Jean-Philippe Pignol

Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

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Publications (85)398.89 Total impact

  • International journal of radiation oncology, biology, physics 01/2015; · 4.59 Impact Factor
  • Source
    Nirmala Bhoo-Pathy, Jean-Philippe Pignol, Helena M Verkooijen
    The Lancet 11/2014; 384(9957):1846. · 39.21 Impact Factor
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    ABSTRACT: After breast conserving surgery, early stage breast cancer patients are currently treated with a wide range of radiation techniques including whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) using high-dose rate (HDR) brachytherapy, or 3D-conformal radiotherapy (3D-CRT). This study compares the mean heart's doses for a left breast irradiated with different breast techniques. An anthropomorphic Rando phantom was modified with gelatin-based breast of different sizes and tumors located medially or laterally. The breasts were treated with WBI, 3D-CRT, or HDR APBI. The heart's mean doses were measured with Gafchromic films and controlled with optically stimulated luminescent dosimeters. Following the model reported by Darby (1), major cardiac were estimated assuming a linear risk increase with the mean dose to the heart of 7.4% per gray. WBI lead to the highest mean heart dose (2.99 Gy) compared to 3D-CRT APBI (0.51 Gy), multicatheter (1.58 Gy), and balloon HDR (2.17 Gy) for a medially located tumor. This translated into long-term coronary event increases of 22, 3.8, 11.7, and 16% respectively. The sensitivity analysis showed that the tumor location had almost no effect on the mean heart dose for 3D-CRT APBI and a minimal impact for HDR APBI. In case of WBI large breast size and set-up errors lead to sharp increases of the mean heart dose. Its value reached 10.79 Gy for women with large breast and a set-up error of 1.5 cm. Such a high value could increase the risk of having long-term coronary events by 80%. Comparison among different irradiation techniques demonstrates that 3D-CRT APBI appears to be the safest one with less probability of having cardiovascular events in the future. A sensitivity analysis showed that WBI is the most challenging technique for patients with large breasts or when significant set-up errors are anticipated. In those cases, additional heart shielding techniques are required.
    Frontiers in Oncology 10/2014; 4:284.
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    ABSTRACT: During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities.
    Annals of Surgical Oncology 05/2014; · 3.94 Impact Factor
  • Merrylee A. McGuffin, Jean-Philippe Pignol, Brian Keller
    Brachytherapy 03/2014; 13:S17–S18. · 1.99 Impact Factor
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    ABSTRACT: Purpose: The authors' aims were to model how various factors influence radiation dose enhancement by gold nanoparticles (AuNPs) and to propose a new modeling approach to the dose enhancement factor (DEF).Methods: The authors used Monte Carlo N-particle (MCNP 5) computer code to simulate photon and electron transport in cells. The authors modeled human breast cancer cells as a single cell, a monolayer, or a cluster of cells. Different numbers of 5, 30, or 50 nm AuNPs were placed in the extracellular space, on the cell surface, in the cytoplasm, or in the nucleus. Photon sources examined in the simulation included nine monoenergetic x-rays (10-100 keV), an x-ray beam (100 kVp), and (125)I and (103)Pd brachytherapy seeds. Both nuclear and cellular dose enhancement factors (NDEFs, CDEFs) were calculated. The ability of these metrics to predict the experimental DEF based on the clonogenic survival of MDA-MB-361 human breast cancer cells exposed to AuNPs and x-rays were compared.Results: NDEFs show a strong dependence on photon energies with peaks at 15, 30∕40, and 90 keV. Cell model and subcellular location of AuNPs influence the peak position and value of NDEF. NDEFs decrease in the order of AuNPs in the nucleus, cytoplasm, cell membrane, and extracellular space. NDEFs also decrease in the order of AuNPs in a cell cluster, monolayer, and single cell if the photon energy is larger than 20 keV. NDEFs depend linearly on the number of AuNPs per cell. Similar trends were observed for CDEFs. NDEFs using the monolayer cell model were more predictive than either single cell or cluster cell models of the DEFs experimentally derived from the clonogenic survival of cells cultured as a monolayer. The amount of AuNPs required to double the prescribed dose in terms of mg Au∕g tissue decreases as the size of AuNPs increases, especially when AuNPs are in the nucleus and the cytoplasm. For 40 keV x-rays and a cluster of cells, to double the prescribed x-ray dose (NDEF = 2) using 30 nm AuNPs, would require 5.1 ± 0.2, 9 ± 1, 10 ± 1, 10 ± 1 mg Au∕g tissue in the nucleus, in the cytoplasm, on the cell surface, or in the extracellular space, respectively. Using 50 nm AuNPs, the required amount decreases to 3.1 ± 0.3, 8 ± 1, 9 ± 1, 9 ± 1 mg Au∕g tissue, respectively.Conclusions: NDEF is a new metric that can predict the radiation enhancement of AuNPs for various experimental conditions. Cell model, the subcellular location and size of AuNPs, and the number of AuNPs per cell, as well as the x-ray photon energy all have effects on NDEFs. Larger AuNPs in the nucleus of cluster cells exposed to x-rays of 15 or 40 keV maximize NDEFs.
