Detection of clinically significant prostate cancer with 18F-DCFPyL PET/multiparametric MR.

PURPOSE: To assess whether 18F-DCFPyL PET/multiparametric (mp)MR contributes to the diagnosis of clinically significant (cs) prostate cancer (PCa) compared to mpMR in patients with suspicion of PCa, or patients being considered for focal ablative therapies (FT). PATIENTS AND METHODS: This ethics review board-approved, prospective study included 55 men with suspicion of PCa and negative systematic biopsies or clinically discordant low-risk PCa (n = 21) or those being considered for FT (n = 34) who received 18F-DCFPyL PET/mpMR. Each modality, PET, mpMR, and PET/MR (using the PROMISE classification), was assessed independently. All suspicious lesions underwent PET/MR-ultrasound fusion biopsies. RESULTS: There were 45/55 patients (81.8%) that had histologically proven PCa and 41/55 (74.5%) were diagnosed with csPCa. Overall, 61/114 lesions (53.5%) identified on any modality were malignant; 49/61 lesions (80.3%) were csPCa. On lesion-level analysis, for detection of csPCa, the sensitivity of PET was higher than that of mpMR and PET/MR (86% vs 67% and 69% [p = 0.027 and 0.041, respectively]), but at a lower specificity (32% vs 85% and 86%, respectively [p < 0.001]). The performance of MR and PET/MR was comparable. For identification of csPCa in PI-RADS ≥ 3 lesions, the AUC (95% CI) for PET, mpMR, and PET/MR was 0.75 (0.65-0.86), 0.69 (0.56-0.82), and 0.78 (0.67-0.89), respectively. The AUC for PET/MR was significantly larger than that of mpMR (p = 0.04). CONCLUSION: PSMA PET detects more csPCa than mpMR, but at low specificity. The performance PET/MR is better than mpMR for detection of csPCa in PI-RADS ≥ 3 lesions. CLINICAL REGISTRATION: NCT03149861.

Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation.

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.

Role of antibody-mediated tumor targeting and route of administration in nanoparticle tumor accumulation in vivo.

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 GdCl3 (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.

Design and characterization of HER-2-targeted gold nanoparticles for enhanced X-radiation treatment of locally advanced breast cancer.

Our purpose was to develop a human epidermal growth factor receptor-2 (HER-2) targeted nanotechnology-based radiosensitizer. HER-2 is overexpressed in 20-30% of all breast cancers and up to 2-fold higher in locally advanced disease (LABC). Trastuzumab was derivatized with a polyethylene glycol (OPSS-PEG-SVA) cross-linker to produce trastuzumab-PEG-OPSS. These immunoconjugates were analyzed by SDS-PAGE, and their immunoreactivity was assessed by flow cytometry using HER-2 overexpressing SK-BR-3 breast cancer cells. Reacting trastuzumab with increasing ratios of PEG resulted in an increase in molecular weight from approximately 148 kDa to 243 kDa, associated with increasing PEG substitution (0.6 to 18.9 PEG chains per trastuzumab). Attachment of approximately 7 PEG chains per trastuzumab resulted in 56% retention in immunoreactivity assessed by flow cytometry. The conjugates were then linked to 30 nm AuNPs. Using a novel (123)iodine-radiotracer based assay that overcomes the current limitations of spectrophotometric quantification of biological molecules on AuNPs we estimate 14.3 ± 2.7 antibodies were attached to each AuNP when 2 × 10(11) AuNPs were reacted with 20 µg of trastuzumab-PEG-OPSS. Specificity of trastuzumab-PEG-AuNPs for HER-2 and internalization in SK-BR-3 cells was demonstrated by comparing the uptake of trastuzumab-PEG-AuNPs or PEG-AuNPs by darkfield microscopy. The ability of trastuzumab-PEG-AuNPs in combination with 300 kVp X-rays to enhance DNA double strand breaks (DSBs) in SK-BR-3 cells was assessed by immunofluorescence using the γ-H2AX assay. γ-H2AX assay results revealed 5.1-fold higher DNA-DSBs with trastuzumab-PEG-AuNPs and X-radiation as compared to treatment with X-radiation alone. The trastuzumab-PEG-AuNPs are a promising targeted nanotechnology-based radiosensitizer for improving LABC therapy. The design and systematic approaches taken to surface modify and characterize trastuzumab-PEG-AuNPs described in this study would have application to other molecularly targeted AuNPs for cancer treatment.

