Sir Peter MacCallum Department of Oncology - Research Publications
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ItemUtility of 68Ga prostate specific membrane antigen - positron emission tomography in diagnosis and response assessment of recurrent renal cell carcinoma(WILEY, 2017-06)INTRODUCTION: Prostate specific membrane antigen (PSMA) positron emission tomography (PET) is an emerging imaging modality in prostate cancer. However, 68 Ga-PSMA-PET may also have diagnostic utility in the setting of renal cell carcinoma (RCC). We investigate the differential role of 18 F-fluorodeoxyglucose (FDG) and PSMA-PET/CT scanning in patients with oligometastatic RCC. In particular, we focus on the utility of PSMA-PET for diagnostic evaluation of isolated or limited metastases planned for local surgery or radiation, as well as the potential utility of PSMA-PET for therapeutic response assessment in patients receiving stereotactic ablative body radiotherapy (SABR). METHODS: We present a retrospective series of eight patients in which comparative imaging modalities are evaluated against PSMA-PET scanning. FDG-PET and PSMA-PET scans were performed prior to definitive treatment (either surgery or SABR) of limited recurrent disease. Response assessment after SABR was performed with both PET imaging modalities at multiple time points in a subset of four patients. RESULTS: Prostate specific membrane antigen uptake is typically more intense than FDG in RCC. In all but two cases, one of which was papillary carcinoma, FDG-PET and PSMA-PET are concordant for detection of sites of disease. We demonstrate for the first time the differential kinetics of post-treatment response using PSMA and FDG-PET, with a more rapid metabolic response observed on FDG-PET. Both modalities demonstrate response earlier than morphological appearances on CT or MRI imaging. CONCLUSIONS: Our series suggests that PSMA shows early promise as a diagnostic and therapeutic response assessment tool in patients with metastatic RCC receiving definitive local therapies.
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ItemThe VAMPIRE challenge: A multi-institutional validation study of CT ventilation imaging(WILEY, 2019-03)PURPOSE: CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities. METHODS: The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA-SPECT, and 4 sheep imaged with Xenon-CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). Seven research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B-splines, Free-form, Diffeomorphisms, or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel-wise Spearman coefficient rS , and Dice similarity coefficients evaluated for low function lung ( DSClow ) and high function lung ( DSChigh ). RESULTS: A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant-submitted DIR motion fields using the in-house software, VESPIR. The rS and DSC results reveal a high degree of inter-algorithm and intersubject variability among the validation subjects, with algorithm rankings changing by up to ten positions depending on the choice of evaluation metric. The algorithm with the highest overall cross-modality correlations used a biomechanical model-based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27-0.73) for rS , 0.52 (0.36-0.67) for DSClow , and 0.45 (0.28-0.62) for DSChigh . All other algorithms exhibited at least one negative rS value, and/or one DSC value less than 0.5. CONCLUSIONS: The VAMPIRE Challenge results demonstrate that the cross-modality correlation between CTVIs and the RefVIs varies not only with the choice of CTVI algorithm but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a "gold standard," highlights the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts.
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ItemAutomated assessment of functional lung imaging with 68Ga-ventilation/perfusion PET/CT using iterative histogram analysis(SPRINGER, 2021-03-07)PURPOSE: Functional lung mapping from Ga68-ventilation/perfusion (V/Q) PET/CT, which has been shown to correlate with pulmonary function tests (PFTs), may be beneficial in a number of clinical applications where sparing regions of high lung function is of interest. Regions of clumping in the proximal airways in patients with airways disease can result in areas of focal intense activity and artefact in ventilation imaging. These artefacts may even shine through to subsequent perfusion images and create a challenge for quantitative analysis of PET imaging. We aimed to develop an automated algorithm that interprets the uptake histogram of PET images to calculate a peak uptake value more representative of the global lung volume. METHODS: Sixty-six patients recruited from a prospective clinical trial underwent both V/Q PET/CT imaging and PFT analysis before treatment. PET images were normalised using an iterative histogram analysis technique to account for tracer hotspots prior to the threshold-based delineation of varying values. Pearson's correlation between fractional lung function and PFT score was calculated for ventilation, perfusion, and matched imaging volumes at varying threshold values. RESULTS: For all functional imaging thresholds, only FEV1/FVC PFT yielded reasonable correlations to image-based functional volume. For ventilation, a range of 10-30% of adapted peak uptake value provided a reasonable threshold to define a volume that correlated with FEV1/FVC (r = 0.54-0.61). For perfusion imaging, a similar correlation was observed (r = 0.51-0.56) in the range of 20-60% adapted peak threshold. Matched volumes were closely linked to ventilation with a threshold range of 15-35% yielding a similar correlation (r = 0.55-0.58). CONCLUSIONS: Histogram normalisation may be implemented to determine the presence of tracer clumping hotspots in Ga-68 V/Q PET imaging allowing for automated delineation of functional lung and standardisation of functional volume reporting.