    Medical Physics 11/2013; 40(11):114101. · 3.01 Impact Factor
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    ABSTRACT: To determine if older women with early stage breast cancer have sufficient decisional support during their breast cancer journey, a questionnaire-based study was conducted at the Sunnybrook Odette Cancer Centre, in Toronto, Ontario, Canada. Women with stages I and II breast cancer, ≥60 years, were contacted upon completion of their adjuvant treatment. A questionnaire was developed based on focus groups, the literature, and consultation with patients and a multidisciplinary team of experts. The questionnaire was divided into six domains as follows: (1) information support surrounding diagnosis, (2) impact of cancer diagnosis on the patient, (3) quality of interaction with healthcare team, (4) decisional support from the healthcare team, (5) additional information needs surrounding treatment decision, and (6) information support during radiation treatment. Ninety-two of 137 patients approached were included in the analysis. Ninety percent were > 60 years at the time of diagnosis and 65 % had stage I invasive breast cancer. The majority of women received adequate decisional support during their cancer journey. Approximately 90 % of women indicated that they received a high level of support during their cancer diagnosis. We found no significant differences in overall decisional support based on age at diagnosis, education level, ethnicity, or the presence of co-morbidities. However, participants desired additional educational resources such as a worksheet, consultation summary, or workbook to assist in making a treatment decision. The majority of participants felt that they had sufficient support while making a treatment decision for breast cancer.
    Journal of Cancer Education 10/2013; · 0.88 Impact Factor
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    ABSTRACT: The American Association of Physicists in Medicine Task Group No. 43 (AAPM TG-43) formalism is the standard for seeds brachytherapy dose calculation. But for breast seed implants, Monte Carlo simulations reveal large errors due to tissue heterogeneity. Since TG-43 includes several factors to account for source geometry, anisotropy and strength, we propose an additional correction factor, called the inhomogeneity correction factor (ICF), accounting for tissue heterogeneity for Pd-103 brachytherapy. This correction factor is calculated as a function of the media linear attenuation coefficient and mass energy absorption coefficient, and it is independent of the source internal structure. Ultimately the dose in heterogeneous media can be calculated as a product of dose in water as calculated by TG-43 protocol times the ICF. To validate the ICF methodology, dose absorbed in spherical phantoms with large tissue heterogeneities was compared using the TG-43 formalism corrected for heterogeneity versus Monte Carlo simulations. The agreement between Monte Carlo simulations and the ICF method remained within 5% in soft tissues up to several centimeters from a Pd-103 source. Compared to Monte Carlo, the ICF methods can easily be integrated into a clinical treatment planning system and it does not require the detailed internal structure of the source or the photon phase-space.
    Physics in Medicine and Biology 08/2013; 58(18):6299-6315. · 2.92 Impact Factor
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    ABSTRACT: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.
