Surgery (Austin & Northern Health) - Research Publications

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    Original Article Impact of delay from transperineal biopsy to radical prostatectomy upon objective measures of cancer control
    Qu, LG ; Jack, G ; Perera, M ; Evans, M ; Evans, S ; Bolton, D ; Papa, N (ELSEVIER SINGAPORE PTE LTD, 2022-04-01)
    Objective: Treatment delays in prostate cancer have been characterised, although not explicitly in men undergoing transperineal prostate biopsies. We aimed to determine if delays to radical prostatectomy correlate with adverse outcomes using a contemporary population-based cohort of men diagnosed by transperineal biopsies. Methods: This study analysed men with prostate cancer of the International Society for Urological Pathology grade group ≥2, diagnosed by transperineal prostate biopsies who underwent prostatectomy, using the prospectively data from 1 January 2014 to 30 June 2018 Prostate Cancer Outcomes Registry-Victoria. Data were analysed according to stratified demographic and disease characteristics. Time intervals from biopsy (28, 60, 90, 120, and 270 days) were compared using odds ratios and regression analyses for proportion of upgrading, early biochemical recurrence, pT3 disease at prostatectomy, and positive surgical margins. Results: In total, 2008 men were analysed. There were 306 (16.7%) men with upgrading, 151 (8.4%) with biochemical recurrence, 1068 (54.1%) with pT3 disease, and 464 (23.1%) with positive surgical margins (percentages excluded patients with missing data). All adverse outcomes studied were significantly associated with higher prostate-specific antigen and grade at diagnosis. Delays of 120-270 days did not adversely alter the incidence of Gleason upgrading, pT3, or recurrence. Delays (most frequent 60-89 days, 28%) were associated with positive surgical margins but not monotonically. Regression modelling demonstrated no increased likelihood of most adverse outcomes for up to 270 days. Conclusion: Men with prostate cancer of grade group ≥2 diagnosed through transperineal biopsy may wait up to 270 days for a prostatectomy without a greater likelihood of upgrading, pT3 disease, positive surgical margins, or biochemical recurrence.
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    Clash of the calculators: External validation of prostate cancer risk calculators in men undergoing mpMRI and transperineal biopsy.
    Wei, G ; Kelly, BD ; Timm, B ; Perera, M ; Lundon, DJ ; Jack, G ; Bolton, DM (Wiley, 2021-05)
    Objective: To compare the accuracy of the European Randomized Study of Screening for Prostate Cancer (ERSPC) RC, MRI-ERSPC-RC, and Prostate Biopsy Collaborative Group (PBCG) RC in patients undergoing transperineal prostate biopsy. Patients and methods: We identified 392 patients who underwent mpMRI before transperineal prostate biopsy across multiple public and private institutions between January 2017 and August 2019. The estimated probabilities of detecting PCa and significant PCa were calculated using the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC. Receiver operating characteristic (ROC) curves for each calculator were generated and the area underneath the curve (AUC) was compared. Calibration and clinical utility were assessed with calibration plots and decision curve analysis, respectively. Results: PCa was detected in 285 patients (72.7%) with significant PCa found in 200 patients (51.1%). ROC curve analysis found the MRI-ERSPC-RC outperformed the ERSPC-RC and PBCG-RC. For the prediction of PCa, the AUC was 0.756, 0.696, and 0.675 for the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC, respectively. The AUC for the prediction of significant PCa was 0.803, 0.745, and 0.746 for the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC, respectively. Conclusions: Our study validated the ERSPC-RC, MRI-ERSPC-RC, and PBCG-RC in a cohort undergoing transperineal prostate biopsy with the MRI-ERSPC-RC performing the best. These RCs may enable improved shared decision making and help to guide patient selection for biopsy.
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    The impact of health-policy-driven subsidisation of prostate magnetic resonance imaging on transperineal prostate biopsy practice and outcomes.
    Wei, G ; Reeves, F ; Perera, M ; Kelly, BD ; Esler, S ; Bolton, D ; Jack, G (Wiley, 2022-07)
    Background: From 1 July 2018, the Australian Medicare Benefits Schedule (MBS) introduced rebates for multi-parametric magnetic resonance imaging (mpMRI) for the workup for prostate cancer (PCa). We aimed to determine if subsidisation of mpMRI prior to transperineal biopsy altered our institution's prostate biopsy practice patterns and outcomes. Methods: All patients who underwent transperineal prostate biopsy at an Australian tertiary institution from 1 January 2017 to 1 January 2020 were identified. Patients with known PCa were excluded. Patients were stratified into two groups: a pre-subsidisation cohort comprising patients biopsied prior to the introduction of mpMRI subsidisation on 1 July 2018 and a post-subsidisation cohort comprising patients biopsied after 1 July 2018. Histopathological results were compared with further stratification based on mpMRI results. Clinically significant cancer was defined as ISUP Grade Group ≥ 2. Results: Six hundred and fifty men fulfilled the inclusion criteria. Three hundred and sixty-one patients were in the pre-subsidisation cohort and 289 in the post-subsidisation cohort. Of the patients in the pre-subsidisation group, 36.3% underwent a pre-biopsy mpMRI compared with 77.5% in the post-subsidisation group. Of the patients in the pre-subsidisation group, 59.6% had positive biopsies (p = 0.024) compared with 68.2% in the post-subsidisation group. The rate of clinically significant PCa was lower in the pre-subsidisation group (39.1%) compared with the post-subsidisation (49.5%, p = 0.008). The negative predictive value of mpMRI for clinically significant PCa was 86.5%. Conclusion: Our institution experienced a reduction of negative prostate biopsies and an increase in clinically significant PCa within transperineal biopsy specimens after the Australian healthcare system introduced financial subsidisation of mpMRI.