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ItemSingle-arm prospective interventional study assessing feasibility of using gallium-68 ventilation and perfusion PET/CT to avoid functional lung in patients with stage III non-small cell lung cancer(BMJ PUBLISHING GROUP, 2020)BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses. METHODS AND ANALYSIS: This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment. DISCUSSION: Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung avoidance radiation therapy. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee. All participants will provide written informed consent. Results will be disseminated via publications. TRIALS REGISTRATION NUMBER: NCT03569072; Pre-results.
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ItemShort communication: timeline of radiation-induced kidney function loss after stereotactic ablative body radiotherapy of renal cell carcinoma as evaluated by serial 99mTc-DMSA SPECT/CT(BMC, 2014-11-26)BACKGROUND: Stereotactic ablative body radiotherapy (SABR) has been proposed as a definitive treatment for patients with inoperable primary renal cell carcinoma. However, there is little documentation detailing the radiobiological effects of hypofractionated radiation on healthy renal tissue. FINDINGS: In this study we describe a methodology for assessment of regional change in renal function in response to single fraction SABR of 26 Gy. In a patient with a solitary kidney, detailed follow-up of kidney function post-treatment was determined through 3-dimensional SPECT/CT imaging and (51)Cr-EDTA measurements. Based on measurements of glomerular filtration rate, renal function declined rapidly by 34% at 3 months, plateaued at 43% loss at 12 months, with minimal further decrease to 49% of baseline by 18 months. CONCLUSIONS: The pattern of renal functional change in (99m)Tc-DMSA uptake on SPECT/CT imaging correlates with dose delivered. This study demonstrates a dose effect relationship of SABR with loss of kidney function.
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Item68Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography in advanced prostate cancer: Current state and future trends(ELSEVIER INC, 2017-12)The early and accurate detection of prostate cancer is important to ensure timely management and appropriate individualized treatment. Currently, conventional imaging has limitations particularly in the early detection of metastases and at prostate-specific antigen (PSA) levels < 2.0 ng/mL. Furthermore, disease management such as salvage radiotherapy is best at low PSA levels. Thus, it is critical to capture the disease in the oligometastatic stage as disease progression and commencement of systemic therapies can be delayed by metastasis-directed therapy. Prostate-specific membrane antigen (PSMA) is overexpressed in prostatic cancer cells. Novel imaging modalities using radiolabeled tracers with PSMA such as 68Ga-PSMA-positron emission tomography (PET)/computed tomography (CT) have shown promising results. We review the literature regarding 68Ga-PSMA-PET/CT in the setting of primary prostate cancer and biochemical recurrence. At present, the best utilization of 68Ga-PSMA-PET/CT appears to be in biochemical recurrence. 68Ga-PSMA-PET/CT has high diagnostic accuracy for lymph node metastases and has been shown to have superior detection rates to conventional imaging, especially at low PSA levels. The exact role of 68Ga-PSMA-PET/CT in primary prostate cancer is not yet entirely clear. It has an improved detection rate for smaller lesions and may be able to identify nodal or distant metastatic disease at an earlier stage. While still experimental, there may also be value in combining 68Ga-PSMA-PET to multiparametric magnetic resonance imaging for staging of intraprostatic disease. To date, 68Ga-PSMA-PET/CT has been shown to have considerable clinical value and to impact treatment selection for patients with prostate cancer. Still in its infancy, the results of future clinical trials will be excitedly awaited.