    Translational oncology 02/2013; 6(1):17-24. · 3.40 Impact Factor
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    ABSTRACT: Purpose: Seed brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. In this technique low dose rate (LDR) radioactive seeds are permanently implanted across the treatment volume to deliver a prescribed amount of dose. The current standard for calculation of dose surrounding the brachytherapy seeds is based on American Association of Physicist in Medicine Task Group No. 43 (TG43 formalism) which generates the dose in homogeneous water medium. For low energy sources and especially in breast, the absorbed dose is highly influenced by heterogeneities. Our work focuses on the development of a dose calculation algorithm similar to TG43 applicable in heterogeneous media. Methods: An Inhomogeneity Correction Factor (ICF) is introduced as the ratio of absorbed dose in tissue to that in water medium. ICF is a function of tissue properties and independent of source structure. The absorbed dose in tissue can then be calculated by multiplying the dose as calculated by the TG43 formalism times ICF. We used Monte Carlo simulations in a heterogeneous model of breast to benchmark the improvements achieved in the calculation of dose using the ICF methodology. Results: The dose distributions obtained through applying ICF to TG43 protocol agreed very well with those of Monte Carlo simulations. Over all and across the whole calculation domain, the mean relative error was reduced from 40.8% to 12.7% when ICF correction factor is applied to the TG43 protocol. Conclusion: We have developed a new analytical dose calculation method which enables personalized dose calculations in heterogeneous media. The methodology offers several advantages including the use of standard TG43 formalism, fast calculation time and extraction of the ICF parameters directly from Hounsfield Units. Funding: NSERC
    Medical Physics 01/2013; 40(6):336. · 3.01 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the effect of molecularly targeted gold nanoparticles (AuNPs) on tumor radiosensitization both in vitro and in vivo. Human Epidermal Growth Factor Receptor-2 (HER-2)-targeted AuNPs (Au-T) were synthesized by conjugating trastuzumab (Herceptin) to 30 nm AuNPs. In vitro, the cytotoxicity of Au-T or non-targeted AuNPs (Au-P) was assessed by γ-H2AX immunofluorescence microscopy for DNA damage and clonogenic survival assays. In vivo, athymic mice bearing subcutaneous MDA-MB-361 xenografts were treated with a single dose of 11 Gy of 100 kVp X-rays 24 h after intratumoral injection of Au-T (~0.8 mg of Au) or no X-radiation. Normal tissue toxicity was determined by hematology or biochemistry parameters. The combination of Au-P or Au-T with X-ray exposure increased the formation of γ-H2AX foci by 1.7 (P = 0.054) and 3.3 (P = 0.024) fold in comparison to X-radiation alone, respectively. The clonogenic survival of cells exposed to Au-T and X-rays was significantly lower from that of cells exposed to X-radiation alone, which translated to a dose enhancement factor of 1.6. In contrast, survival of cells exposed to Au-P and X-rays versus X-radiation alone were not significantly different. In vivo, the combination of Au-T and X-radiation resulted in regression of MDA-MB-361 tumors by 46 % as compared to treatment with X-radiation (16.0 % increase in tumor volume). No significant normal tissue toxicity was observed. Radiosensitization of breast cancer to X-radiation with AuNPs was successfully achieved with an optimized therapeutic strategy of molecular targeting of HER-2 and intratumoral administration.
    Breast Cancer Research and Treatment 11/2012; · 4.47 Impact Factor
  • Ivo A Olivotto, Jean-Philippe Pignol
    Oncology (Williston Park, N.Y.) 09/2012; 26(9):831, 837. · 2.98 Impact Factor
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    ABSTRACT: In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl(3) (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial.
    Molecular Pharmaceutics 06/2012; · 4.57 Impact Factor
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    ABSTRACT: Brachytherapy is associated with highly heterogeneous spatial dose distributions. This heterogeneity is usually ignored when estimating the biological effective dose (BED). In addition, the heterogeneities of the medium including the tissue heterogeneity (TH) and the interseed attenuation (ISA) are also contributing to the heterogeneity of the dose distribution, but they are both ignored in Task Group 43 (TG43)-based protocols. This study investigates the effect of dose heterogeneity, TH and ISA on metrics that are commonly used to quantify biological efficiency in brachytherapy. The special case of 29 breast cancer patients treated with permanent (103)Pd seed implant is considered here. BED is compared to equivalent uniform BED (EUBED) capable of considering the spatial heterogeneity of the dose distribution. The effects of TH and ISA on biological efficiency of treatments are taken into account by comparing TG43 with Monte Carlo (MC) dose calculations for each patient. The effect of clonogenic repopulation is also considered. The analysis is performed for different sets of (α/β, α) ratios of (2, 0.3), (4, 0.27) and (10, 0.3) [Gy, Gy(-1)] covering the whole range of reported α/β values in the literature. BED is sometimes larger and sometimes smaller than EUBED(TG43) indicating that the effect of the dose heterogeneity is not similar among patients. The effect of the dose heterogeneity can be characterized by using the D(99) dose metric. For each set of the radiobiological parameters considered, a D(99) threshold is found over which dose heterogeneity will cause an overestimation of the biological efficiencies while the inverse happens for smaller D(99) values. EUBED(MC) is always larger than EUBED(TG43) indicating that by neglecting TH and ISA in TG43-based dosimetry algorithms, the biological efficiencies may be underestimated by about 10 Gy. Overall, by going from BED to the more accurate EUBED(MC) there is a gain of about 9.6 to 13 Gy on the biological efficiency. The efficiency gain is about 10.8 to 14 Gy when the repopulation is considered. Dose heterogeneity does not have a constant impact on the biological efficiencies and may under- or overestimate the efficacy in different patients. However, the combined effect of neglecting dose heterogeneity, TH and ISA results in underestimation of the biological efficiencies in permanent breast seed implants.
