ORCID Profile
0000-0002-9620-6876
Current Organisations
Princess Margaret Cancer Centre
,
University Health Network
,
Royal College of Physicians and Surgeons of Canada
,
University of Toronto
,
Medical Council of Canada
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Publications
Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor–mediated upregulation of caveolin-1
Publisher: Proceedings of the National Academy of Sciences
Date: 12-03-2012
Abstract: Caveolin-1 (CAV1) is an essential structural constituent of caveolae, specialized lipid raft microdomains on the cell membrane involved in endocytosis and signal transduction, which are inexplicably deregulated and are associated with aggressiveness in numerous cancers. Here we identify CAV1 as a direct transcriptional target of oxygen-labile hypoxia-inducible factor 1 and 2 that accentuates the formation of caveolae, leading to increased dimerization of EGF receptor within the confined surface area of caveolae and its subsequent phosphorylation in the absence of ligand. Hypoxia-inducible factor–dependent up-regulation of CAV1 enhanced the oncogenic potential of tumor cells by increasing the cell proliferative, migratory, and invasive capacities. These results support a concept in which a crisis in oxygen availability or a tumor exhibiting hypoxic signature triggers caveolae formation that bypasses the requirement for ligand engagement to initiate receptor activation and the critical downstream adaptive signaling during a period when ligands required to activate these receptors are limited or are not yet available.
TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair.
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2013
DOI: 10.1158/1078-0432.CCR-13-1049
Abstract: Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) & 8, prostate-specific antigen (PSA) & 20 ng/mL & years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA s les assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy s les were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response. Clin Cancer Res 19(18) 5202–9. ©2013 AACR.
Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake
Publisher: Society of Nuclear Medicine
Date: 14-01-2016
DOI: 10.2967/JNUMED.115.167650
Abstract: Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia nor did we see an association between tumor volume and hypoxia. Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.
Relations between non–protein sulfydryl levels in the nucleus and cytoplasm, tumor oxygenation, and clinical outcome of patients with uterine cervical carcinoma
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.IJROBP.2004.02.020
Abstract: The non-protein sulfydryls (NPSH) glutathione and cysteine are able to effect chemical repair of radiation-induced DNA damage, particularly under hypoxic conditions, and are implicated in radioresistance. The levels of NPSH in the nucleus are predicted to be more important than those in cytoplasm. We, therefore, investigated the relation between nuclear NPSH and the clinical outcome of radical radiotherapy (RT). A fluorescence image analysis technique to measure nuclear NPSH was developed, based on the SH-reactive probe 1(4-chloromercuryphenyl-azo-2-naphthol) and the DNA dye 4,6-diamidino-2-phenylindole. This was used to measure nuclear and tissue NPSH levels in biopsies obtained from 58 patients with locally advanced uterine cervical carcinoma, treated with radical RT. An approximately twofold range in the nuclear and tissue NPSH levels between in idual tumors was found, although the intratumoral heterogeneity was much smaller. Nuclear and tissue NPSH values correlated closely in all cases. No statistically significant associations were noted between NPSH levels and tumor size, stage, or tumor hypoxia as determined at the time of biopsy using an Eppendorf po(2) probe. The response to RT and patient survival did not correlate with tumor NPSH. These results did not support the existence of an independently regulated nuclear pool of NPSH and showed that tissue and nuclear NPSH are not predictive of the outcome of patients with locally advanced cervical carcinomas treated with RT.
Quality standards in radiation medicine
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.PRRO.2013.09.004
Abstract: Identifying and conducting "best practice" medicine is arguably the ubiquitous goal of practitioners. However, to distill the many available quality standards, guidelines, recommendations, and indicators down to a best practice set requires a logical schema to group standards addressing similar quality issues and, from manageable lists of related standards, to extract the essential dimensions of quality. The purpose of this study was to explore a method of collating publicly available quality standards, in this case in radiation therapy, using a 2-step decision tree approach with statistical analysis. Successful grouping into manageable lists, addressing related quality issues, informs the ongoing development of quality indicators that are one expression of "best practice." A comprehensive literature search was used to identify quality standards currently in use and publicly available. Using 2 decision trees, 5 evaluators assigned each standard to Donabedian's structure, process, or outcome and also to the target of the standard: patients, staff, equipment or clinical process, or organization for a total of 3 × 4 = 12 primary categories. A total of 454 radiation medicine program quality standards spread across 8 national and international documents was identified. Agreement between the 5 evaluators, using the free marginal kappa statistic, ranged from fair to almost perfect. In all but 2% of 5 × 454 evaluations were the evaluators able to assign a statement to categories in the decision trees suggesting that these trees are appropriate to the task. In only 3/454 was a majority (≥ 3/5) decision not reached on the assignment to structure, process, or outcome. Sixty-four percent of the standards were identified with structure, 26% with process and 10% with outcome. Donabedian's model constitutes a reliable method of managing quality standards. The 2-step decision tree framework can be applied to inform the further development of national and international quality standards.
