Surgery (Austin & Northern Health) - Research Publications

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    PEDAL protocol: a prospective single-arm paired comparison of multiparametric MRI and 18F-DCPFyl PSMA PET/CT to diagnose prostate cancer
    Tran, V ; Hong, A ; Sutherland, T ; Taubman, K ; Lee, S-F ; Lenaghan, D ; Sethi, K ; Corcoran, NM ; Lawrentschuk, N ; Woo, H ; Tarlinton, L ; Bolton, D ; Spelman, T ; Thomas, L ; Booth, R ; Hegarty, J ; Perry, E ; Wong, L-M (BMJ PUBLISHING GROUP, 2022-09-01)
    INTRODUCTION: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has emerged as valuable imaging to assessing metastatic disease in prostate malignancy. However, there has been limited studies exploring the utility PSMA-PET as primary imaging assessing for index lesions prior to biopsy. The primary objective of this study is to compare the diagnostic accuracy of 18-fluorine PSMA (18F DCFPyL PSMA) PET scans to multiparametric MRI (mpMRI) to detect primary prostate cancer at prostate biopsy. METHODS AND ANALYSIS: The PEDAL trial is a multicentre, prospective, single-arm, paired comparison, non-randomised phase III trial in subjects considered for diagnostic prostate biopsy. Subjects who are eligible for a diagnostic mpMRI prostate will undergo additional same-day 18 F DCFPyl PSMA PET/CT of the chest, abdomen and pelvis. Software coregistration of the mpMRI and PSMA-PET/CT images will be performed. The reporting of the mpMRI prostate, PSMA-PET/CT and PSMA PET/MRI coregistration will be performed blinded. The diagnostic accuracy of PSMA PET/CT alone, and in combination with mpMRI, to detect prostate cancer will be assessed. Histopathology at prostate biopsy will be used as the reference standard. Sample size calculations estimate that 240 subjects will need to be recruited to demonstrate 20% superiority of PSMA-PET/CT. The sensitivity, specificity, positive predictive value and negative predictive value of the combination of mpMRI prostate and PSMA PET/CT compared with targeted and systematic prostate biopsy will be evaluated. It is hypothesised that PSMA PET/CT combined with mpMRI prostate will have improved diagnostic accuracy compared with mpMRI prostate alone for detection of prostate cancer in biopsy-naïve men, resulting in a significant impact on patient management. ETHICS AND DISSEMINATION: This study was approved by the independent Human Research Ethics Committee. Results will be published in peer-reviewed medical journals with eligible investigators will significantly contribute. TRIAL REGISTRATION NUMBER: ACTRN12620000261910.
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    Contributions to expenditure in endoscopic stone management: a costly process
    Mondschein, R ; Bolton, D ; Tan, S ; Minh, HV ; McCahy, P (SPRINGER, 2022-07-08)
    No comprehensive cost estimates exist for performing ureteropyeloscopy (URS), which is increasingly utilised as a treatment of upper tract urolithiasis in Australia. To estimate expenditure associated with URS in an Australian public hospital setting and determine factors contributing to increased cost. Patients who underwent flexible URS for urolithiasis over a 2-year period at a Victorian public health site were included. Data describing demographics, stone factors, disposable equipment and admission length were retrospectively collected. Procedures were performed using reusable flexible scopes. Previously validated costing models for cystoscopic stent extraction, theatre and recovery per hour and ward admission were used to attach cost to individual episodes. The cost of emergency stent insertion was beyond the scope of this study. 222 patients underwent URS; the combined total number of procedures was 539, comprising 202 stent extractions and 115 stent insertions in addition to 222 URS. Mean procedural cost was $2885 (range $1380-$4900). Mean episode cost excluding emergency stent insertion was $3510 (range $1555-$7140). A combination of flexible scopes, operative time and disposable equipment accounted for nearly 90% of the total procedural cost. Significant cost is associated with URS for treatment of renal and ureteric stones. A large burden of the cost is time in theatre, equipment and the need for multiple associated procedures per episode. Utilising other available treatments such as extracorporeal shockwave therapy (SWL) where appropriate may reduce the financial burden of URS and associated procedures.
