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1.  Bevacizumab for Advanced Breast Cancer: Hope, Hype, and Hundreds of Headlines 
The Oncologist  2013;18(11):1174-1179.
In February 2008, the U.S. Food and Drug Administration granted accelerated approval for the use of bevacizumab in metastatic breast cancer; however, approval was revoked in November 2011. We sought to categorize and analyze the newspaper reports related to bevacizumab's use in advanced breast cancer. Media reports are a common source of medical information, and we observed substantial fluidity of media reports over time.
Learning Objectives
Summarize findings regarding the media's portrayal of bevacizumab with each phase of therapeutic development.Identify media sources of information about bevacizumab in each phase of therapeutic development.
On February 22, 2008, the Food and Drug Administration granted accelerated approval for the use of bevacizumab (Avastin) in metastatic breast cancer. Based on subsequent clinical trials, this approval was revoked on November 18, 2011. In this study, we categorize and analyze the newspaper reports related to bevacizumab's use in advanced breast cancer.
Using the Factiva media database, we reviewed all newspaper reports published in North America from January 4, 2002, to January 4, 2013, containing the words “breast cancer” and “Avastin,” or “bevacizumab.” Articles were classified as pre-approval (January 4, 2002–February 21, 2008), approval (February 22, 2008–November 17, 2011), or post-approval loss (November 18, 2011–January 4, 2013). Information regarding benefits, side effects, costs, interviewees, and article tone and theme were abstracted from each article by two independent reviewers. Differences among the three study phases were compared using the chi square analysis.
A total of 359 articles met study inclusion criteria. The number of reports having a positive headline tone and/or positive article tone declined with each study period. The proportion of articles discussing side effects and financial costs increased, whereas those discussing efficacy decreased with each study period. Drug representatives were most likely to be quoted in newspaper articles prior to bevacizumab's approval.
Media reports are a common source of medical information for patients, practitioners, and policy makers. We observed substantial fluidity of media reports over time.
PMCID: PMC3825300  PMID: 24072217
Media; Health services; Bevacizumab; Breast cancer; Drug funding
4.  Immunoisolation: where regenerative medicine meets solid organ transplantation 
Expert review of clinical immunology  2012;8(7):10.1586/eci.12.64.
Immunoisolation refers to an immunological strategy in which nonself antigens present on an allograft or xenograft are not allowed to come in contact with the host immune system, and it is implemented to prevent allorecognition and avoid immunosuppression. In this setting, the two most promising technologies, encapsulation of pancreatic islets (EPI) and immunocloaking (IC), are used. In the case of EPI, islets are inserted in capsules that, allow exchange of oxygen, nutrients and other molecules. In the case of IC, a natural nanofilm is injected prior to renal transplantation within the vasculature of the graft with the intent to pave the inner surface of the vascular lumen and camouflage the antigens located on the membrane of endothelia cells. Significant progress achieved in experimental models is leading EPI and IC to clinical translation.
PMCID: PMC3810353  PMID: 23078065
immunocloaking; immunoisolation; islet encapsulation; regenerative medicine
5.  Spontaneous regression of metastatic pulmonary renal cell carcinoma in the setting of sarcomatoid differentiation of the primary tumour 
Canadian Urological Association Journal  2013;7(9-10):E587-E589.
We present a case of spontaneous regression of pulmonary metastases from renal cell carcinoma (RCC) with sarcomatoid differentiation, prior to intervention. The patient presented with conventional type RCC with Furhman Grade 4/4 and sarcomatoid differentiation, complicated by pulmonary metastases. Palliative systemic therapy was planned, but prior to the onset of treatment, serial computed tomography scans demonstrated regression of metastatic disease. Spontaneous regression of metastases is rare, but well-documented in conventional clear cell RCC. To the best of our knowledge, this has not previously been described in the setting of sarcomatoid differentiation of the primary tumour.
PMCID: PMC3776034  PMID: 24069101
7.  Treatment Success in Cancer: Industry Compared to Publicly Sponsored Randomized Controlled Trials 
PLoS ONE  2013;8(3):e58711.
To assess if commercially sponsored trials are associated with higher success rates than publicly-sponsored trials.
Study Design and Settings
We undertook a systematic review of all consecutive, published and unpublished phase III cancer randomized controlled trials (RCTs) conducted by GlaxoSmithKline (GSK) and the NCIC Clinical Trials Group (CTG). We included all phase III cancer RCTs assessing treatment superiority from 1980 to 2010. Three metrics were assessed to determine treatment successes: (1) the proportion of statistically significant trials favouring the experimental treatment, (2) the proportion of the trials in which new treatments were considered superior according to the investigators, and (3) quantitative synthesis of data for primary outcomes as defined in each trial.