Vulnerabilities of radiomic signature development: The need for safeguards
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.RADONC.2018.10.027
Abstract: Refinement of radiomic results and methodologies is required to ensure progression of the field. In this work, we establish a set of safeguards designed to improve and support current radiomic methodologies through detailed analysis of a radiomic signature. A radiomic model (MW2018) was fitted and externally validated using features extracted from previously reported lung and head and neck (H&N) cancer datasets using gross-tumour-volume contours, as well as from images with randomly permuted voxel index values i.e. images without meaningful texture. To determine MW2018's added benefit, the prognostic accuracy of tumour volume alone was calculated as a baseline. MW2018 had an external validation concordance index (c-index) of 0.64. However, a similar performance was achieved using features extracted from images with randomized signal intensities (c-index = 0.64 and 0.60 for H&N and lung, respectively). Tumour volume had a c-index = 0.64 and correlated strongly with three of the four model features. It was determined that the signature was a surrogate for tumour volume and that intensity and texture values were not pertinent for prognostication. Our experiments reveal vulnerabilities in radiomic signature development processes and suggest safeguards that can be used to refine methodologies, and ensure productive radiomic development using objective and independent features.
The Effects of External Beam Radiotherapy on the Normal Urinary Bladder—A Histopathological Review
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.JMIR.2011.03.002
Abstract: This literature review presents information relevant to medical radiation technologists with respect to new knowledge on the function of the urinary bladder. These new insights are also explored in relation to radiation-induced histopathological effects and the symptoms of bladder dysfunction reported after external beam radiotherapy. The peer-reviewed scientific literature was examined using various electronic medical search engines with appropriate keywords and MeSH headings. Inclusion criteria comprised English language articles published between 1999 and January 2010, with full manuscript available. A critical review was then performed, synthesizing the information contained in those multiple sources into the following subject categories: normal urinary bladder function (basic review and new knowledge), and effect of fractionated radiotherapy on normal bladder (histopathological changes and symptoms of dysfunction). Previously considered an inert vessel for urine storage, the urinary bladder is actually a complex system of morphologically different tissues, which play an interconnected role in its physiological functions. Injury or abnormal repair in any of the bladder cell layers results in a multifaceted display of interrelated manifestations of dysfunction. In this complex environment, not only can a single symptom of dysfunction have multiple histopathological causes, but the presence of one symptom may exacerbate the presentation of another. To date, this new knowledge has had little impact on radiotherapy clinical practice because subjective methods of collecting toxicity data prevent the identification of a link between radiotherapy dose and urinary dysfunction. The new understanding of the histopathological cause of radiation-induced symptoms, however, has led to the preclinical investigation of many promising methods to prevent or reduce radiotherapy toxicity.
Up-Regulation of the Redox Mediators Thioredoxin and Apurinic/Apyrimidinic Excision (APE)/Ref-1 in Hypoxic Microregions of Invasive Cervical Carcinomas, Mapped Using Multispectral, Wide-Field Fluoresc
Publisher: Elsevier BV
Date: 02-2004
Chromosomal instability as a prognostic marker in cervical cancer
Publisher: Springer Science and Business Media LLC
Date: 06-05-2015
The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure
Publisher: Elsevier BV
Date: 07-2004
DOI: 10.1016/J.SEMRADONC.2004.04.006
Abstract: Invasive needle-based assessments of the extracellular environment in human tumors have yielded important prognostic information that has shaped the direction of future translational research and begun to influence clinical practice. This review focuses on electrode measurements of oxygenation in human tumors, particularly in relation to the practicalities of applying these techniques in the clinic and the relationship to patient outcome. Elevated tumor interstitial fluid pressure (IFP) has been shown to be an important independent prognostic factor in cervix cancer. The pathophysiology of elevated IFP is discussed, along with possible explanations for the strong influence on patient outcome and directions for future research.