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ItemAutomatic delineation of functional lung volumes with 68Ga-ventilation/perfusion PET/CT(SPRINGER HEIDELBERG, 2017-10-10)BACKGROUND: Functional volumes computed from 68Ga-ventilation/perfusion (V/Q) PET/CT, which we have shown to correlate with pulmonary function test parameters (PFTs), have potential diagnostic utility in a variety of clinical applications, including radiotherapy planning. An automatic segmentation method would facilitate delineation of such volumes. The aim of this study was to develop an automated threshold-based approach to delineate functional volumes that best correlates with manual delineation. Thirty lung cancer patients undergoing both V/Q PET/CT and PFTs were analyzed. Images were acquired following inhalation of Galligas and, subsequently, intravenous administration of 68Ga-macroaggreted-albumin (MAA). Using visually defined manual contours as the reference standard, various cutoff values, expressed as a percentage of the maximal pixel value, were applied. The average volume difference and Dice similarity coefficient (DSC) were calculated, measuring the similarity of the automatic segmentation and the reference standard. Pearson's correlation was also calculated to compare automated volumes with manual volumes, and automated volumes optimized to PFT indices. RESULTS: For ventilation volumes, mean volume difference was lowest (- 0.4%) using a 15%max threshold with Pearson's coefficient of 0.71. Applying this cutoff, median DSC was 0.93 (0.87-0.95). Nevertheless, limits of agreement in volume differences were large (- 31.0 and 30.2%) with differences ranging from - 40.4 to + 33.0%. For perfusion volumes, mean volume difference was lowest and Pearson's coefficient was highest using a 15%max threshold (3.3% and 0.81, respectively). Applying this cutoff, median DSC was 0.93 (0.88-0.93). Nevertheless, limits of agreement were again large (- 21.1 and 27.8%) with volume differences ranging from - 18.6 to + 35.5%. Using the 15%max threshold, moderate correlation was demonstrated with FEV1/FVC (r = 0.48 and r = 0.46 for ventilation and perfusion images, respectively). No correlation was found between other PFT indices. CONCLUSIONS: To automatically delineate functional volumes with 68Ga-V/Q PET/CT, the most appropriate cutoff was 15%max for both ventilation and perfusion images. However, using this unique threshold systematically provided unacceptable variability compared to the reference volume and relatively poor correlation with PFT parameters. Accordingly, a visually adapted semi-automatic method is favored, enabling rapid and quantitative delineation of lung functional volumes with 68Ga-V/Q PET/CT.
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ItemReduced ventilation-perfusion (V/Q) mismatch following endobronchial valve insertion demonstrated by Gallium-68 V/Q photon emission tomography/computed tomography(WILEY, 2017-09)Endobronchial valves (EBVs) are increasingly deployed in the management of severe emphysema. Initial studies focussed on volume reduction as the mechanism, with subsequent improvement in forced expiratory volume in 1 s (FEV1). More recent studies have emphasized importance of perfusion on predicting outcomes, though findings have been inconsistent. Gallium-68 ventilation-perfusion (V/Q) photon emission tomography (PET)/computed tomography (CT) is a novel imaging modality with advantages in spatial resolution, quantitation, and speed over conventional V/Q scintigraphy. We report a pilot case in which V/Q-PET/CT demonstrated discordant findings compared with quantitative CT analysis, and directed left lower lobe EBV placement. The patient experienced a significant improvement in 6-min walk distance (6MWD) without change in spirometry. Post-EBV V/Q-PET/CT demonstrated a marked decrease in unmatched (detrimental) V/Q areas and improvement in overall V/Q matching on post-EBV V/Q-PET/CT. These preliminary novel findings suggest that EBVs improve V/Q matching and may explain the observed functional improvements.
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ItemGlut-1 expression in small cervical biopsies is prognostic in cervical cancers treated with chemoradiation(ELSEVIER IRELAND LTD, 2017-02)BACKGROUND/PURPOSE: Chemoradiation (CRT) is standard therapy for locally advanced cervical cancer (LACC). However, there is a lack of biomarkers to identify patients at high relapse-risk. We examine metabolic (glucose transporter-1 [Glut-1]), hypoxic (hypoxia inducible factor [HIF-1α]; carbonic anhydrase [CA-9]) and proliferative (Ki-67) markers for prognostic utility in LACC. MATERIALS/METHODS: 60 LACC patients treated with CRT had pre-treatment biopsies. Immunohistochemistry was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore from intensity and percentage staining; and Ki-67 scored by percentage of positive cells. For each biomarker, treatment response and survival was compared between low and high-staining groups by logrank testing and multivariate analyses. RESULTS: High Glut-1 expression was associated with inferior progression-free survival (PFS), (hazard ratio [HR] 2.8, p = 0.049) and overall survival (OS), (HR 5.0, p = 0.011) on multifactor analysis adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High Glut-1 correlated with increased risk of distant failure (HR 14.6, p = 0.001) but not local failure. Low Glut-1 was associated with higher complete metabolic response rate on post-therapy positron emission tomography scan (odds ratio 3.4, p = 0.048). Ki-67 was significantly associated with PFS only (HR 1.19 per 10 units increase, p = 0.033). Biomarkers for hypoxia were not associated with outcome. CONCLUSIONS: High Glut-1 in LACC is associated with poor outcome post CRT. If prospectively validated, Glut-1 may help select patients for more intensive treatment regimens.