Convolutional neural networks for improving image quality with noisy PET data.

GOAL: PET is a relatively noisy process compared to other imaging modalities, and sparsity of acquisition data leads to noise in the images. Recent work has focused on machine learning techniques to improve PET images, and this study investigates a deep learning approach to improve the quality of reconstructed image volumes through denoising by a 3D convolution neural network. Potential improvements were evaluated within a clinical context by physician performance in a reading task. METHODS: A wide range of controlled noise levels was emulated from a set of chest PET data in patients with lung cancer, and a convolutional neural network was trained to denoise the reconstructed images using the full-count reconstructions as the ground truth. The benefits, over conventional Gaussian smoothing, were quantified across all noise levels by observer performance in an image ranking and lesion detection task. RESULTS: The CNN-denoised images were generally ranked by the physicians equal to or better than the Gaussian-smoothed images for all count levels, with the largest effects observed in the lowest-count image sets. For the CNN-denoised images, overall lesion contrast recovery was 60% and 90% at the 1 and 20 million count levels, respectively. Notwithstanding the reduced lesion contrast recovery in noisy data, the CNN-denoised images also yielded better lesion detectability in low count levels. For example, at 1 million true counts, the average true positive detection rate was around 40% for the CNN-denoised images and 30% for the smoothed images. CONCLUSION: Significant improvements were found for CNN-denoising for very noisy images, and to some degree for all noise levels. The technique presented here offered however limited benefit for detection performance for images at the count levels routinely encountered in the clinic.

Cost-effectiveness of magnetic resonance carotid plaque imaging for primary stroke prevention in Canada.

OBJECTIVE: Magnetic resonance of the carotid arteries provides important insight into plaque composition and vulnerability in addition to the traditional measure of stenosis. The purpose of this study was to evaluate the cost-effectiveness of MR imaging as a first-line modality to assess carotid disease and guide management for high-risk patients with <50% stenosis. METHODS: Using TreeAge Pro, a cost-effectiveness simulation was conducted comparing two strategies: (a) standard of care first-line carotid duplex ultrasound (DUS) with regular follow-up, vs (b) first-line MR assessment of stenosis and intraplaque haemorrhage (MRIPH) in which patients with IPH received annual DUS surveillance and immediate carotid endarterectomy in case of plaque progression. RESULTS: For patients aged 70 years old, using a first-line MRIPH strategy resulted in a 16.8% relative risk reduction in strokes compared to DUS (0.080 vs 0.097 strokes per patient per lifetime), and an increased quality-adjusted-life years (12.23 vs 12.20) at an increased cost of $897.33 over a patient's lifetime ($5784.53 vs $4887.20 average total cost per patient per lifetime). The incremental cost-effectiveness ratio was $29,744 per quality-adjusted-life years. MRIPH remained cost-effective below a willingness-to-pay threshold of $50,000 for 91.8% of sensitivity analyses. CONCLUSION: MRIPH was found to be a cost-effective first-line tool to identify asymptomatic patients at high risk for stroke requiring annual surveillance and prompt management. Advances in Knowledge: Using MR imaging as a fist-line method to detect the presence of IPH provides clinically useful and cost-effective information that allows for enhanced risk evaluation and primary stroke prevention.

Evaluation of an Online Education Resource on Radiation Therapy Created for Patients with Postprostatectomy Prostate Cancer and Their Caregivers.