MicroRNA-196b Regulates the Homeobox B7-Vascular Endothelial Growth Factor Axis in Cervical Cancer
Publisher: Public Library of Science (PLoS)
Date: 04-07-2013
Quantifying hypoxia in human cancers using static PET imaging
Publisher: IOP Publishing
Date: 25-10-2016
DOI: 10.1088/0031-9155/61/22/7957
Abstract: Compared to FDG, the signal of
Heterogeneity and Power in Clinical Biomarker Studies
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2009
Abstract: Many recent studies have suggested the possibility that a variety of different biomarkers may be associated with treatment outcome. However, it is also apparent that some of these biomarkers are heterogeneously distributed within a tumor. Due to this heterogeneous distribution of the biomarker, the association sought may appear weak or nonexistent. Thus, there is a wide range of conclusions in the literature on the association between a biomarker and an outcome. This article presents how to quantify the heterogeneity and how it influences the observed effect size and the ability to detect it (power of the study). It can be shown that the estimated effect size and the power of the study are diminished when the biomarker is measured with error. The estimated effect of the association with outcome of the average of several replicates per patient is closer to the true effect size when the number of replicates increases. The first step in designing a study of association between a biomarker and outcome is to conduct a pilot study in which several measurements per patient are taken. Based on these data, the heterogeneity of the marker within and between in iduals can be estimated and used in the process of designing an appropriate study of the association between the biomarker and outcome.
The Effect of Dose Grid Resolution on Dose Volume Histograms for Slender Organs at Risk during Pelvic Intensity-modulated Radiotherapy
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.JMIR.2014.01.006
Abstract: There are enduring uncertainties regarding the optimal dose grid resolution for use with pelvic intensity-modulated radiotherapy (IMRT) plans in which the adjacent organs at risk are slender and transect the field edge. Therefore, this study evaluated the effect of dose grid resolution on bladder wall dose-volume histogram (DVH) calculations for prostate IMRT plans. The planning computed tomography scans and clinical plans from 15 prostate cancer patients were included in this analysis. For each study computed tomography, the entire inner and outer bladder surfaces were delineated. Nine versions of the clinical plan were created, varying interval between the dose grid calculation points uniformly in three dimensions, whereas all other plan parameters were kept constant. The dose grid increments tested were 1-10 mm. The plans were recalculated and the bladder wall DVH compared against the study benchmark (1 mm grid). All the dose grid increments evaluated resulted in a systematic overestimation of the bladder wall volume receiving low doses and an underestimation of the volume receiving high doses. Grid increments <2.5 mm all resulted in mean volume differences less than 1 cm For an accurate DVH calculation for bladder wall during IMRT planning for prostate cancer, a 1.5 mm dose grid increment is recommended. This finding was unaffected by a normal range in bladder wall thickness. It is suggested that the application of any new treatment planning technique or organ delineation method be accompanied with an evaluation of optimal dose grid resolution.
Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus
Publisher: EMBO
Date: 07-2010
Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation
Publisher: Wiley
Date: 25-10-2011
DOI: 10.1002/CNCR.26635
Abstract: Hedgehog (Hh) signaling was assessed in patients with primary cervical carcinoma who were receiving chemoradiation. Because the up-regulation of Hh has been reported in response to hypoxia, the authors examined associations between Hh gene expression and measurements of HP5 (the percentage of oxygen pressure readings in each tumor <5 mm Hg) and interstitial fluid pressure (IFP). Sonic hedgehog (SHH), Indian hedgehog (IHH), patched 1 and 2 (PTCH1 and PTCH2), smoothened (SMO), and glioma-associated oncogene family zinc finger 1 (Gli1) expression levels were determined using quantitative reverse transcriptase-polymerase chain reaction analysis on 85 frozen s les of primary cervical carcinoma and on 16 normal cervical s les. Clinicopathologic data were collected prospectively. Possible correlations between Hh expression and tumor hypoxia (HP5 and IFP) measured at the time of biopsy, the time to local recurrence, and disease-free survival (DFS) were examined. At least 1 member of the Hh pathway was elevated in all but 1 tumor compared with normal tissue (P 3 Hh genes (HR, 2.56 95% CI, 1.09-6.00 P = .026), tumor size (HR, 1.41 95% CI, 1.14-1.74 P = .0015), and lymph node-positive disease (HR, 2.82 95% CI, 1.16-6.86 P = .022). The proportion of tumors that expressed Hh genes in cervical cancer was very high. The current data support a role for the Hh pathway in repopulation after chemoradiation and suggest that SMO may be a valid therapeutic target. The authors concluded that further investigation into this pathway after radiation and Hh inhibition are warranted.
Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts
Publisher: Springer Science and Business Media LLC
Date: 22-11-2016
DOI: 10.1038/BJC.2016.383
The Utility of Serum CA9 for Prognostication in Prostate Cancer
Publisher: Anticancer Research USA Inc.
Date: 09-09-2016
DOI: 10.21873/ANTICANRES.10994
Abstract: Carbonic anhydrase IX (CA9) catalyses the interconversion of carbon dioxide to carbonic acid and bicarbonate and is considered a putative biomarker of tumour hypoxia. We set out to evaluate the prognostic significance of CA9 in prostate cancer. Plasma s les were assessed from 68 men with high-risk localised prostate cancer treated with radical prostatectomy (RP) or radiotherapy (RT), and 20 men with castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy between 2010 and 2012 at the Princess Margaret Cancer Centre, Canada. Of the 68 patients with high-risk localised prostate cancer, 57 underwent RP and 11 underwent RT. Baseline CA9 was not associated with recurrence or prostate-specific antigen in either group (p=0.98 and 0.20, respectively). CA9 levels before chemotherapy correlated with overall survival (r=-0.37 two-sided p=0.11). Baseline CA9 in men with CRPC may portend a more aggressive prostate cancer phenotype with poorer survival.
Developing a Prognostic Micro-RNA Signature for Human Cervical Carcinoma
Publisher: Public Library of Science (PLoS)
Date: 16-04-2015
High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone
Publisher: Wiley
Date: 25-04-2014
DOI: 10.1002/IJC.28403
Abstract: Radiotherapy (RT) with concurrent cisplatin (CRT) is standard treatment for locally advanced cervical cancer. However, not all patients benefit from the addition of cisplatin to RT alone. This study explored the value of pretreatment tumor interstitial fluid pressure (IFP) and hypoxia measurements as predictors of cisplatin response in 291 patients who were treated with RT (1994-1998) or RT plus concurrent cisplatin (1999-2009). Clinical characteristics were similar between the two groups, apart from a greater proportion of patients with pelvic lymph node metastases and hypoxic tumors in the CRT cohort. Patients were followed for a median duration of 5.6 years. Information about recurrence and survival was recorded prospectively. The addition of cisplatin to RT improved survival compared to treatment with RT alone (HR 0.61, p = 0.0097). This improvement was confined to patients with high-IFP tumors at diagnosis (HR 0.40, p = 0.00091). There was no benefit of adding cisplatin in those with low-IFP tumors (HR 1.05, p = 0.87). There was no difference in the effectiveness of cisplatin in patients with more or less hypoxic tumors. In conclusion, patients with locally advanced cervical cancer and high tumor IFP at diagnosis have greater benefit from the addition of cisplatin to RT than those with low IFP. This may reflect high tumor cell proliferation, which is known to influence IFP, local tumor control and patient survival.
Related Organisations
Shanghai Fourth People's Hospital Affiliated To Tongji University School Of Medicine
Location: China
Harvard T.H. Chan School Of Public Health
Location: United States of America
Harvard T.H. Chan School Of Public Health
Location: No location found
Related Funding Activities
The Terry Fox New Frontiers Program Project Grant In Hypoxia In Tumours: Clinical And Experimental Studies
Start Date: 2009
End Date: 2014
Funder: Terry Fox Foundation
View Funded ActivityImage-based Quantitative Assessment Of Tumor Hypoxia
Start Date: 2014
End Date: 2019
Funder: Canadian Institutes of Health Research
View Funded ActivityHypoxia: Effects On Tumour Response And Progression In Cervix Cancer
Start Date: 2010
End Date: 2014
Funder: Canadian Institutes of Health Research
View Funded ActivityThe Terry Fox New Frontiers Program Project Grant In Research Pipeline For Hypoxia-Directed Precision Cancer Medicine
Start Date: 2014
End Date: 2019
Funder: Terry Fox Foundation
View Funded ActivityThe Terry Fox New Frontiers Program Project Grant In Hypoxia In Tumours: Clinical And Experimental Studies
Start Date: 1999
End Date: 2004
Funder: Terry Fox Foundation
View Funded ActivityThe Terry Fox New Frontiers Program Project Grant In Hypoxia In Tumours: Clinical And Experimental Studies
Start Date: 2004
End Date: 2009
Funder: Terry Fox Foundation
View Funded Activity