GSK conducted 40 cancer RCTs accruing 19,889 patients and CTG conducted 77 trials enrolling 33,260 patients. 42% (99%CI 24 to 60) of the results were statistically significant favouring experimental treatments in GSK compared to 25% (99%CI 13 to 37) in the CTG cohort (RR = 1.68; p = 0.04). Investigators concluded that new treatments were superior to standard treatments in 80% of GSK compared to 44% of CTG trials (RR = 1.81; p<0.001). Meta-analysis of the primary outcome indicated larger effects in GSK trials (odds ratio = 0.61 [99%CI 0.47–0.78] compared to 0.86 [0.74–1.00]; p = 0.003). However, testing for the effect of treatment over time indicated that treatment success has become comparable in the last decade.
While overall industry sponsorship is associated with higher success rates than publicly-sponsored trials, the difference seems to have disappeared over time.
PMCID: PMC3605423  PMID: 23555593
8.  Liver bioengineering: Current status and future perspectives 
The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes. There are two general pathways to liver bioengineering and regeneration. The first consists of creating a supporting scaffold, either synthetically or by decellularization of human or animal organs, and seeding cells on the scaffold, where they will mature either in bioreactors or in vivo. This strategy seems to offer the quickest route to clinical translation, as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin. Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development. The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways. In fact, it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume. Infusion of autologous bone marrow cells, which aids in liver regeneration, into patients was shown to be safe and to improve their clinical condition, but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown. A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies. As well, it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix, and how this latter supports and drives cell fate.
PMCID: PMC3531676  PMID: 23322990
Liver; Regenerative medicine; Tissue engineering; Extracellular matrix; Scaffold; Stem cells
10.  Essential function of the built-in lid in the allosteric regulation of eukaryotic and archaeal chaperonins 
Chaperonins are allosteric double-ring ATPases that mediate cellular protein folding. ATP binding and hydrolysis control opening and closing of the central chaperonin chamber, which transiently provides a protected environment for protein folding. During evolution, two strategies to close the chaperonin chamber have emerged. Archaeal and eukaryotic group II chaperonins contain a built-in lid, whereas bacterial chaperonins use a ring-shaped cofactor as a detachable lid. Here we show that the built-in lid is an allosteric regulator of group II chaperonins, which helps synchronize the subunits within one ring and, to our surprise, also influences inter-ring communication. The lid is dispensable for substrate binding and ATP hydrolysis, but is required for productive substrate folding. These regulatory functions of the lid may serve to allow the symmetrical chaperonins to function as ‘two-stroke’ motors and may also provide a timer for substrate encapsulation within the closed chamber.
PMCID: PMC3339572  PMID: 17460696
11.  Adoption of Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Population-Based Outcomes Study  
Journal of Clinical Oncology  2010;28(21):3472-3478.
Since 2004, several clinical trials have demonstrated that adjuvant chemotherapy (ACT) improves survival in patients with early-stage non–small-cell lung cancer (NSCLC). Here, we evaluate the uptake of ACT and its impact on outcomes in the general population of Ontario, Canada.
All patients diagnosed with NSCLC in Ontario from 2001 to 2006 who underwent surgical resection (n = 6,304) were identified using the Ontario Cancer Registry. We linked electronic records of treatment to the registry. We described uptake of ACT and compared survival of all patients with surgically resected NSCLC diagnosed from 2001 to 2003 with patients diagnosed from 2004 to 2006. As a proxy measure of ACT-related toxicity, we evaluated hospitalizations within 6 months of surgery.
Demographic, disease, and treatment-related characteristics did not differ between the 2001 to 2003 and 2004 to 2006 study cohorts. Over the study period, the proportion of patients receiving ACT increased from 7% (192 of 2,950 patients) to 31% (1,032 of 3,354 patients; P < .001). The proportion of patients admitted to hospital within 6 months of surgery remained stable and (36% in the 2001 to 2003 cohort and 37% in the 2004 to 2006 cohort). However, within 2 years of surgery, there was a 33% reduction in the proportion of patients admitted to hospital with metastatic disease (P < .001). During the study period, there was a substantial improvement in 4-year survival among surgically resected patients, from 52.5% (2001 to 2003) to 56.1% (2004 to 2006; P = .001).
There has been a rapid uptake of ACT for NSCLC, which was not associated with an increased rate of hospitalization. The adoption of ACT was associated with a substantial improvement in overall survival, suggesting that the benefits seen in clinical trials are generalizable to the general population.
PMCID: PMC2917211  PMID: 20567022
12.  Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma 
To carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma (RCC) and to determine their significance relative to clinicopathological characteristics and outcome.
Experimental design:
The VHL status in 86 conventional RCCs was determined by mutation detection, loss of heterozygosity (LOH) and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data was analysed to investigate potential relationships between VHL changes, clinical parameters and outcome.
LOH was found in 89.2%, mutation in 74.6% and methylation in 31.3% of evaluable tumours; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whilst no involvement of VHL was found in only 3.4% of samples. Several associations were suggested including between LOH and grade, nodal status and necrosis, between mutation and sex and between methylation and grade. Biallelic inactivation may be associated with better overall survival compared to patients with no VHL involvement although small sample numbers in the latter group severely limit this analysis which requires independent confirmation.
