Surgery (RMH) - Research Publications
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ItemAAV capsid bioengineering in primary human retina models(NATURE PORTFOLIO, 2023-12-11)Adeno-associated viral (AAV) vector-mediated retinal gene therapy is an active field of both pre-clinical as well as clinical research. As with other gene therapy clinical targets, novel bioengineered AAV variants developed by directed evolution or rational design to possess unique desirable properties, are entering retinal gene therapy translational programs. However, it is becoming increasingly evident that predictive preclinical models are required to develop and functionally validate these novel AAVs prior to clinical studies. To investigate if, and to what extent, primary retinal explant culture could be used for AAV capsid development, this study performed a large high-throughput screen of 51 existing AAV capsids in primary human retina explants and other models of the human retina. Furthermore, we applied transgene expression-based directed evolution to develop novel capsids for more efficient transduction of primary human retina cells and compared the top variants to the strongest existing benchmarks identified in the screening described above. A direct side-by-side comparison of the newly developed capsids in four different in vitro and ex vivo model systems of the human retina allowed us to identify novel AAV variants capable of high transgene expression in primary human retina cells.
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ItemIL-10 in glioma(Springer Nature [academic journals on nature.com], 2021-08-04)The prognosis for patients with glioblastoma (GBM), the most common and malignant type of primary brain tumour, is very poor, despite current standard treatments such as surgery, radiotherapy and chemotherapy. Moreover, the immunosuppressive tumour microenvironment hinders the development of effective immunotherapies for GBM. Cytokines such as interleukin-10 (IL-10) play a major role in modulating the activity of infiltrating immune cells and tumour cells in GBM, predominantly conferring an immunosuppressive action; however, in some circumstances, IL-10 can have an immunostimulatory effect. Elucidating the function of IL-10 in GBM is necessary to better strategise and improve the efficacy of immunotherapy. This review discusses the immunostimulatory and immunosuppressive roles of IL-10 in the GBM tumour microenvironment while considering IL-10-targeted treatment strategies. The molecular mechanisms that underlie the expression of IL-10 in various cell types are also outlined, and how this resulting information might provide an avenue for the improvement of immunotherapy in GBM is explored.
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ItemNo Preview AvailableTrabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth(eLIFE SCIENCES PUBL LTD, 2023-12-15)ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterized these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organization and neural development. Zranb1 knock-in mice harboring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalized causing impaired organization of the cytoskeleton that underlie the neuronal and developmental phenotypes.
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ItemReal-world adjuvant chemotherapy treatment patterns and outcomes over time for resected stage II and III colorectal cancer(Wiley, 2023-06)BACKGROUND: The administration of adjuvant chemotherapy (AC) to colorectal cancer (CRC) patients in Australia and impact of recent trial data has not been well reported. We aim to evaluate temporal trends in AC treatment and outcomes in real-world Australian patients. METHODS: CRC patients were analyzed from 13 hospitals, stratified by stage (II or III) and three 5-year time periods (A: 2005-2009, B: 2010-2014, C: 2015-2019). Stage III was further stratified as pre- and post publication of the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration (March 2018). AC prescription, time-to-recurrence (TTR), and overall survival (OS) was compared across the time periods. RESULTS: Of 3977 identified patients, 1148 (stage II: 640, stage III: 508), 1525 (856 vs. 669), and 1304 (669 vs. 635) were diagnosed in Period A, B, and C, respectively. Fewer patients in Period C received AC compared to Period B in stage II (10% vs. 15%, p <.01) and III (70% vs. 79%, p <.01). Post-IDEA, the proportion of patients receiving ≤3 months of oxaliplatin-based AC increased (45% vs. 13%, p <.01). The proportion of patients who remained recurrence free at 3 years was similar between time periods in stage II (A: 89% vs. B: 88% vs. C: 90%, p = .53) and stage III (72% vs. 76% vs. 72%, p = .08). OS significantly improved for stage II (80%-85%, p = .04) and stage III (69%-77%, <.01) from period A to B. CONCLUSION: AC use has moderately decreased over time with no impact on recurrence rates. Improved survival in more recent years despite similar recurrence rates may be related to improved baseline staging, better postrecurrence treatment, and reduced noncancer-related mortality.