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    Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer
    Mondschein, R ; Bolton, D ; Clouston, D ; Dowty, J ; Kavanagh, L ; Murphy, D ; Scott, P ; Taylor, RA ; Thorne, H (MDPI, 2022-08-01)
    Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4-5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D'Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.
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    Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes
    Trigos, AS ; Pasam, A ; Banks, P ; Wallace, R ; Guo, C ; Keam, S ; Thorne, H ; Mitchell, C ; Lade, S ; Clouston, D ; Hakansson, A ; Liu, Y ; Blyth, B ; Murphy, D ; Lawrentschuk, N ; Bolton, D ; Moon, D ; Darcy, P ; Haupt, Y ; Williams, SG ; Castro, E ; Olmos, D ; Goode, D ; Neeson, P ; Sandhu, S (BMJ PUBLISHING GROUP, 2022-06-01)
    BACKGROUND: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. METHODS: We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. RESULTS: Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. CONCLUSIONS: gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
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    PSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up
    Ong, S ; Pascoe, C ; Kelly, BD ; Ballok, Z ; Webb, D ; Bolton, D ; Murphy, D ; Sengupta, S ; Bowden, P ; Lawrentschuk, N (MDPI, 2022-06-01)
    Prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) is a novel imaging modality used to stage recurrent prostate cancer. It has the potential to improve prognostication and ultimately guide the timing of treatment for men with recurrent prostate cancer. This study aims to assess the clinical impact of PSMA PET-CT by analyzing its predictive value of treatment progression after 3 years of follow-up. In this prospective cohort study of 100 men, patients received a PSMA PET-CT for restaging of their disease which was used by a multi-disciplinary team to make a treatment decision. The primary endpoint was treatment progression. This was defined as the addition or change of any treatment modalities such as androgen deprivation therapy (ADT), radiation therapy or chemotherapy. The median follow-up time was 36 months (IQR 24-40 months). No treatment progression was found in 72 (75%) men and therefore 24 (25%) patients were found to have treatment progression. In men with a negative PSMA PET-CT result, 5/33 (15.1%) had treatment progression and 28/33 (84.8%) had no treatment progression. In conclusion, clinical decisions made with PSMA PET-CT results led to 75% of men having no treatment progression at 3 years of follow-up. In men with negative PSMA PET-CT results, this increased to 85% of men.
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    Vesico-urethral anastomosis sampling: a forgotten tool for guiding salvage radiation after radical prostatectomy
    Timm, B ; Farag, M ; Liodakis, P ; Angus, D ; Joon, DL ; Bolton, D (WILEY, 2021-05-01)
    OBJECTIVE: To review the utility of vesicourethral anastomosis (VUA)-directed biopsy in the setting of biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer (PCa) in patients who have undergone evaluation by gallium-68 prostate-specific membrane antigen positron emission tomography with computed tomography (68 Ga-PSMA PET/CT). METHODS: We completed a retrospective review of a prospectively maintained dataset from January 2015 to August 2020. Patient demographics were recorded for those who experienced BCR, as defined by a rise in prostate-specific antigen (PSA) level to above 0.2 ng/mL, who had a 68 Ga-PSMA PET/CT that did not demonstrate recurrence within the prostate bed, and who subsequently underwent a transperineal ultrasonography (TPUS)-guided biopsy directed at the VUA. Histological reporting of the biopsies was undertaken in order to determine whether the benefits of salvage radiation therapy (SRT) could be justified by the presence of cancer cells. RESULTS: Eighteen patients who had a 68 Ga-PSMA PET/CT and underwent VUA-directed biopsy were identified as having BCR. 68 Ga-PSMA PET/CT scans demonstrated avidity at the VUA in none of the patients, although two out of 18 patients showed avidity in the seminal vesicles and two out of 18 patients showed avidity within regional lymph nodes. Histology from the TPUS-guided, VUA-directed biopsies demonstrated no prostatic tissue in six out of 18 and presence of prostatic tissue in 12 out of 18 of patients, respectively. In 7 out of 18 cases, there was histological evidence of recurrent PCa at the VUA in the absence of a positive 68 Ga-PSMA PET/CT scan. CONCLUSION: This study highlights the potential value of VUA-directed biopsy. We are reminded that a negative 68 Ga-PSMA PET/CT does not exclude local recurrence and that the addition of a VUA-directed biopsy may aid in the decision-making process for patients with BCR following RP, especially when 68 Ga-PSMA PET/CT is locally negative. When the result of both 68 Ga-PSMA PET/CT and VUA-directed biopsy are negative, it should encourage clinicians to share decision-making in regard to undertaking SRT vs continuing BCR surveillance. This may delay the possible side effects associated with SRT, despite its excellent PSA failure-free survival rate.