This study reports one of the highest proportions of conventional RCC with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggests that VHL defects may define conventional RCCs but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone.
PMCID: PMC2795746  PMID: 19996202
VHL; Renal cell carcinoma (RCC); mutation; methylation; prognosis
13.  JADAS: A Customizable Automated Data Acquisition System and its Application to Ice-embedded Single Particles 
Journal of structural biology  2008;165(1):1-9.
The JEOL Automated Data Acquisition System (JADAS) is a software system built for the latest generation of the JEOL Transmission Electron Microscopes. It is designed to partially or fully automate image acquisition for ice-embedded single particles under low dose conditions. Its built-in flexibility permits users to customize the order of various imaging operations. In this paper, we describe how JADAS is used to accurately locate and image suitable specimen areas on a grid of ice-embedded particles. We also demonstrate the utility of JADAS by imaging the epsilon 15 bacteriophage with the JEM3200FSC electron cryo-microscope, showing that sufficient images can be collected in a single 8-hour session to yield a subnanometer resolution structure which agrees with the previously determined structure.
PMCID: PMC2634810  PMID: 18926912
Single-particle; Automated data collection; Reconstruction; Cryo-EM
14.  Evolution of the Randomized Controlled Trial in Oncology Over Three Decades 
Journal of Clinical Oncology  2008;26(33):5458-5464.
The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs.
Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non–small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure.
A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively).
RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.
PMCID: PMC2651075  PMID: 18955452
15.  Methods for aligning and for averaging 3D volumes with missing data 
Journal of structural biology  2007;161(3):243-248.
The visibility and resolution of a tomographic reconstruction containing multiple copies of discrete particles can be enhanced by averaging subtomograms after they are corrected aligned. However, the “missing wedge” in electron tomography can easily lead to erroneous alignment. We have explored a Fourier space cross-correlation method with a proper weighting scheme to align and average different sets of volumetric data, each of which has different missing data due to the limited specimen tilts. This approach depends neither on a preexisting template, nor an exact knowledge of the geometry, orientation, or amount of the missing data. This paper introduces a procedure where the missing data might be gradually “filled in” by consecutively aligning and averaging volumes with different orientations of their missing data. We have validated these techniques by a set of simulated data with various symmetries and extent of missing data. We have also successfully applied these procedures to experimental cryo-electron tomographic data (Chang et al., 2007; Schmid et al., 2006).
PMCID: PMC2680136  PMID: 18299206
16.  Mechanism of lid closure in the eukaryotic chaperonin TRiC/CCT 
All chaperonins mediate ATP-dependent polypeptide folding by confining substrates within a central chamber. Intriguingly, the eukaryotic chaperonin TRiC (also called CCT) uses a built-in lid to close the chamber, whereas prokaryotic chaperonins use a detachable lid. Here we determine the mechanism of lid closure in TRiC using single-particle cryo-EM and comparative protein modeling. Comparison of TRiC in its open, nucleotide-free, and closed, nucleotide-induced states reveals that the interdomain motions leading to lid closure in TRiC are radically different from those of prokaryotic chaperonins, despite their overall structural similarity. We propose that domain movements in TRiC are coordinated through unique interdomain contacts within each subunit and, further, these contacts are absent in prokaryotic chaperonins. Our findings show how different mechanical switches can evolve from a common structural framework through modification of allosteric networks.
PMCID: PMC2546500  PMID: 18536725
17.  External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer 
BMC Cancer  2007;7:110.
Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer.
A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario.
During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14–46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56).
Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting.
PMCID: PMC1925109  PMID: 17598896
18.  Book Review 
Medical History  2006;50(4):541.
PMCID: PMC1592629
20.  Book Review 
Medical History  2006;50(2):263-264.
PMCID: PMC1472113
21.  Book Review 
Medical History  2005;49(2):240-242.
PMCID: PMC1088243
22.  Book Review 
Medical History  2004;48(4):521-522.
PMCID: PMC546378
23.  Book Review 
Medical History  2004;48(3):392-393.
PMCID: PMC547938
24.  A physician objects 
PMCID: PMC1079346  PMID: 14996986
25.  Communication in the Toronto critical care community: important lessons learned during SARS 
Critical Care  2003;7(6):405-406.
The SARS outbreak in 2003 pushed Toronto's health care system to its limits. Staffing shortages, transmission of SARS within the ICU, and the influx of critically ill SARS patients were some unique challenges to the delivery of critical care. Communication strategies were a key component in the critical care response to SARS. Regular teleconference calls, web-based training and education, and the rapid coordination of research studies were some of the initiatives developed within the Toronto critical care community during the SARS outbreak. Other critical care communities should consider their communication strategies in advance of similar events.
PMCID: PMC374381  PMID: 14624673
communication; critical care; disease outbreaks; SARS

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