    Physics in Medicine and Biology 02/2012; 57(3):809-23. · 2.92 Impact Factor
  • Jean-Philippe Pignol, Eli Lechtman
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    ABSTRACT: In a comment on a recent paper by Lechtman et al (2011 Phys. Med. Biol. 56 4631-47), McMahon critiques one of Lechtman's conclusion that gold nanoparticle radiosensitization may not be applicable to megavoltage radiotherapy. He refers to recently published experimental studies showing radiosensitization with 6 MV x-rays and low gold concentrations. However those published studies show conflicting results, presenting survival curves with a small cell death increased with gold and some with no difference. In regards to gold nanoparticle radiosensitization physical, chemical, pharmacological and biological constraints all interplay. There are plenty of experimental and theoretical data to confirm the strong dependence to the primary photon energy and gold concentration. The manuscript of Lechtman added the dependence to microscopic localization, analysing the spatial distribution and the quality of secondary electrons, as a major player in the feasibility of the technique. We agree that radiobiological dose modification factor should be considered, but it is unlikely that accounting for a maximum RBE of 2 can compensate for the drastic decrease of photoelectric events shifting from kV to MV. Lechtman calculated that to achieve similar radiosensitization for low energy beams and intra-cellular gold concentration of 0.5%, concentrations 300 times higher are required for 6 MV beams. To date it seems unlikely that concentration higher than 1% could be achieved such that it is unlikely that megavoltage would yield a measurable clinical effect.
    Physics in Medicine and Biology 12/2011; 57(1):291-295. · 2.92 Impact Factor
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    ABSTRACT: Breast tissue is heterogeneous and is mainly composed of glandular (G) and adipose (A) tissues. The proportion of G versus A varies considerably among the population. The absorbed dose distributions in accelerated partial breast irradiation therapy with low energy photon brachytherapy sources are very sensitive to tissue heterogeneities. Current clinical algorithms use the recommendations of the AAPM TG43 report which approximates the human tissues by unit density water. The aim of this study is to investigate various breast tissue modeling schemes for low energy brachytherapy. A special case of breast permanent seed implant is considered here. Six modeling schemes are considered. Uniform and non-uniform water breast (UWB and NUWB) consider the density but neglect the effect of the composition of tissues. The uniform and the non-uniform G/A breast (UGAB and NUGAB) as well the age-dependent breast (ADB) models consider the effect of the composition. The segmented breast tissue (SBT) method uses a density threshold to distinguish between G and A tissues. The PTV D(90) metric is used for the analysis and is based on the dose to water (D(90(w,m))). D(90(m,m)) is also reported for comparison to D(90(w,m)). The two-month post-implant D(90(w,m)) averaged over 38 patients is smaller in NUWB than in UWB by about 4.6% on average (ranging from 5% to 13%). Large average differences of G/A breast models with TG43 (17% and 26% in UGAB and NUGAB, respectively) show that the effect of the chemical composition dominates the effect of the density on dose distributions. D(90(w,m)) is 12% larger in SBT than in TG43 when averaged. These differences can be as low as 4% or as high as 20% when the individual patients are considered. The high sensitivity of dosimetry on the modeling scheme argues in favor of an agreement on a standard tissue modeling approach to be used in low energy breast brachytherapy. SBT appears to generate the most geometrically reliable breast tissue models in this report.