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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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    Age-Related Mental Health Consequences of COVID-19: A Global Perspective
    de la Rosette, J ; Laguna, P ; Zeng, G ; Coloby, P ; Momesso, A ; Azhar, RA ; Chłosta, P ; Heesakkers, J ; Crişan, N ; Ruiz, L ; Bolton, D ; Gómez, R ; Klotz, L ; Kulkarni, S ; Tanguay, S ; Gravas, S (Societe Internationale d'Urologie, 2021-01-18)
    Purpose: The Société Internationale d’Urologie (SIU) conducted a survey to determine whether the pandemic has harmed the mental health of practicing urologists worldwide. Methods: Members of the Executive Board of the SIU designed a self-selected survey consisting of multiple-choice questions about the safety and mental health of urologists during the COVID-19 pandemic. The survey was disseminated by email to SIU members worldwide. Results: A total of 3448 SIU members from 109 countries responded to the survey, which sought to determine the extent of mental health symptoms, including depression, anxiety, insomnia, and distress—experienced during the COVID-19 pandemic. Overall, 21% of urologists who responded reported that their mental health was very challenged, with 58% indicating increased stress levels, and 15% indicating greatly increased stress levels. Older urologists were less likely to report any of the negative mental health symptom queried (ie, delirium [rs = −0.06, P = 0.001], psychosis [rs = −0.04, P = 0.019], anxiety [rs = −0.09, P < 0.001], depression [rs = −0.08, P <.001], distress [rs = −0.07, P < 0.001]), except insomnia (P > 0.20). Furthermore, 29% of urologists indicated they were afraid to go to work, while 53% reported being afraid to go home to their families after work. Conclusion: In this worldwide survey of practicing urologists, more than half of the participants reported an increase in insomnia, distress, and other psychological symptoms as they managed patients during the COVID-19 pandemic, although half of respondents did not experience any mental health symptoms. Institutions should provide psychological coping resources to all health care staff, not only for the front-line workers during the pandemic.
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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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    Cribriform pattern disease over-represented in pelvic lymph node metastases identified on 68GA PSMA-PET/CT.
    Bolton, D ; Hong, A ; Papa, N ; Perera, M ; Kelly, B ; Duncan, C ; Clouston, D ; Lawrentschuk, N (Wiley, 2022-09)
    Objectives: To determine whether any specific histologic subtype of prostate cancer was preferentially represented in pelvic lymph node metastases identified on 68GA-PSMA-PET/CT. Subjects and Methods: A consecutive series of 66 men with biochemical recurrent prostate cancer was evaluated with 68GA-PSMA-PET/CT. Where disease was confined to pelvic lymph nodes, patients were offered salvage extended pelvic lymph node dissection. Twenty patients ultimately proceeded to extended bilateral template pelvic lymph node dissection. Lymph node positivity and the histologic subtype of apparent cancer were assessed, as was PSA response to this intervention. Results: Mean PSA at time of PSMA scanning for patients undergoing lymphadenectomy was 2.49 (n = 20, range 0.21-12.0). In 16 of 20 patients, there was evidence of metastatic cribriform pattern prostate cancer in excised nodes (100% cribriform pattern in 11/16). Only four of 20 patients had no evidence of this histologic subtype of disease. PSA response was not related to the presence or proportional amount of cribriform pattern disease identified. Conclusions: Cribriform pattern adenocarcinoma appears to be the histologic subtype preferentially identified in pelvic lymph nodes on 68GA-PSMA-PET/CT. The use of PSMA-PET may be particularly valuable in staging of primary or biochemically recurrent prostate cancer in patients with cribriform pattern disease detected on initial biopsy or radical prostatectomy. Further research is required to further confirm the observed association.