Medicine (St Vincent's) - Research Publications
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ItemAutomated preparation of 2-[18F]fluoropropionate labeled peptides using a flexible, multi-stage synthesis platform (iPHASE Flexlab)(WILEY, 2018-02)Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi-step procedures, especially for fluorine-18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2-[18 F]fluoropropionate labeled RGD-peptides through use of the iPHASE Flexlab as an effective dual-stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD-peptides, [18 F]FP-GalactoRGD and [18 F]FP-c(RGDy(SO3 )K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD-peptides, [18 F]F-PRGD2 and [18 F]FP-E(RGDy(SO3 )K)2 , was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride.
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ItemIntense focal pituitary FDG uptake due to intravascular large B-cell lymphoma in pyrexia of unknown origin(WILEY-BLACKWELL, 2016-11)
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ItemLong term, continuous exposure to panobinostat induces terminal differentiation and long term survival in the TH-MYCN neuroblastoma mouse model(WILEY, 2016-07-01)Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for ∼15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.
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ItemA Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention(WILEY-V C H VERLAG GMBH, 2019-10-14)Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.
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ItemA Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention(Wiley, 2019-10-14)Abstract Molecules containing lysine‐ureido‐glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine‐ureido‐glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron‐emitting copper‐64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper‐67 variant.
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ItemAccess, knowledge and experience with fluorodeoxyglucose positron emission tomography/computed tomography in infection management: a survey of Australia and New Zealand infectious diseases physicians and microbiologists(WILEY, 2019-05)BACKGROUND: Despite fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) being funded only for staging and restaging of some malignancies in Australia, there is evidence of benefit of FDG-PET/CT for infection indications such as pyrexia of unknown origin (PUO), prolonged neutropenic fever (NF) and prosthetic device infection. AIM: To evaluate the current knowledge, utilisation of and gaps in access to FDG-PET/CT for infectious indications by Australasian infectious diseases (ID) physicians and microbiologists. METHODS: An online survey was administered to ID and microbiology doctors practising in adult medicine in Australia and New Zealand through two established email networks. Using targeted questions and case-based examples, multiple themes were explored, including access to FDG-PET/CT, use and perceived benefit of FDG-PET/CT in diagnosis and monitoring of non-malignant conditions such as NF and PUO, and barriers to clinical use of FDG-PET/CT. RESULTS: A response was received from 120 participants across all states and territories. Onsite and offsite FDG-PET/CT access was 63% and 31% respectively. Eighty-six percent reported using FDG-PET/CT for one or more infection indications and all had found it clinically useful, with common indications being PUO, prosthetic device infections and use in the immunocompromised host for prolonged NF and invasive fungal infection. Thirty-eight percent reported barriers in accessing FDG-PET/CT for infection indications and 76% would utilise FDG-PET/CT more frequently if funding existed for infection indications. CONCLUSION: Access to FDG-PET/CT in Australia and New Zealand is modest and is limited by lack of reimbursement for infection indications. There is discrepancy between recognised ID indications for FDG-PET/CT and funded indications.
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ItemVoxel-wise correlation of positron emission tomography/computed tomography with multiparametric magnetic resonance imaging and histology of the prostate using a sophisticated registration framework(WILEY, 2019-06)OBJECTIVES: To develop a registration framework for correlating positron emission tomography/computed tomography (PET/CT) images with multiparametric magnetic resonance imaging (mpMRI) and histology of the prostate, thereby enabling voxel-wise analysis of imaging parameters. PATIENTS AND METHODS: In this prospective proof-of-concept study, nine patients scheduled for radical prostatectomy underwent mpMRI and PET/CT imaging before surgery. One had PET imaging using 18 F-fluoromethylcholine, five using 68 Ga-labelled prostate-specific membrane antigen (PSMA)-HBED-CC (PMSA-11), and three using a trial 68 Ga-labelled THP-PSMA tracer. PET/CT data were co-registered with mpMRI via the CT scan and an in vivo three-dimensional T2-weighted (T2w) MRI, and then co-registered with ground truth histology data using ex vivo MRI of the prostate specimen. Maximum and mean standardised uptake values (SUVmax and SUVmean ) were extracted from PET data using tumour annotations from histology, and Kolmogorov-Smirnov tests were used to compare between tumour- and benign-voxel values. Correlation analysis was performed between mpMRI and PET SUV tumour voxel values using Pearson's correlation coefficient and R2 statistics. RESULTS: PET/CT data from all nine patients were successfully registered with mpMRI and histology data. SUVmax and SUVmean ranged from 2.21 to 12.11 and 1.08 to 4.21, respectively. All patients showed the PET SUV values in benign and tumour voxels were from statistically different distributions. Correlation analysis showed no consistent trend between the T2w or apparent diffusion coefficient values and PET SUV. However, parameters from dynamic contrast-enhanced (DCE) MRI including the maximum enhancement, volume transfer constant (Ktrans ), and the initial area under the contrast agent concentration curve for the first 60 s after injection (iAUGC60), showed consistent positive correlations with PET SUV. Furthermore, R2* values from blood oxygen level-dependent (BOLD) MRI showed consistent negative correlations with PET SUV-voxel values. CONCLUSION: We have developed a novel framework for registering and correlating PET/CT data at a voxel-level with mpMRI and histology. Despite registration uncertainties, perfusion and oxygenation parameters from DCE MRI and BOLD imaging showed correlations with PET SUV. Further analysis will be performed on a larger patient cohort to quantify these proof-of-concept findings. Improved understanding of the correlation between mpMRI and PET will provide supportive information for focal therapy planning of the prostate.
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ItemMetabolic patterns and seizure outcomes following anterior temporal lobectomy(WILEY, 2019-02)OBJECTIVE: We investigated the relationship between the interictal metabolic patterns, the extent of resection of 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) hypometabolism, and seizure outcomes in patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection. METHODS: Eighty-two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant 18 FDG-PET hypometabolism, and at least 2 years of postoperative follow-up were included in this 2-center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre- and postoperative MRI scans coregistered with interictal 18 FDG-PET. RESULTS: Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). INTERPRETATION: The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1-10 ANN NEUROL 2019;85:241-250.
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ItemA pilot study of cardiopulmonary exercise testing and cardiac stress positron emission tomography before major non-cardiac surgery(WILEY, 2018-12)Cardiac events are a common cause of peri-operative morbidity. Cardiopulmonary exercise testing can objectively assess risk, but it does not quantify myocardial ischaemia. With appropriate dietary preparation to suppress basal myocardial glucose uptake, positron emission tomography with 18 F-fluorodeoxyglucose can identify post-ischaemic myocardium, providing an attractive complement to exercise testing. We aimed to investigate the feasibility of this diagnostic algorithm. Patients referred for cardiopulmonary exercise testing before major cancer surgery were prospectively recruited. Exercise testing and positron emission tomography imaging were performed after a high fat-low carbohydrate meal. Protocol feasibility (primary end-point) included compliance with pre-test diet instructions and the completion of tests. Stress myocardial perfusion imaging was performed if either exercise testing or positron emission tomography was equivocal or positive for ischaemia. We recorded cardiac complications for 30 postoperative days. We enrolled 26 participants, 20 of whom completed protocol. Twenty-one participants proceeded to surgery: myocardial injury or infarction was diagnosed in three participants, two of whom had positive or equivocal positron emission tomography but negative myocardial perfusion imaging. We have shown that pre-operative cardiac positron emission tomography after cardiopulmonary exercise testing is feasible; protocol deviations were minor and did not affect image quality. Our findings warrant further investigation to compare the diagnostic utility of cardiac positron emission tomography imaging with standard pre-operative stress tests.