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    Zinc supplementation as an adjunct therapy for COVID-19: Challenges and opportunities
    Chinni, V ; El-Khoury, J ; Perera, M ; Bellomo, R ; Jones, D ; Bolton, D ; Ischia, J ; Patel, O (WILEY, 2021-06-02)
    An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. Patients with COVID-19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID-19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically.
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    A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients
    Patel, O ; Chinni, V ; El-Khoury, J ; Perera, M ; Neto, AS ; McDonald, C ; See, E ; Jones, D ; Bolton, D ; Bellomo, R ; Trubiano, J ; Ischia, J (WILEY, 2021-03-09)
    Zinc inhibits replication of the SARS-CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high-dose intravenous zinc (HDIVZn) to patients with COVID-19. We performed a Phase IIa double-blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID-19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p < .001) on Day 6. Our study did not reach its target enrollment because stringent public health measures markedly reduced patient hospitalizations. Hospitalized COVID-19 patients demonstrated zinc deficiency. This can be corrected with HDIVZn. Such treatment appears safe, feasible, and only associated with minimal peripheral infusion site irritation. This pilot study justifies further investigation of this treatment in COVID-19 patients.
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    Management of benign prostatic hyperplasia in the 21st century: temporal trends in Australian population-based data
    Morton, A ; Williams, M ; Perera, M ; Teloken, PE ; Donato, P ; Ranasinghe, S ; Chung, E ; Bolton, D ; Yaxley, J ; Roberts, MJ (WILEY, 2020-06-17)
    OBJECTIVE: To examine national trends in the medical and surgical treatment of benign prostatic hyperplasia (BPH) using Australian Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) population data from 2000 to 2018. PATIENTS AND METHODS: Annual data was extracted from the MBS, PBS and Australian Institute of Health and Welfare databases for the years 2000-2018. Population-adjusted rates of BPH procedures and medical therapies were calculated and compared in relation to age. Cost analysis was performed to estimate financial burden due to BPH. RESULTS: Overall national hospital admissions due to BPH declined between 2000 and 2018, despite an increased proportion of admissions due to private procedures (42% vs 77%). Longitudinal trends in the medical management of BPH showed an increased prescription rate of dutasteride/tamsulosin combined therapy (111 vs 7649 per 100 000 men) and dutasteride monotherapy (149 vs 336 per 100 000 men) since their introduction to the PBS in 2011. Trends in BPH surgery showed an overall progressive increase in rate of total procedures between 2000 and 2018 (92 vs 133 per 100 000 men). Transurethral resection of the prostate (TURP) remained the most commonly performed surgical procedure, despite reduced utilisation since 2009 (118 vs 89 per 100 000 men), offset by a higher uptake of photoselective vaporisation of prostate, holmium:YAG laser enucleation of prostate, and later likely due to minimally invasive surgical therapies including prostatic urethral lift and ablative technologies (including Rezūm™). Financial burden due to BPH surgery has remained steady since 2009, whilst the burden due to medical therapy has risen sharply. CONCLUSION: Despite reduced national BPH-related hospitalisations, overall treatment for BPH has increased due to medical therapy and surgical alternatives to TURP. Further exploration into motivators for particular therapies and effect of medical therapy on BPH progression in clinical practice outside of clinical trials is warranted.
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    Declining use of radical prostatectomy and pelvic lymphadenectomy despite more robotics: National population data over 15 years
    Roberts, MJ ; Papa, N ; Perera, M ; Joshi, A ; Scott, S ; Bolton, D ; Lawrentschuk, N ; Yaxley, J (WILEY, 2020-04-01)
    AIM: To describe national surgical patterns of prostate cancer (PCa) care considering radical prostatectomy with or without pelvic lymphadenectomy and consideration of robotic-assisted techniques. METHODS: Retrospective analysis of publicly accessible Medicare claims data was performed for the period 2001-2016 and included patients undergoing radical prostatectomy with or without pelvic lymphadenectomy relative to total and PCa-specific populations among men aged 45-84 years. Proportion of cases performed robotically was considered. RESULTS: Total procedures performed increased from 2001, peaked in 2009 and subsequently decreased until 2016. Since 2009, the age-specific rate of surgery in men aged 75-84 increased by 2.3-fold, whereas the rates for men aged 55-64 and 45-54 reduced by 44% and 55%, respectively. Rates of concurrent pelvic lymphadenectomy fell until 2009 with subsequent stabilization (ratio 1.05-1.14) through to 2016. Significant regional practice patterns were observed, as was an increasing trend toward a robotic-assisted laparoscopic approach, comprising more than 80% of radical prostatectomies in 2016. CONCLUSION: Since the peak in 2009, radical prostatectomy is performed less in men <65 years and more in men ≥65 years. An increasing proportion of cases omit concurrent pelvic lymphadenectomy and are performed robotically.