INTRODUCTION: Radiation therapy (RT) after prostatectomy is an important curative treatment option for patients with prostate cancer. It can be delivered immediately after surgery as adjuvant treatment, or after biochemical PSA failure as salvage treatment. There is currently a lack of consensus regarding whether salvage RT in the event of biochemical failure or immediate adjuvant RT is the optimal postprostatectomy RT treatment. Although both types of postprostatectomy RT are generally well tolerated, patients may develop some toxicity that can impact their quality of life and the duration and frequency of treatments can be challenging for patients. It is imperative that patients be provided with evidence-based information so that they are able to make a treatment decision most aligned with their values. METHODS: To help address patients' informational needs, an online education resource was created for patients with prostate cancer considering postoperative RT. Patients and their families were asked to evaluate the effectiveness of this resource using a validated purpose-based information assessment. RESULTS: Nineteen patients were approached and 14 participated, but only five patients returned their evaluations (35%). Sixty percent found the information to be important with regards to each of the six commonly identified purposes in the purpose-based information assessment: organizing, understanding, decision-making, planning, emotional support, and discussing. Only one participant found the information hard to understand and had difficulty finding specific information. DISCUSSION: Patients should be encouraged to actively participate in their treatment decision-making process involving postprostatectomy RT. For patients to make well-informed decisions, patients must be provided with clear and accessible information so that they may understand their disease and the treatment options. CONCLUSION: An online education resource has been developed that most study respondents found clear and helpful for a variety of identified purposes. Overall, this online education resource has the potential to reach a large number of patients and their caregivers who desire specific information and involvement in future treatment decisions.

Interplay between the gold nanoparticle sub-cellular localization, size, and the photon energy for radiosensitization.

There are large variations in the reported efficiency of gold nanoparticle (GNP) radiosensitization. We have previously reported on a predictive model, which accounts for the detailed Auger and photoelectron tracks to calculate the cell survival probability. After validating our model using PC-3 cells incubated with 2 mg/ml of 30 nm GNPs and irradiated with 100 kVp or 300 kVp beams, we evaluated the interplay between photon energy, GNP size (1.9 and 100 nm) and sub-cellular localization. Experiments were in excellent agreement with the model. In predictive modeling, using a 100 kVp source and 1.9 nm nanoparticles, GNP localization had a significant impact on cell survival. A sensitizer enhancement ratio of 1.34 was achieved when GNPs were localized outside the cells, increasing to 2.56 when GNPs were also distributed in the cytoplasm and nucleus. Using a 300 kVp source, which emits photons mainly above the gold K-edge, the dependence on GNP localization and size was barely detectable, since long ranged electrons dominate the energy deposition. In summary, achieving intracellular uptake with targeted-GNPs can significantly enhance radiosensitization for photon energies below the gold K-edge, where Auger electrons contribute significantly to the local energy deposition. For higher energies, this is much less important.

Monte Carlo simulation of radiation transport and dose deposition from locally released gold nanoparticles labeled with 111In, 177Lu or 90Y incorporated into tissue implantable depots.

Permanent seed implantation (PSI) brachytherapy is a highly conformal form of radiation therapy but is challenged with dose inhomogeneity due to its utilization of low energy radiation sources. Gold nanoparticles (AuNP) conjugated with electron emitting radionuclides have recently been developed as a novel form of brachytherapy and can aid in homogenizing dose through physical distribution of radiolabeled AuNP when injected intratumorally (IT) in suspension. However, the distribution is unpredictable and precise placement of many injections would be difficult. Previously, we reported the design of a nanoparticle depot (NPD) that can be implanted using PSI techniques and which facilitates controlled release of AuNP. We report here the 3D dose distribution resulting from a NPD incorporating AuNP labeled with electron emitters (90Y, 177Lu, 111In) of different energies using Monte Carlo based voxel level dosimetry. The MCNP5 Monte Carlo radiation transport code was used to assess differences in dose distribution from simulated NPD and conventional brachytherapy sources, positioned in breast tissue simulating material. We further compare these dose distributions in mice bearing subcutaneous human breast cancer xenografts implanted with 177Lu-AuNP NPD, or injected IT with 177Lu-AuNP in suspension. The radioactivity distributions were derived from registered SPECT/CT images and time-dependent dose was estimated. Results demonstrated that the dose distribution from NPD reduced the maximum dose 3-fold when compared to conventional seeds. For simulated NPD, as well as NPD implanted in vivo, 90Y delivered the most homogeneous dose distribution. The tumor radioactivity in mice IT injected with 177Lu-AuNP redistributed while radioactivity in the NPD remained confined to the implant site. The dose distribution from radiolabeled AuNP NPD were predictable and concentric in contrast to IT injected radiolabeled AuNP, which provided irregular and temporally variant dose distributions. The use of NPD may serve as an intermediate between PSI and radiation delivered by radiolabeled AuNP by providing a controlled method to improve delivery of prescribed doses as well as homogenize dose from low penetrating electron sources.