    Physics in Medicine and Biology 11/2011; 56(22):7045-60. · 2.92 Impact Factor
  • Ananth Ravi, Brian M Keller, Jean-Philippe Pignol
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    ABSTRACT: Permanent breast seed implantation (PBSI) is an accelerated partial breast irradiation technique performed using stranded (103)Pd radioactive seeds (average energy of 21 keV, 16.97 day half-life). Since 2004, (131)Cs brachytherapy sources have become clinically available. The (131)Cs radionuclide has a higher energy (average energy of 30 keV) and a shorter half-life (9.7 days) than (103)Pd. The purpose of this study was to determine whether or not there are dosimetric benefits to using (131)Cs brachytherapy seeds for PBSI. The prescribed dose for PBSI using (103)Pd is 90 Gy, which was adjusted for (131)Cs implants to account for the shorter half-life. A retrospective cohort of 30 patients, who have already undergone a (103)Pd implant, was used for this study. The treatments were planned using the Variseed treatment planning system. The air kerma strength of the (131)Cs seeds was adjusted in all preimplantation treatment plans so that the V(100) (the volume within the target that receives 100% or more of the prescribed dose) were equivalent at time of implantation. Two month follow-up CT scans were available for all 30 patients and each patient was reevaluated using (131)Cs seeds. The postimplant dosimetric parameters were compared using a two tailed t-test. The prescribed dose for (131)Cs was calculated to be 77 Gy; this dose would have the same biological effect as a PBSI implant with (103)Pd of 90 Gy. The activities of the (131)Cs sources were adjusted to an average of 2.2 ± 0.8 U for (131)Cs compared to 2.5 ± 1.1 U for (103)Pd in order to get an equivalent V(100) as the (103)Pd preimplants. While the use of (131)Cs significantly reduces the preimplant V(200) (the volume within the target that receives 200% or more of the prescribed dose) compared to (103)Pd by 13.5 ± 9.0%, the reduction observed on the 2 month postimplant plan was 12.4 ± 5.1% which accounted for seed motion, implantation inaccuracies and tissue changes. This translates into an absolute reduction of 4.1 cm(3) of tissue receiving 200% of the dose. This analysis of 30 early stage breast cancer patients who underwent the PBSI procedure shows that there is a theoretical dosimetric advantage to using (131)Cs. However, in a realistic implant that will have seed misplacements and tissue changes, the use of (131)Cs may not result in any clinically significant benefit.
    Medical Physics 11/2011; 38(11):6046-52. · 3.01 Impact Factor
  • Brian M Keller, Ananth Ravi, Raxa Sankreacha, Jean-Philippe Pignol
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    ABSTRACT: A permanent breast seed implant is a novel method of accelerated partial breast irradiation for women with early-stage breast cancer. This article presents pre- and post-implant dosimetric data, relates these data to clinical outcomes, and makes recommendations for those interested in starting a program. A total of 95 consecutive patients were accrued into one of three clinical trials after breast-conserving surgery: a Phase I/II trial (67 patients with infiltrating ductal carcinoma); a Phase II registry trial (25 patients with infiltrating ductal carcinoma); or a multi-center Phase II trial for patients with ductal carcinoma in situ (3 patients). Contouring of the planning target volume (PTV) was done on a Pinnacle workstation and dosimetry calculations, including dose-volume histograms, were done using a Variseed planning computer. The mean pre-implant PTV coverage for the V(90), V(100), V(150), and V(200) were as follows: 98.8% ± 1.2% (range, 94.5-100%); 97.3% ± 2.1% (range, 90.3-99.9%), 68.8% ± 14.3% (range, 32.7-91.5%); and 27.8% ± 8.6% (range, 15.1-62.3%). The effect of seed motion was characterized by post-implant dosimetry performed immediately after the implantation (same day) and at 2 months after the implantation. The mean V(100) changed from 85.6% to 88.4% (p = 0.004) and the mean V(200) changed from 36.2% to 48.3% (p < 0.001). Skin toxicity was associated with maximum skin dose (p = 0.014). Preplanning dosimetry should aim for a V(90) of approximately 100%, a V(100) between 95% and 100%, and a V(200) between 20% and 30%, as these numbers are associated with no local recurrences to date and good patient tolerance. In general, the target volume coverage improved over the duration of the seed therapy. The maximum skin dose, defined as the average dose over the hottest 1 × 1-cm(2) surface area, should be limited to 90% of the prescription dose to minimize delayed skin toxicity.
    International journal of radiation oncology, biology, physics 10/2011; 83(1):84-92. · 4.59 Impact Factor
  • Fuel and Energy Abstracts 10/2011; 81(2).
  • Fuel and Energy Abstracts 10/2011; 81(2).

Publication Stats

1k Citations
398.89 Total Impact Points


  • 2005–2014
    • Sunnybrook Health Sciences Centre
      • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2004–2014
    • University of Toronto
      • • Department of Medical Biophysics
      • • Leslie L. Dan Faculty of Pharmacy
      • • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2012
    • University of British Columbia - Vancouver
      • Division of Radiation Oncology and Developmental Radiotherapeutics
      Vancouver, British Columbia, Canada
  • 2010–2012
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands
    • McMaster University
      Hamilton, Ontario, Canada
    • Université du Québec
      Québec, Quebec, Canada
  • 2011
    • Centre Hospitalier Universitaire de Québec (CHUQ)
      Québec, Quebec, Canada
  • 2007
    • Ryerson University
      Toronto, Ontario, Canada