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    Zinc Preconditioning Provides Cytoprotection following Iodinated Contrast Media Exposure in In Vitro Models
    Perera, M ; Ischia, J ; Bolton, D ; Shulkes, A ; Baldwin, GS ; Patel, O ; de Barros, ALB (WILEY-HINDAWI, 2021-02-17)
    Methods: Normal human proximal renal kidney cells (HK-2) were preconditioned with either increasing doses of ZnCl2 or control. Following this preconditioning, cells were exposed to increasing concentrations of Iohexol 300 mg I2/ml for four hours. Key outcome measures included cell survival (MTT colorimetric assay) and ROS generation (H2DCFDA fluorescence assay). Results: Contrast media induced a dose-dependent reduction in survival of HK-2 cells. Compared to control, contrast media at 150, 225, and 300 mg I2/ml resulted in 69.5% (SD 8.8%), 37.3% (SD 4.8%), and 4.8% (SD 6.6%) cell survival, respectively (p < 0.001). Preconditioning with 37.5 μM and 50 μM ZnCl2 increased cell survival by 173% (SD 27.8%) (p < 0.001) and 219% (SD 32.2%) (p < 0.001), respectively, compared to control preconditioning. Zinc preconditioning resulted in a reduction of ROS generation. Zinc pre-conditioning with 37.5 μM μM ZnCl2 reduced ROS generation by 46% (p < 0.001) compared to control pre-conditioning. Conclusions: Zinc preconditioning reduces oxidative stress following exposure to radiographic contrast media which in turn results in increased survival of renal cells. Translation of this in vitro finding in animal models will lay the foundation for future use of zinc preconditioning against contrast induced nephropathy.
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    Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients: trial protocol
    Perera, M ; El Khoury, J ; Chinni, V ; Bolton, D ; Qu, L ; Johnson, P ; Trubiano, J ; McDonald, CF ; Jones, D ; Bellomo, R ; Patel, O ; Ischia, J (BMJ PUBLISHING GROUP, 2020-01-01)
    INTRODUCTION: SARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been demonstrated to have beneficial effects on coronaviruses and other viral respiratory infections due to its effect on RNA polymerase. Additionally, zinc has well-demonstrated protective effects against hypoxic injury-a clear mechanism of end-organ injury in respiratory distress syndrome. We aimed to assess the effect of high-dose intravenous zinc (HDIVZn) on SARS-CoV-2 infection. The end of study analyses will evaluate the reduction of impact of oxygen saturations or requirement of oxygen supplementation. METHODS AND ANALYSIS: We designed a double-blind randomised controlled trial of daily HDIVZn (0.5 mg/kg) versus placebo. Primary outcome measures are lowest oxygen saturation (or greatest level of supplemental oxygenation) for non-ventilated patients and worst PaO2/FiO2 for ventilated patients. Following power calculations, 60 hospitalised patients and 100 ventilated patients will be recruited to demonstrate a 20% difference. The duration of follow-up is up to the point of discharge. ETHICS AND DISSEMINATION: Ethical approval was obtained through the independent Human Research Ethics Committee. Participant recruitment will commence in May 2020. Results will be published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: ACTRN126200000454976.
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    Experimental rat models for contrast-induced nephropathy; A comprehensive review
    Perera, M ; Ischia, J ; Bolton, D ; Shulkes, A ; Baldwin, GS ; Patel, O (Society of Diabetic Nephropathy Prevention, 2020-04-01)
    Contrast-induced nephropathy (CIN) is an iatrogenic disease caused by the parenteral administration of iodinated contrast media (CM). A number of agents are currently being assessed to minimise or prevent CIN. Such agents are typically assessed using rat models. The aim of this study was to provide a comprehensive review of the rat models of CIN used in pre-clinical research. The MEDLINE, EMBASE, Web of Science and Cochrane databases were systematically searched. Articles reporting rat models of CIN were included for assessment. Study designs, contrast agents and outcome measures were assessed. Of the assessed studies, a majority report a requirement for pre-existing renal impairment prior to the administration of CM. Outcome measures are heterogenous between studies, but typically include assessment and quantification of serum biochemical markers, cellular oxidative stress and histopathological changes. The significant variation in methodology reported in the current literature highlights the lack of consensus. The use of a reliable pre-contrast insult appears critical to result in the development of contrast nephropathy. The use of acceptable outcome measures appears to include serum laboratory markers, quantification of reactive oxygen species (ROS) and objective histopathological outcomes.