and thus actively promote tumor invasion and recurrent tumor growth. This review focusses on (1) mechanisms of tumor angiogenesis in human malignant glioma that are of particular relevance for targeted therapy and (2) controversial issues in tumor angiogenesis such as cancer stem-like cell-derived vasculogenesis and bone-marrow-derived vasculogenesis. © 2012 The Author(s).

High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs.

Wunsch H.,Sunnybrook Research Institute
Anesthesiology | Year: 2016

BACKGROUND:: Use of intensive care after major surgical procedures and whether routinely admitting patients to intensive care units (ICUs) improve outcomes or increase costs is unknown. METHODS:: The authors examined frequency of admission to an ICU during the hospital stay for Medicare beneficiaries undergoing selected major surgical procedures: elective endovascular abdominal aortic aneurysm (AAA) repair, cystectomy, pancreaticoduodenectomy, esophagectomy, and elective open AAA repair. The authors compared hospital mortality, length of stay, and Medicare payments for patients receiving each procedure in hospitals admitting patients to the ICU less than 50% of the time (low use), 50 to 89% (moderate use), and 90% or greater (high use), adjusting for patient and hospital factors. RESULTS:: The cohort ranged from 7,878 patients in 162 hospitals for esophagectomies to 69,989 patients in 866 hospitals for endovascular AAA. Overall admission to ICU ranged from 35.6% (endovascular AAA) to 71.3% (open AAA). Admission to ICU across hospitals ranged from less than 5% to 100% of patients for each surgical procedure. There was no association between hospital use of intensive care and mortality for any of the five surgical procedures. There was a consistent association between high use of intensive care with longer length of hospital stay and higher Medicare payments only for endovascular AAA. CONCLUSIONS:: There is little consensus regarding the need for intensive care for patients undergoing major surgical procedures and no relationship between a hospital’s use of intensive care and hospital mortality. There is also no consistent relationship across surgical procedures between use of intensive care and either length of hospital stay or payments for care. Copyright © by 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

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