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ItemCase of the Month from Peter MacCallum Cancer Centre, Melbourne, Australia: ICG-assisted robotic Boari flap ureteric reimplantation in a case of missed ureteric injury(Wiley, 2023-01)Itroductrion: Iatrogenic ureteric injuries are not uncommon, with reported incidences ranging from 0.5% to as high as 11.8% in some studies [1-3]. The mechanism of injury varies widely from intraluminal perforations resulting from endourology procedures to diathermy and ligation injuries in abdominopelvic operations [4, 5]. Regardless of aetiology, the management of iatrogenic ureteric injuries is challenging and requires various considerations to ensure optimal outcomes. In this BJUI Case of the Month, a patient with a missed ureteric injury following an emergency Hartmann's procedure is presented and discussed.
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ItemSalvage irreversible electroporation for radio-recurrent prostate cancer - the prospective FIRE trial(Wiley, 2023-06)OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage radio recurrent prostate tumours.
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ItemSynchronous vs independent reading of prostate-specific membrane antigen positron emission tomography (PSMA-PET) and magnetic resonance imaging (MRI) to improve diagnosis of prostate cancer(Wiley, 2023-05-01)Objectives: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology. Methods: This was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. ‘Concordance’ between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality. Results: International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans. Conclusion: Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.
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ItemNo Preview AvailableA phase 1b open label study of sodium selenate as a disease‐modifying treatment for behavioural variant fronto‐temporal dementia(Wiley, 2021-12)Abstract Background Hyperphosphorylated tau is a pathological hallmark of ∼45% of behavioural variant frontotemporal dementia (bvFTD). For this reason, hyperphosphorylated tau represents a promising treatment target for this population. Sodium selenate stimulates the PP2A enzyme, which directly dephosphorylates hyperphosphorylated tau. This Phase 1b, open‐labelled, study investigated sodium selenate as a disease‐modifying treatment for patients with bvFTD. Method Twelve patients with bvFTD were treated with sodium selenate (15mg tds) for twelve months. Participants underwent a cognitive and behavioural battery, MRI, lumbar puncture and safety assessments at screening, baseline, and at regular intervals following treatment commencement. Adverse events were monitored via diary cards between clinic visits. Result All 12 patients completed the study. Safety analysis found that sodium selenate was safe and well tolerated, with no study withdrawals. Commonly reported mild‐moderate adverse events were nail changes (n=6), muscles aches (n=4), headache, fatigue, hair loss and fall (n=3). Five patients reduced their dose to 10mg tds due to adverse events. No treatment‐related serious adverse events occurred. Analyses of efficacy data are ongoing. A mixed‐effects analysis showed an overall small but significant decline on cognition and behaviour, including total NUCOG score (b=‐0.18, 95% CI=‐0.28–0.08) Cambridge Behavioural Index (b=0.32, 95% CI=0.18‐0.46) and Carer Burden Scale score (b=0.1, 95% CI = 0.02‐0.18). Percentage change in whole‐brain volume from baseline to week 52 ranged from ‐0.26% to ‐6.51% (n=7 >‐1.8%, n=4 <‐1.8%). Plasma tau levels (n=6) did not change from baseline (3.73±0.26pg/mL) to week 52 (4.66±0.24pg/mL). CSF tau also showed no change from baseline (167.8±11.2pg/mL) to week 52 (156.1±2.49pg/mL). Although not significant, the directional changes are in line with the proposed mechanism of sodium selenate. Exploratory analyses of “responders” (brain volume change >‐1.8%, n=7) found no change in NUCOG total score (b=‐0.03, 95% CI ‐0.14‐0.07) or CBS score (b=‐0.05, 95% CI ‐0.04‐0.13) over time. Conclusion Sodium selenate is safe and well tolerated in patients with bvFTD. Exploratory analyses indicate it may reduce atrophy and halt cognitive decline in a subset of bvFTD patients. Sodium selenate should be further investigated as a potential treatment for bvFTD, and biomarkers to identify the subset of “responder” patients explored.
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ItemNo Preview AvailableExtracellular vesicular lipids as biomarkers for the diagnosis of Alzheimer’s disease(Wiley, 2021-12-31)An increasing number of studies have revealed that dysregulated lipid homeostasis is associated with the pathological processes that lead to Alzheimer’s disease (AD). If changes in key lipid species could be detected in the periphery, it would advance our understanding of the disease and facilitate biomarker discovery. Global lipidomic profiling of sera/blood however has proved challenging with limited disease or tissue specificity. Small extracellular vesicles (EV) in the central nervous system, can pass the blood-brain barrier and enter the periphery, carrying a subset of lipids that could reflect lipid homeostasis in brain. This makes EVs uniquely suited for peripheral biomarker exploration.