Depot system for controlled release of gold nanoparticles with precise intratumoral placement by permanent brachytherapy seed implantation (PSI) techniques.

We report the design of a nanoparticle depot (NPD) system for local delivery of gold nanoparticles (AuNP) that facilitates their controlled release and is implantable into tumors by permanent seed implantation (PSI) brachytherapy techniques. Various sizes (5, 15, 30, and 50nm) of polyethylene glycol (PEG) coated AuNP and concentrations (6%, 8%, and 10% w/v) of calcium alginate used to form the NPD were studied. AuNP release rate, diffusion characteristics and spatial distribution were characterized in a tissue equivalent phantom model, and in a breast cancer tumor xenograft model and compared to a Fickian diffusion computational model, to identify the optimal NPD composition. In phantoms, 5nm and 15nm AuNP were released more rapidly than 30nm or 50nm AuNP but when implanted into tumor xenografts, AuNP exhibited slower release from NPD. Controlled prolonged release of AuNP was observed in tumor tissue over durations which were dependent on AuNP size. Maximum release and distribution in tumors were achieved using 5nm AuNP incorporated into the NPD. These results demonstrate the potential for the NPD as an effective local delivery system for AuNP-based therapies.

Clinical Significance of Accounting for Tissue Heterogeneity in Permanent Breast Seed Implant Brachytherapy Planning.

PURPOSE: The inhomogeneity correction factor (ICF) method provides heterogeneity correction for the fast calculation TG43 formalism in seed brachytherapy. This study compared ICF-corrected plans to their standard TG43 counterparts, looking at their capacity to assess inadequate coverage and/or risk of any skin toxicities for patients who received permanent breast seed implant (PBSI). METHODS AND MATERIALS: Two-month postimplant computed tomography scans and plans of 140 PBSI patients were used to calculate dose distributions by using the TG43 and the ICF methods. Multiple dose-volume histogram (DVH) parameters of clinical target volume (CTV) and skin were extracted and compared for both ICF and TG43 dose distributions. Short-term (desquamation and erythema) and long-term (telangiectasia) skin toxicity data were available on 125 and 110 of the patients, respectively, at the time of the study. The predictive value of each DVH parameter of skin was evaluated using the area under the receiver operating characteristic (ROC) curve for each toxicity endpoint. RESULTS: Dose-volume histogram parameters of CTV, calculated using the ICF method, showed an overall decrease compared to TG43, whereas those of skin showed an increase, confirming previously reported findings of the impact of heterogeneity with low-energy sources. The ICF methodology enabled us to distinguish patients for whom the CTV V100 and V90 are up to 19% lower compared to TG43, which could present a risk of recurrence not detected when heterogeneity are not accounted for. The ICF method also led to an increase in the prediction of desquamation, erythema, and telangiectasia for 91% of skin DVH parameters studied. CONCLUSIONS: The ICF methodology has the advantage of distinguishing any inadequate dose coverage of CTV due to breast heterogeneity, which can be missed by TG43. Use of ICF correction also led to an increase in prediction accuracy of skin toxicities in most cases.

Investigation of the effects of cell model and subcellular location of gold nanoparticles on nuclear dose enhancement factors using Monte Carlo simulation.

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.

A simplified analytical dose calculation algorithm accounting for tissue heterogeneity for low-energy brachytherapy sources.

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.